Rationale and study design of the prospective, longitudinal, observational cohort study "rISk strAtification in end-stage renal disease" (ISAR) study.

BACKGROUND: The ISAR study is a prospective, longitudinal, observational cohort study to improve the cardiovascular risk stratification in endstage renal disease (ESRD). The major goal is to characterize the cardiovascular phenotype of the study subjects, namely alterations in micro- and macrocirculation and to determine autonomic function. METHODS/DESIGN: We intend to recruit 500 prevalent dialysis patients in 17 centers in Munich and the surrounding area. Baseline examinations include: (1) biochemistry, (2) 24-h Holter Electrocardiography (ECG) recordings, (3) 24-h ambulatory blood pressure measurement (ABPM), (4) 24 h pulse wave analysis (PWA) and pulse wave velocity (PWV), (5) retinal vessel analysis (RVA) and (6) neurocognitive testing. After 24 months biochemistry and determination of single PWA, single PWV and neurocognitive testing are repeated. Patients will be followed up to 6 years for (1) hospitalizations, (2) cardiovascular and (3) non-cardiovascular events and (4) cardiovascular and (5) all-cause mortality. DISCUSSION/CONCLUSION: We aim to create a complex dataset to answer questions about the insufficiently understood pathophysiology leading to excessively high cardiovascular and non-cardiovascular mortality in dialysis patients. Finally we hope to improve cardiovascular risk stratification in comparison to the use of classical and non-classical (dialysis-associated) risk factors and other models of risk stratification in ESRD patients by building a multivariable Cox-Regression model using a combination of the parameters measured in the study. CLINICAL TRIALS IDENTIFIER: ClinicalTrials.gov NCT01152892 (June 28, 2010).

Plasma total C-terminal agrin fragment (tCAF) as a marker for kidney function in patients with chronic kidney disease.

BACKGROUND: Total C-terminal agrin fragment (tCAF) is a new biomarker that was previously correlated with kidney function. This article studies the validity of tCAF as a biomarker for kidney function in chronic kidney disease (CKD). METHODS: Plasma tCAF, serum creatinine (Cr), cystatin C (CyC), blood urea-nitrogen (BUN) concentrations and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals [71 without CKD (CKD 0°) and 355 CKD patients]. In addition to descriptive statistics, univariate correlation between tCAF and biomarkers/eGFR was calculated; multiple linear regression modeling was applied between logarithmic (log) tCAF and log eGFR and adjusted for demographic data. The same methods were used to analyze the association of demographic factors and the different biomarkers adjusted for eGFR. RESULTS: Mean tCAF levels were 1012.2±789.9 pM. tCAF correlated with all biomarkers/eGFR in univariate analysis (eGFR: r=-0.77, Cr: r=0.74, BUN: r=0.66, CyC: r=0.75). Linear regression modeling revealed an excellent coefficient estimate between log tCAF and log eGFR (CKD-EPIcrea-cystatin) (-0.91, p<0.001). tCAF was the parameter least associated with demographic parameters in both univariate and multivariate regression modeling (only with age, coefficient estimate r=-0.159, p=0.001 in multivariate regression). CONCLUSIONS: In conclusion, tCAF is a promising biomarker for the assessment of kidney function in CKD patients showing an excellent correlation with eGFR and being less influenced by demographic parameters compared to conventional biomarkers. These preliminary results encourage further evaluation of tCAF in larger CKD cohorts and other clinical settings such as acute renal failure.

Reduction of Amyloid-ß Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy?

BACKGROUND: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-ß (Aß). OBJECTIVE: To measure plasma levels of Aß42 and Aß40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients. METHODS: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aß42 and Aß40 levels were measured by a high-sensitivity ELISA for human amyloid-ß. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously. RESULTS: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aß42 and Aß40, respectively. Aß42 but not Aß40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001). CONCLUSION: In cognitively impaired hemodialysis patients plasma Aß42 levels were associated with cognitive performance and both Aß42 and Aß40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aß sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

Early postoperative C-terminal agrin fragment (CAF) serum levels predict graft loss and proteinuria in renal transplant recipients.

BACKGROUND: C-terminal agrin fragment (CAF), cleavage product of agrin, was previously correlated with kidney function in renal transplant patients. This article studies the predictive value of CAF for long-term outcomes in renal transplant recipients. METHODS: In this observational cohort study, serum CAF, creatinine and blood-urea-nitrogen (BUN) concentrations and eGFR (CKD-EPI) were assessed 1-3 months after transplantation in 105 patients undergoing kidney transplantation. Cox regression models were used to analyse the predictive value of all parameters concerning all-cause mortality (ACM), graft loss (GL), doubling of creatinine/proteinuria at the end of follow-up. RESULTS: Median follow-up time was 3.1 years. The mean concentrations were 191.9±152.4 pM for CAF, 176±96.8 µmol/L for creatinine, 12.6±6.2 mmol/L for BUN and 44.9±21.2 mL/min for CKD-EPI formula, respectively. In univariate analysis CAF and BUN concentrations predicted ACM (CAF: HR=1.003, 1.1-fold risk, p=0.043; BUN: HR=1.037, 1.3-fold risk, p=0.006). Concerning GL, CAF (HR=1.006, 3.1-fold risk, p<0.001), creatinine (HR=2.396, 2.6-fold risk, p<0.001), BUN (HR=1.048, 1.7-fold risk, p=0.001) and eGFR (CKD-EPI) (HR=0.941, 0.45-fold risk reduction, p=0.006) showed a statistically significant association. CAF was the only parameter significantly associated with doubling of proteinuria (HR=1.005, 1.7-fold risk, p<0.001). In multiple regression analysis (CAF only) the association remained significant for GL and doubling of proteinuria but not ACM. CONCLUSIONS: Early postoperative serum CAF appears to be a useful tool for the assessment of long-term outcomes in renal transplant recipients. Most importantly it represents a promising predictor for the development of proteinuria.

Variability of cognitive performance during hemodialysis: standardization of cognitive assessment.

BACKGROUND/AIMS: Up to 70% of hemodialysis patients over the age of 54 have relevant cognitive impairment. No standardized protocol for the evaluation and monitoring of this population is available today. We hypothesized that the dialysis procedure and the testing environment induce fluctuations of cognitive performance. METHODS: 26 hemodialysis patients were randomly tested using the Montreal Cognitive Assessment (MoCA) before, during and after hemodialysis and inside the dialysis room or alone in a separate room. Tests were performed at weekly intervals using five test variations to prevent learning effects. The Mini-Mental State Examination (MMSE) was performed as a reference test. RESULTS: MoCA scores significantly differed between the conditions: 'before hemodialysis' revealed the best MoCA score as compared to 'during hemodialysis' or 'after hemodialysis' (p = 0.013). During the combined condition 'before dialysis AND separate room', best performance was achieved (p < 0.001). The BP decline had no significant influence on cognitive performance, whereas the fluid shift showed a significant impact (p = 0.008). CONCLUSION: Cognitive performance in hemodialysis patients highly depends on the time point and testing environment. Therefore, we strongly suggest a standardization, using the MoCA before hemodialysis in a separate room, in order to make testing results of future research in this field comparable.

Progression of aortic pulse wave velocity in patients with chronic kidney disease.

Aortic pulse wave velocity (aPWV) is elevated in patients with chronic kidney disease (CKD) and predicts cardiovascular risk. However, the natural progression of arterial stiffness in these patients remains uncertain. Therefore, the main aim of this study was to investigate the development of aPWV and to identify potential factors associated with its progression. aPWV measurement was carried out in 70 CKD patients at baseline and after 12 months. Correlations to several variables, in particular annual glomerular filtration rate reduction and diabetes mellitus, were studied. In the cohort, aPWV significantly increased in 1 year by 1.1 m/s (P<.01). Dividing the group into patients with stable and progressive aPWV, factors associated with accelerated progression were age, systolic blood pressure, and diabetes, whereas loss of renal function had no significant impact. The annual aPWV progression in CKD patients reached 1 m/s, which predicts an increased cardiovascular risk. Variables involved with progressive arterial stiffness need further evaluation.

Progression of cerebral amyloid load is associated with the apolipoprotein E ε4 genotype in Alzheimer's disease.

BACKGROUND: Pittsburgh Compound B ([¹¹C] PiB) is a specific positron emission tomography (PET) marker of cerebral amyloid deposits. Only few data have been published on in vivo longitudinal changes of amyloid load in Alzheimer's disease (AD) patients, with conflicting results. Therefore, little is known about the factors that influence these changes. METHODS: A group of 24 patients with probable AD diagnosed by combining established clinical criteria with an AD-typical pattern in [(18)F] fluoro-deoxy-glucose PET underwent [¹¹C] PiB-PET examinations at baseline and after 24 months. The difference of amyloid load between the two examinations and the association with clinical and neurobiological variables was examined with a regions-of-interest approach and voxel-based analyses. RESULTS: Cerebral [¹¹C] PiB uptake ratio increased significantly by an annual rate of 3.92%. Although the increase occurred in all parts of the neocortex, no increase was detected in the archipallium. The increase was gene-dose-dependent (analysis of variance p = .012) to the number of apolipoprotein E ε4 alleles. Progression of dementia symptoms was correlated to the [¹¹C] PiB increase in numerous regions associated with cognition. CONCLUSIONS: The results of this study indicate that a significant increase of amyloid deposition occurs in patients with AD during a relatively short interval of its clinical course. The rate of amyloid aggregation rate is closely associated with the apolipoprotein E genotype, which might be important for the evaluation of antiamyloid drug treatment effects. The present study further emphasizes the value of amyloid-plaque imaging as a marker of disease progression and as a potential surrogate marker to be used in antiamyloid drug trials.