Francis Verbeke

Noninvasive Assessment of Local Pulse Pressure: Importance of Brachial-to-Radial Pressure Amplification

The advocated SphygmoCor procedure uses a radial-to-aorta transfer function with calibration on brachial instead of radial artery pressure to assess the central pulse pressure. We compared these values with carotid artery pulse pressures obtained from a validated calibration method, assuming mean minus diastolic blood pressure constant throughout the large artery tree. From 44 healthy subjects (21 males; 22 to 68 years) pressure waves were obtained at the radial, brachial, and carotid artery with applanation tonometry. Using the calibration method, radial and carotid artery pressures were assessed from brachial artery waves and pressures. The effect of brachial-to-radial pulse pressure amplification, brachial pulse pressure, mean pressure, age, gender, height, body mass index, and smoking on differences between the 2 methods was assessed. Brachial artery pressure was 118±12/72±10 mm Hg. SphygmoCor central pulse pressure was 9.7±4.6 mm Hg lower (P<0.001) than the carotid artery pulse pressure (33.0±6.8 versus 42.7±8.9 mm Hg). The difference between the 2 methods strongly depended (P<0.001) on brachial-to-radial artery pulse pressure amplification (5.8±5.1 mm Hg; 12±11%) and less on brachial artery pulse pressure (P=0.005). After calibration of the radial pressure wave with radial instead of brachial artery pressures, the difference between SphygmoCor central pulse pressure and carotid pulse pressure decreased with 4 mm Hg. The advocated SphygmoCor procedure systematically underestimates the central pulse pressure with brachial-to-radial pulse pressure amplification as important determinant. Therefore, calibration of radial artery pressure waves on brachial artery pressures should be avoided. The underestimation of central aortic pulse pressure caused by the radial-to-aorta transfer function itself is much less than previously reported.

Prognostic value of aortic stiffness and calcification for cardiovascular events and mortality in dialysis patients: outcome of the calcification outcome in renal disease (CORD) study

BACKGROUND AND OBJECTIVES Radiographic calcification and arterial stiffness each individually are predictive of outcome in dialysis patients. However, it is unknown whether combined assessment of these intermediate endpoints also provides additional predictive value. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Scoring of abdominal aortic calcification (AAC) using plain lateral abdominal x-ray and measurement of carotid-femoral pulse wave velocity (PWV) were performed in a cohort of 1084 prevalent dialysis patients recruited from 47 European dialysis centers. RESULTS During a follow-up of 2 years, 234 deaths and 91 nonfatal cardiovascular (CV) events occurred. Compared with the lowest tertile of AAC, the risk of an event was increased by a factor 3.7 in patients with a score of 5 to 15 (middle tertile), and by a factor 8.6 in patients with scores of 16 to 24. Additionally, each 1-m/s increase in PWV was associated with a 15% higher risk. At higher AAC (scores ≥ 5), the effect of PWV was attenuated because of a negative PWV × AAC interaction (hazard ratio [HR]: 0.895 and 0.865 for middle and upper AAC tertiles). After accounting for age, diabetes, and serum albumin, AAC and PWV remained independent predictors of outcome. CONCLUSIONS AAC and central arterial stiffness are independent predictors of mortality and nonfatal CV events in dialysis patients. The risk associated with an increased PWV is less pronounced at higher levels of calcification. Assessment of AAC and PWV is feasible in a clinical setting and both may be used for an accurate CV risk estimation in this heterogeneous population.

Abdominal aortic calcification in dialysis patients: results of the CORD study

Background. Patients with chronic kidney disease stage 5 have a high prevalence of vascular calcification, but the specific anatomical distribution and severity of abdominal aortic calcification (AAC), in contrast to coronary calcification, is less well documented. AAC may be recorded using plain radiographs. The present report is an analysis of baseline data on AAC in patients enrolled in the CORD (Calcification Outcome in Renal Disease) study. Methods. A total of 47 centres in six European countries participated in this cross-sectional study. Inclusion criteria were age ≥18 years and duration of dialysis ≥3 months. Lateral lumbar radiography of the abdominal aorta was used to determine the overall AAC score, which is related to the severity of calcific deposits at lumbar vertebral segments L1–L4. The reliability of the method was tested by double reading of 64 radiographs (coefficient of correlation 0.9). Results. A lateral lumbar radiograph was obtained in 933 patients. Calcification (AAC score ≥ 1) was present in 81% of the patients; its severity increased significantly from L1 to L4 (P < 0.0001) and affected all of these segments in 51% of patients. Independent predictors for the presence and severity of calcification were age (odds ratio [OR] 1.103/year; P < 0.0001), duration of dialysis (OR 1.110/year; P = 0.002) and history of cardiovascular disease (OR 3.247; P < 0.0001). Conclusions. AAC detected by lateral lumbar radiograph is associated with several risk factors of uraemic calcification. This semi-quantitative method is more widely available and less expensive than the current procedures for studying calcification and could form part of a pre-transplant workup and cardiovascular risk stratification.

Aortic Stiffness and Central Wave Reflections Predict Outcome in Renal Transplant Recipients

Although renal transplantation improves survival, cardiovascular morbidity and mortality remain significantly elevated compared with nonrenal populations. The negative impact of traditional, uremia-related, and transplantation-related risk factors in this process remains, however, largely unexplored. Surrogate markers such as aortic stiffness and central wave reflections may lead to more accurate cardiovascular risk stratification, but outcome data in renal transplant recipients are scarce. We aimed to establish the prognostic significance of these markers for fatal and nonfatal cardiovascular events in renal transplant recipients. Carotid-femoral pulse wave velocity, central augmentation pressure, and central augmentation index were measured in a cohort of 512 renal transplant recipients using the SphygmoCor system. After a mean follow-up of 5 years, 20 fatal and 75 nonfatal cardiovascular events were recorded. Using receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.718 (95% CI 0.659–0.776) for pulse wave velocity, 0.670 (95% CI 0.604–0.736) for central augmentation pressure, and 0.595 (95% CI 0.529–0.660) for central augmentation index. When we accounted for age, gender, and C-reactive protein in Cox-regression analysis, pulse wave velocity (hazard ratio: 1.349 per 1 SD increase; 95% CI 1.104–1.649; P=0.003) and central augmentation pressure (hazard ratio: 1.487 per 1 SD increase; 95% CI 1.219–1.814; P<0.001) remained independent predictors of outcome. Aortic stiffness and increased wave reflections are independent predictors of cardiovascular events in renal transplant recipients. As single parameter of wave reflection, central augmentation pressure was better than central augmentation index. Combined measurement of pulse wave velocity and central augmentation pressure may contribute to an accurate cardiovascular risk estimation in this heterogeneous population.

Posttransplantation Hypomagnesemia and Its Relation with Immunosuppression as Predictors of New-Onset Diabetes after Transplantation

New‐onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients.

Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins.

BACKGROUND AND OBJECTIVES The degree of chronic kidney disease (CKD) is currently expressed in terms of GFR, which can be determined directly or estimated according to different formulas on the basis of serum creatinine and/or cystatin C measurements (estimated GFR [eGFR]). The purpose of this study was to investigate whether eGFR values are representative for uremic toxin concentrations in patients with different degrees of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Associations between eGFR based on serum cystatin C and different uremic solutes (mol wt range 113 to 240 D; determined by colorimetry, HPLC, or ELISA) were evaluated in 95 CKD patients not on dialysis (CKD stage 2 to 5). The same analysis was also applied for six other eGFR formulas. RESULTS There was a substantial disparity in fits among solutes. In linear regression, explained variance of eGFR was extremely low for most solutes, with eGFR > 0.4 only for creatinine. The other eGFR formulations gave comparably disappointing results with regard to their association to uremic solutes. Relative similarity in R(2) values per solute for the different eGFR values and the strong disparity in values between solutes suggest that the differences in R(2) are mainly due to discrepancies in solute handling apart from GFR. CONCLUSIONS eGFR is poorly associated with concentrations of all studied uremic toxins in patients with different degrees of CKD, correlates differently with each individual solute, and can thus not be considered representative for evaluating the accumulation of solutes in the course of CKD.

Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans

Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53R-homozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium-high potassium diet to stimulate TK synthesis and a high sodium-low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50-60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people.

Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease.

BACKGROUND Hypomagnesemia predicts cardiovascular morbidity and mortality in the general population and accelerated loss of kidney function in renal transplant recipients and diabetics. It is associated with risk factors for cardiovascular and renal injury such as hyperaldosteronism, endothelial dysfunction, oxidative stress, insulin resistance, and hypertension. We aimed to establish the prognostic significance of hypomagnesemia for all-cause mortality and decline in estimated glomerular filtration rate (eGFR) in chronic kidney disease. METHODS Baseline parameters and serial follow-up measurements of serum creatinine were obtained in 1650 patients with chronic kidney disease and follow-up in a tertiary hospital between January 2002 and June 2011. We used Cox proportional hazards regression to assess the predictive value of magnesium for all-cause mortality and a random-effects mixed linear model for longitudinal analysis of the effect of serum magnesium on eGFR decline. RESULTS After a median follow-up of 5.1 years, 284 deaths occurred. Higher magnesium was associated with reduced mortality (adjusted hazard ratio 0.930 per 0.1 mg/dL increase; 95% confidence interval [CI], 0.887-0.974; P = .002) after adjustment for potential confounders including age, sex, diabetes, kidney function, and hypertension. Patients with low (<1.8 mg/dL) versus high (>2.2 mg/dL) serum magnesium had a 61% increased mortality risk (adjusted hazard ratio 1.613; 95% CI, 1.113-2.338; P = .012). On average, eGFR changed by 0.934 per year (95% CI, 0.927-0.941; P <.0001) or an annual decrease of 6.6%. After adjustment for age, sex, diabetes, and hypertension, this change was modified by a factor of 1.033 (95% CI, 1.003-1.065; P = .032) per 1-mg/dL increase in baseline magnesium, corresponding to an annual eGFR decrease of 3.5%. The effect of magnesium lost significance after adjustment for additional covariates, including diuretics. CONCLUSION Hypomagnesemia predicts mortality and kidney function decline in chronic kidney disease patients. Confounding factors and treatment effects may affect these associations. Its potential as a modifiable risk factor remains to be established.

Noninvasive assessment of central and peripheral arterial pressure (waveforms): implications of calibration methods

Objectives Noninvasive estimation of central blood pressure (BP) from radial artery pressure waveforms is increasingly applied. We investigated the impact of radial artery waveform calibration on central BP assessment and calculated pressure amplification, with focus on the one-third rule used to estimate mean arterial BP (MAP). Methods Pressure waveforms were noninvasively measured at the radial and carotid arteries in 1873 individuals (age 45.8±6.1 years). Radial and carotid artery waveforms were calibrated using brachial artery DBP and SBP, MAP estimated with the one-third rule and MAP estimated as brachial DBP along with 40% of brachial artery pulse pressure. Results Central SBP obtained via a transfer function was 123.5 ± 15.7, 117.8 ± 14.2 and 126.0 ± 15.4 mmHg (mean ± SD) following above-mentioned three calibration schemes, respectively. Using the same calibration schemes, carotid artery SBP was 131.4 ± 15.2, 118.4 ± 14.4 and 126.8 ± 15.7 mmHg, respectively. Central-to-brachial amplification was 13.0 ± 3.6 mmHg using second method as compared with 4.6 ± 3.8 mmHg with third method. Brachial-to-radial amplification was actually negative (−6.3 ± 4.5 mmHg) using second method, whereas 3.4 ± 5.5 mmHg was found with third method. Conclusion Both carotid artery SBP and central SBP obtained via a transfer function are highly sensitive to the calibration of the respective carotid artery and radial artery pressure waveforms. Our data suggest that the one-third rule to calculate MAP from brachial cuff BP should be avoided, especially when used to calibrate radial artery pressure waveforms for subsequent application of a pressure transfer function. Until more precise estimation methods become available, it is advisable to use 40% of brachial pulse pressure instead of 33% to assess MAP.

Local Shear Stress and Brachial Artery Functions in End-Stage Renal Disease

Physiologic laminar shear stress (SS) is crucial for normal vascular structure and function. As a result of anemia-related lower whole-blood viscosity (WBV), SS could be reduced in patients with ESRD and might be associated with arterial functional alterations. In 44 patients with ESRD and 25 control subjects, brachial artery (BA) compliance and BA diameter changes (flow-mediated dilation [FMD[) were evaluated in response to local shear rate and SS changes during hand warming-induced hyperemia. Patients with ESRD and control subjects had similar BA blood flow, but SS was lower in patients with ESRD (P < 0.001), with lower shear rate (P < 0.01) and lower WBV (P < 0.0001). In control subjects, SS was positively (and physiologically) correlated with arterial diameter (P < 0.001). In contrast, in patients with ESRD, larger arterial diameter was associated with low SS (P < 0.05) and increased arterial wall elastic modulus (P < 0.001). Anemia-associated low WBV aggravates low shear rate, further contributing to SS reduction. These abnormalities were associated with decreased vasodilating response to endothelial mechanical stimulation. Compared with control subjects, BA compliance and FMD increases in response to hand warming-induced increased SS were lower in ESRD patients (P < 0.01), whereas their BA diameter response to glyceryl trinitrate did not differ. The long-term WBV and SS increases after anemia correction improved FMD (P < 0.01) and BA compliance (P < 0.05) and heightened arterial wall sensitivity to mechanical stimulation. Maintenance low SS as a result of anemia could play an indirect role in arterial dysfunction in patients with ESRD.