Novel aspects regarding mechanisms and consequences of albuminuria

De studies beschreven in dit proefschrift beogen te onderzoeken welke mechanismen een rol spelen bij het ontstaan van microalbuminurie en welke consequenties verbonden zijn aan het hebben van microalbuminurie. Alle studies zijn verricht met gegevens verkregen uit de Prevention of REnal and Vascular ENd-stage Disease (PREVEND) studie. De PREVEND studie is een studie waarin een groep van 8.592 inwoners van de stad Groningen in de tijd vervolgt worden. Zij komen eens per 3 jaar op een polikliniek, waar allerlei metingen worden verricht. Recent is bij hen het vijfde vervolgonderzoek afgerond. De studie beoogt de relatie tussen albuminurie en het optreden van nier-, hart- en vaatziekten te onderzoeken, en loopt in Stad Groningen sinds 1997

High-sensitive troponin T and N-terminal pro-B type natriuretic peptide are associated with cardiovascular events despite the cross-sectional association with albuminuria and glomerular filtration rate

It has been suggested that troponins and natriuretic peptides can be falsely elevated in subjects with impaired kidney function because of decreased renal clearance. The value of these biomarkers in subjects with impaired kidney function has therefore been debated. We tested in a population-based cohort study, first, whether high-sensitive troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels are cross-sectionally associated with the estimated glomerular filtration rate (eGFR) and albuminuria, and secondly, whether these markers are associated with cardiovascular outcome, independent of eGFR, albuminuria and conventional cardiovascular risk factors. We included 8121 subjects from the PREVEND study with both values of hsTnT and NT-pro-BNP available. High-sensitive troponin T 0.01 g/L and NT-pro-BNP 125 ng/L were defined as elevated. We first performed linear regression analyses with hsTnT and NT-pro-BNP as dependent variables. Next, we performed Cox-regression analyses, studying the associations of hsTnT and NT-pro-BNP with incident cardiovascular events. Of our cohort, 6.7 had an elevated hsTnT and 12.2 an elevated NT-pro-BNP. Also, the estimated glomerular filtration rate, albuminuria, and ECG-assessed ischaemia and left ventricular hypertrophy were all significantly associated with hsTnT and NT-pro-BNP in the linear regression analyses. Both hsTnT and NT-pro-BNP appeared associated with cardiovascular events, and these associations remained significant after adjustment for eGFR, albuminuria, age, gender and conventional cardiovascular risk factors (P 0.03 and P 0.001, respectively). Only a few subjects with markedly reduced renal function were included. The results presented are therefore mainly valid for a population with mildly impaired renal function. These data indicate that a finding of an increased hsTnT or NT-pro-BNP in subjects with chronic kidney disease stages 1/3 should be taken seriously as a prognostic marker for a worse cardiovascular outcome and not be discarded as merely a reflection of decreased renal clearance

Urine Albumin-Creatinine Ratio Versus Albumin Excretion for Albuminuria Staging: A Prospective Longitudinal Cohort Study

Background: New guidelines advocate the use of albumin-creatinine ratio (ACR) in a urine sample instead of 24-hour urinary albumin excretion (UAE) for staging albuminuria. Concern has been expressed that this may result in misclassification for reasons including interindividual differences in urinary creatinine excretion. Study Design: Prospective longitudinal cohort study. Setting & Participants: We examined 7,623 participants of the PREVEND and RENAAL studies for reclassified when using ACR instead of 24-hour UAE, the characteristics of reclassified participants, and their outcomes. Albuminuria was categorized into 3 ACR and UAE categories: 300 mg/g or mg/24 h, respectively. Predictors: Baseline ACR and 24-hour UAE. Outcomes: Cardiovascular (CV) morbidity and mortality and all-cause mortality. Results: When using ACR in the early morning void instead of 24-hour UAE, 88% of participants were classified in corresponding albuminuria categories. 307 (4.0%) participants were reclassified to a higher, and 603 (7.9%), to a lower category. Participants who were reclassified to a higher ACR category in general had a worse CV risk profile compared with nonreclassified participants, whereas the reverse was true for participants reclassified to a lower ACR category. Similarly, Cox proportional hazards regression analyses showed that reclassification to a higher ACR category was associated with a tendency for increased risk for CV morbidity and mortality and all-cause mortality, whereas reclassification to a lower ACR category was associated with a tendency for lower risk. Net reclassification improvement, adjusted for age, sex, and duration of follow-up, was 0.107 (P = 0.002) for CV events and 0.089 (P <0.001) for all-cause mortality. Limitations: Early morning void urine collection instead of spot urine collection. Conclusions: Our results indicate that there is high agreement between early morning void ACR and 24-hour UAE categories. Reclassification is therefore limited, but when present, is generally indicative of the presence of CV risk factors and prognosis. (C) 2016 by the National Kidney Foundation, Inc

The Association of Albuminuria With Tubular Reabsorption of Uric Acid: Results From a General Population Cohort

Background-Elevated albuminuria as well as an increased serum uric acid concentration is associated with poor cardiovascular outcome. We questioned whether these 2 variables (albuminuria and serum uric concentration) may be interrelated via tubular uric acid reabsorption. Methods and Results-Included were 7688 participants of the PREVEND Study, an observational, general population-based cohort study. Linear regression analyses were used to test associations of baseline albuminuria with baseline serum uric acid concentration and tubular uric acid reabsorption (calculated as [100-fractional uric acid excretion]%). Cox regression analyses were used to study the association of baseline serum uric acid and albuminuria with incident cardiovascular morbidity and mortality. In cross-sectional analyses, albuminuria was associated positively with serum uric acid concentration, both crude and after adjustment for potential confounders (both P Conclusions-Albuminuria is strongly associated with tubular uric acid reabsorption, and consequently with serum uric acid concentration. This phenomenon may explain in part why albuminuria is associated with cardiovascular outcome

Modifiable Factors Associated With Copeptin Concentration:A General Population Cohort

Background: Vasopressin plays an important role in maintaining volume homeostasis. However, recent studies suggest that vasopressin also may play a detrimental role in the progression of chronic kidney disease. It therefore is of interest to identify factors that influence vasopressin concentration, particularly modifiable ones. Study Design: Cross-sectional analyses. Setting & Participants: Data used are from participants in a large general-population cohort study (Prevention of Renal and Vascular Endstage Disease [PREVEND]). Patients with a missing copeptin value (n = 888), nonfasting blood sample (n = 495), missing or assumed incorrect 24-hour urine collection (n = 388), or heart failure (n = 20) were excluded, leaving 6,801 participants for analysis. Factor: Identification of lifestyle-and diet-related factors that are associated with copeptin concentration. Outcomes: Copeptin concentration as surrogate for vasopressin. Measurements: Copeptin was measured by an immunoluminometric assay as a surrogate for vasopressin. Associations were assessed in uni- and multivariable linear regression analyses. Results: Median copeptin concentration was 4.7 (IQR, 2.9-7.6) pmol/L. When copeptin was studied as a dependent variable, the final stepwise backward model revealed associations with higher copeptin concentrations for lower 24-hour urine volume (P <0.001), higher sodium excretion (P <0.001), higher systolic blood pressure (P <0.001), current smoking (P <0.001), higher alcohol use (P <0.001), higher urea excretion (P = 0.003), lower potassium excretion (P = 0.002), use of glucose-lowering drugs (P = 0.02), higher body mass index (P <0.001), and higher plasma glucose level (P <0.001). No associations with copeptin concentration were found for C-reactive protein or use of diuretics or nondiuretic antihypertensives. Limitations: The cross-sectional study design does not allow firm conclusions on cause-effect relationships. Conclusions: Important lifestyle-and diet-related factors associated with copeptin concentration are current smoking, alcohol use, protein and potassium intake, and particularly fluid and sodium intake. These data form a rationale to investigate whether intervening on these factors results in a lower vasopressin concentration with concomitant beneficial renal effects. (C) 2015 by the National Kidney Foundation, Inc

Association Between Sodium Intake and Change in Uric Acid, Urine Albumin Excretion, and the Risk of Developing Hypertension

Background-A high-sodium diet has little short-term effect on blood pressure in nonhypertensive individuals but, for unclear reasons, is associated with hypertension if consumed long term. We hypothesized that a chronically high sodium intake would be associated with increases in biomarkers of endothelial dysfunction, specifically serum uric acid (SUA) and urine albumin excretion (UAE), and that high sodium intake would be associated with incident hypertension among those with higher SUA and UAE. Methods and Results-We prospectively analyzed the associations between sodium intake and the change in SUA (n = 4062) and UAE (n = 4146) among participants of the Prevention of Renal and Vascular End Stage Disease (PREVEND) study who were not taking antihypertensive medications. We also examined the association of sodium intake with the incidence of hypertension (n = 5556) among nonhypertensive participants. After adjustment for confounders, each 1-g-higher sodium intake was associated with a 1.2-mu mol/L increase in SUA (P = 0.01) and a 4.6-mg/d increase in UAE (P <0.001). The relation between sodium intake and incident hypertension varied according to SUA and UAE. For each 1-g-higher sodium intake, the adjusted hazard ratio for developing hypertension was 0.98 (95% confidence interval, 0.89-1.08) among those in the lowest tertile of SUA and 1.09 (1.02-1.16) among those in the highest tertile. Corresponding hazard ratios were 0.99 (confidence interval, 0.93-1.06) among participants whose UAE was 15 mg/d. Conclusions-Over time, higher sodium intake is associated with increases in SUA and UAE. Among individuals with higher SUA and urine UAE, a higher sodium intake is an independent risk factor for developing hypertension. (Circulation. 2012;125:3108-3116.

Baseline characteristics.

<p>Abbreviations: CVD, cardiovascular disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; UAE, urinary albumin excretion.</p

Score chart.

<p>Score chart.</p

Results of univariable logistic regression analyses exploring subject characteristics associated with progressive albuminuria.

<p>Abbreviations: BMI, body mass index; SBP, systolic blood pressure; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; UAE, urinary albumin excretion; OR, odds ratio; CI, confidence interval.</p

Median (IQR) urinary albumin excretion (UAE) of subjects meeting the definition of progressive albuminuria (open bars) and subjects without progressive albuminuria (dark bars) during the various screening rounds of the PREVEND cohort.

<p>The upper panel shows data of all participants, whereas the lower panel shows data of only participants with follow-up until the last screening. Abbreviations: N denotes the number of participants.</p