Jeroen P. Kooman

Impaired Renal Clearance Explains Elevated Troponin T Fragments in Hemodialysis Patients

Background—Patients with severe renal dysfunction often have unexplained elevated serum concentrations of cardiac troponin T (cTnT). We investigated whether in vivo fragmentation of cTnT could explain these increases. Methods and Results—cTnT, creatine kinase isoenzyme MB, and myoglobin serum concentrations were measured in all 63 dialysis patients of our in-hospital dialysis department. A highly sensitive immunoprecipitation assay, followed by electrophoresis and Western blotting, was used to extract and concentrate cTnT and its possible fragments from serum of these 63 hemodialysis patients. Although creatine kinase isoenzyme MB values excluded recent ischemic myocardial events in 55 of the 63 cases, cTnT fragments ranging in size from 8 to 25 kDa were present in the serum samples of all dialysis patients. Conclusions—cTnT is fragmented into molecules small enough to be cleared by the kidneys of healthy subjects. Impaired renal function causes accumulation of these cTnT fragments and is very likely the cause of the unexplained elevations of serum cTnT found in patients with severe renal failure.

Estimated Glomerular Filtration Rate and Urinary Albumin Excretion Are Independently Associated with Greater Arterial Stiffness: The Hoorn Study

Mild renal insufficiency is a risk factor for cardiovascular disease (CVD). Both a decline in GFR and (micro)albuminuria are associated with greater cardiovascular mortality. In ESRD, arterial stiffness, an important cause of CVD, is known to be greater, but few data exist in individuals with mild renal insufficiency or microalbuminuria. This study investigated the association of impaired renal function expressed as lower GFR or greater urinary albumin excretion with arterial stiffness. In a population-based study in 806 individuals (402 men), mean age 68 yr (range 50 to 87), peripheral arterial stiffness (by compliance and distensibility of the carotid, brachial, and femoral arteries and by the carotid elastic modulus [E(inc)]) and central arterial stiffness (by total systemic arterial compliance, carotid-femoral transit time, and aortic augmentation index) were measured ultrasonically. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. Urinary albumin excretion was expressed as urinary albumin/creatinine ratio (UACR). eGFR was 60.6 +/- 11.1 ml/min per 1.73 m(2). Median UACR was 0.57 mg/mmol (range 0.1 to 26.6). After adjustment for age, mean arterial pressure (MAP), gender, and glucose tolerance status (GTS), each 5-ml/min per 1.73 m(2) lower eGFR was associated with a lower distensibility coefficient of the carotid (regression coefficient beta -0.20 10(-3)/kPa; 95% confidence interval [CI] -0.34 to -0.07 10(-3)/kPa) and brachial artery (-0.15 10(-3)/kPa; 95% CI -0.28 to -0.03 10(-3)/kPa) and a greater carotid E(inc) (0.02 kPa; 95% CI 0.0004 to 0.04 kPa). No statistically significant association was found of eGFR with other arterial stiffness indices. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was associated with a greater E(inc) (0.03 kPa; 95% CI 0.001 to 0.07 kPa) and a trend to a lower distensibility coefficient (-0.24 10(-3)/kPa; 95% CI -0.49 to 0.02 10(-3)/kPa) of the carotid artery. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was in addition associated with a shorter carotid-femoral transit time (-1.67 ms; 95% CI -3.24 to -0.10 ms). These associations were not substantially changed by mutual adjustment for eGFR and UACR. In individuals with mild renal insufficiency, both a lower eGFR and a greater albumin excretion, even below levels that are considered to reflect microalbuminuria, are independently associated with greater arterial stiffness. Moreover, these associations were mutually independent. These findings may explain, in part, why eGFR and microalbuminuria are associated with greater risk for CVD and suggest that amelioration of arterial stiffness could be a target of intervention.

Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients

BACKGROUND Previous studies have shown that simple imaging methods may be useful for detection of vascular calcifications in dialysis patients. Based on annual, plain chest X-rays during follow-up on dialysis, we studied the associations of mineral metabolism with the presence and progression of aortic calcification. In addition, we assessed the impact of aortic calcification on mortality. METHODS Three hundred and eighty-four patients who started haemodialysis or peritoneal dialysis between 1997 and 2007 were included (age 61 ± 15 years, 64% male, 61% haemodialysis). Annual chest X-rays were screened for calcification in the aortic arch, and patients were categorized as having no, moderate or severe calcification. Progression was defined as an increase in calcification category during follow-up on dialysis. RESULTS At baseline, 96 (25%) patients had severe, 205 (53%) patients had moderate and 83 (22%) patients had no aortic calcification. For 237 of the 288 patients with no or moderate calcifications at baseline, X-rays were available for follow-up. During follow-up (mean 2.3 years), aortic calcification progressed in 71 patients (30%). We found that baseline plasma calcium > 9.5 mg/dL and iPTH > 300 pg/mL were associated with progression [odds ratios of 3.1, 95% confidence interval (1.2-8.2) and 4.4 (1.4-14.1), respectively]. Progression of aortic calcification was significantly associated with increased risk of all-cause mortality (hazard ratio: 1.9; 95% CI: 1.2-3.1) and cardiovascular mortality (hazard ratio: 2.7; 95% CI: 1.3-5.6). CONCLUSIONS Aortic calcification progressed in almost a third of the patients during dialysis. Hypercalcaemia and hyperparathyroidism were associated with an increased risk of progression. Progression of aortic calcification was significantly related to an increased mortality risk.

Reimbursement of Dialysis: A Comparison of Seven Countries

Reimbursement for chronic dialysis consumes a substantial portion of healthcare costs for a relatively small proportion of the total population. Each country has a unique reimbursement system that attempts to control rising costs. Thus, comparing the reimbursement systems between countries might be helpful to find solutions to minimize costs to society without jeopardizing quality of treatment and outcomes. We conducted a survey of seven countries to compare crude reimbursement for various dialysis modalities and evaluated additional factors, such as inclusion of drugs or physician payments in the reimbursement package, adjustment in rates for specific patient subgroups, and pay for performance therapeutic thresholds. The comparison examines the United States, the province of Ontario in Canada, and five European countries (Belgium, France, Germany, The Netherlands, and the United Kingdom). Important differences between countries exist, resulting in as much as a 3.3-fold difference between highest and lowest reimbursement rates for chronic hemodialysis. Differences persist even when our data were adjusted for per capita gross domestic product. Reimbursement for peritoneal dialysis is lower in most countries except Germany and the United States. The United Kingdom is the only country that has implemented an incentive if patients use an arteriovenous fistula. Although home hemodialysis (prolonged or daily dialysis) allows greater flexibility and better patient outcomes, reimbursement is only incentivized in The Netherlands. Unfortunately, it is not yet clear that such differences save money or improve quality of care. Future research should focus on directly testing both outcomes.

Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study

BACKGROUND Inflammation, overhydration and elevated cardiac biomarkers are related to outcome in haemodialysis (HD) patients. Here, we explored the relationship between the body composition (BC), inflammation and cardiac biomarker concentrations in HD patients longitudinally. METHODS A total of 44 HD patients were followed for 6 months. BC was assessed by multifrequency bioimpedance (BIA). Serum concentrations of cardiac troponin T (cTnT), high-sensitive C-reactive protein (hsCRP), brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) were assessed at 2 monthly intervals. The longitudinal data analysis was conducted with a marginal model. RESULTS During the follow-up, the parameters describing the BC were highly predictive of both BNP and NT-proBNP and independent of gender, time, hsCRP and cTnT concentrations. The intracellular water (ICW)/body weight (BW) ratio (reflecting malnutrition) exerted a negative effect, whereas the extracellular water (ECW)/BW ratio (reflecting overhydration) had a positive effect on BNP and NT-proBNP concentrations. HsCRP and cTnT concentrations were significantly associated with each other. Furthermore, NT-proBNP concentrations were predictive of cTnT and hsCRP concentrations. CONCLUSIONS In the present study, we find a significant relation between BIA-derived BC parameters and natriuretic peptide concentrations. This relationship was independent of the cardiac history of the patient and suggests that the natriuretic peptide levels are to some degree modifiable by changing a patients fluid distribution. Moreover, cTnT, BNP, NT-proBNP and hsCRP were significantly related, showing a complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in dialysis patients.

Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays

Background Elevated cardiac troponin (cTn) concentrations predict an increased mortality in patients suffering from end-stage renal disease (ESRD). This study compares the performance of a precommercial high-sensitive cTnT assay (hs-cTnT) with two contemporary cTn assays in detecting cTn elevations in ESRD patients during a six-month follow-up. Methods Thirty-two ESRD patients were followed for six months, during which cTn concentrations were assessed every two months. Baseline biomarker concentrations were compared with those in a simultaneously measured reference population of 501 healthy subjects. Results During follow-up 26 (81%), 32 (100%) and 9 (28%) of the patients showed elevated cTn concentrations according to the current cTnT, the hs-cTnT and the cTnI assays, respectively. The range of concentrations measured in each patient had a median (interquartile range) magnitude of 0.03 μg/L (0.02–0.06), 0.017 μg/L (0.011–0.029) and 0.011 μg/L (0–0.017) according to the aforementioned assays. Conclusion According to the hs-cTnT assay, all of the ESRD patients had elevated cTnT concentrations at least once during the follow-up. As elevated cTn concentrations are highly prognostic of adverse events, the use of serial measurements has thus identified additional patients at risk for such events. The fact that we find cTn concentrations to be higher in patients with a history of cardiac disease is in line with this. Additional studies in ESRD patients are needed to investigate the added diagnostic and prognostic value of the very low cTnT concentrations and variations detected only by the hs-cTnT assay.

Similarities in skeletal muscle strength and exercise capacity between renal transplant and hemodialysis patients

Exercise intolerance is common in hemodialysis (HD) and renal transplant (RTx) patients. Aim of the study was to assess to what extent exercise capacity and skeletal muscle strength of RTx patients differ from HD patients and healthy controls and to elucidate potential determinants of exercise capacity in RTx patients. Exercise capacity, muscle strength, lean body mass (LBM) and physical activity level (PAL) were measured by cycle‐ergometry, isokinetic dynamometry, DEXA and Baecke Questionnaire, respectively, in 35 RTx, 16 HD and 21 controls. VO2peak and muscle strength of the RTx patients were significantly lower compared to controls (p < 0.01), but not different compared to HD patients. In RTx patients, strength (p < 0.001), PAL (p = 0.001) and age (p = 0.045) were significant predictors of VO2peak. Muscle strength was related to LBM (p = 0.001) and age (p = 0.001), whereas gender (p < 0.001) and renal function (p = 0.01) turned out to be significant predictors of LBM. No effects of corticosteroids were observed. Exercise capacity and muscle strength seem equally reduced in RTx and HD patients compared to controls. In RTx patients, muscle strength and PAL are highly related to exercise capacity. Renal function appears to be a significant predictor of LBM, and through the LBM, of muscle strength and exercise capacity.

Haemodialysis catheters increase mortality as compared to arteriovenous accesses especially in elderly patients

BACKGROUND Catheter use has been associated with an increased mortality risk in haemodialysis patients. However, differences in the all-cause and cause-specific mortality risk between catheter use and arteriovenous access use in young and elderly haemodialysis patients have not yet been investigated. METHODS In this prospective cohort study of 1109 incident haemodialysis patients from 38 centres in the Netherlands, hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated for 2-year all-cause, infection-related and cardiovascular mortality in patients with a catheter as compared to patients with an arteriovenous access stratified for age (< 65 years and ≥ 65 years). RESULTS Of the 1109 patients, 919 had an arteriovenous access and 190 had a catheter. The mortality rate was 76 per 1000 person-years in young patients with an arteriovenous access, 129 per 1000 person-years in young patients with a catheter, 222 per 1000 person-years in elderly patients with an arteriovenous access and 427 per 1000 person-years in elderly patients with a catheter. The adjusted HR was 3.15 (95% CI: 2.09-4.75) for elderly patients with a catheter as compared to young patients with an arteriovenous access. The adjusted HRs in elderly patients with a catheter as compared to elderly patients with an arteriovenous access were 1.54 (95% CI: 1.13-2.12) for all-cause mortality, 1.60 (95%: CI 0.62-4.19) for infection-related mortality and 1.67 (95% CI: 1.04-2.68) for cardiovascular mortality. CONCLUSIONS Especially, elderly haemodialysis patients with a catheter have an increased all-cause, infection-related and cardiovascular mortality risk as compared to patients with an arteriovenous access.

Acute Hemodynamic Response and Uremic Toxin Removal in Conventional and Extended Hemodialysis and Hemodiafiltration: A Randomized Crossover Study

BACKGROUND Intensive hemodialysis (HD) may have significant benefits. Recently, the role of extended hemodiafiltration (HDF) has gained interest. The aim of this study was to evaluate the acute effects of extended HD and HDF on hemodynamic response and solute removal. STUDY DESIGN Randomized crossover trial. SETTINGS & PARTICIPANTS Stable patients with end-stage renal disease undergoing conventional HD. INTERVENTION 13 patients randomly completed a single study of 4-hour HD (HD4), 4-hour HDF (HDF4), 8-hour HD (HD8), and 8-hour HDF (HDF8), with a 2-week interval between study sessions. Between study sessions, patients received routine conventional HD treatments. OUTCOMES Acute hemodynamic effects and uremic toxin clearance. MEASUREMENTS Blood pressure and heart rate, pulse wave analysis, cardiac output, and microvascular density by sublingual capillaroscopy, as well as relative blood volume and thermal variables, were measured. Clearance and removal of uremic toxins also were studied. RESULTS Long treatments showed more stability of peripheral systolic blood pressure (change during HD4, -21.7±15.6 mm Hg; during HDF4, -23.3±20.8 mm Hg; during HD8, -6.7±15.2 mm Hg [P=0.04 vs. HD4; P=0.08 vs. HDF4]; and during HDF8, -0.5±14.4 mm Hg [P=0.004 vs. HD4; P=0.008 vs. HDF4]). A similar observation was found for peripheral diastolic and central blood pressures. Cardiac output remained more stable in extended sessions (change during HD4, -1.4±1.5 L/min; during HDF4, -1.6±1.0 L/min; during HD8, -0.4±0.9 L/min [P=0.02 vs. HDF4]; and during HDF8, -0.5±0.8 L/min [P=0.06 vs. HD4; P=0.03 vs. HDF4), in line with the decreased relative blood volume slope in long dialysis. No differences in microvascular density were found. Energy transfer rates were comparable (HD4, 13.3±4.7 W; HDF4, 16.2±5.6 W; HD8, 14.2±6.0 W; and HDF8, 14.5±4.3 W). Small-molecule and phosphate removal were superior during long treatments. β2-Microglobulin and fibroblast growth factor 23 (FGF-23) reduction ratios were highest in HDF8. LIMITATIONS Small sample size, only acute effects were studied. CONCLUSIONS Treatment time, and not modality, was the determinant for the hemodynamic response. HDF significantly improved removal of middle molecules, with superior results in extended HDF.

The influence of early steroid withdrawal on body composition and bone mineral density in renal transplantation patients

Abstract.Corticosteroid treatment may have an important effect on body composition and bone mineral density (BMD) in renal transplantation (RTx) patients. We investigated the effect of early steroid withdrawal on body composition and BMD of RTx patients in a prospective design. Post-transplant immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Three months after RTx, 27 patients participating in a multi-center trial were randomized either to continue steroids (at a dose of 10 mg/day, n=17; steroid+) or be withdrawn from steroids within 2 weeks (n=10; steroid–). Body composition and BMD (lumbar spine (L2–L4) and femoral neck) were measured by dual-energy X-ray absorptiometry (DEXA) just before and 3 months after randomization. With regard to body composition, fat mass tended to increase in the steroid+ group (1.1±2.3 kg; P=0.084), but did not change in the steroid– group. Increase in body fat percentage tended to be higher (P=0.08) in the steroid+ group (0.6±2.7%) than in the steroid– group (–0.7±2.1%). The change in lean body mass was not significantly different between the two groups. BMD of the lumbar spine and femoral neck decreased significantly in the steroid+ group (–1.4±3.2% and –2.3±2.9%, respectively, P<0.05) while no changes were observed in the steroid– group. The change in BMD of the lumbar spine was significantly different between the steroid+ and the steroid– group, whereas the change in BMD of the femoral neck was not significantly different. Thus, the increase in fat mass tended to be higher in the group continuing on steroids, though not significant, due to large inter-individual variation. In general, the effect of early steroid withdrawal on body composition after RTx appears to be modest. In addition, early steroid withdrawal seems to have beneficial effects on BMD in RTx patients, especially in the lumbar region.