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: <30, 30 to 300, and >300mg/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.

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.

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<0.001). Albuminuria was found to be associated positively with tubular uric acid reabsorption, again both crude and after adjustment for potential confounders (both P<0.001). In longitudinal analyses during a median follow-up of 10.5 years, 702 cardiovascular events occurred. After adjusting for cardiovascular risk factors, both albuminuria and serum uric acid were associated with incident cardiovascular events (Hazard Ratios 1.09 [1.03 to 1.17], P=0.01 and 1.19 [1.09 to 1.30], P<0.001, respectively). A significant interaction between these variables was present (P<0.001), consistent with high serum uric acid being less predictive for cardiovascular morbidity and mortality in the presence of high albuminuria and vice versa. 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.

Predictors of progression in albuminuria in the general population: results from the PREVEND cohort.

BACKGROUND: Urinary albumin excretion is known to be independently associated with progression of renal and cardiovascular disease. The aim of this study was to identify predictors for progression in albuminuria in the general population. METHODS: Data were used of the first 4 screening rounds of a community-based prospective cohort study (PREVEND). Included were 5,825 subjects that at baseline had no known renal disease or macroalbuminuria. Subjects were defined as having progressive albuminuria when they belonged to the quintile of subjects with highest absolute increase in urinary albumin excretion per year and a urinary albumin excretion during the last screening in which they participated of ≥150 mg/24 h. Change in urinary albumin excretion per year was calculated as last available urinary albumin excretion minus baseline UAE divided by follow-up time. RESULTS: During 9.3 years follow-up 132 subjects had progressive albuminuria. These subjects were significantly older, more often of male gender and had a worse cardiovascular risk profile. In a multivariable model, testing baseline values, significant predictors of progressive albuminuria were male gender (OR 2.23; p<0.001), age (OR 1.03; p<0.001), BMI (OR 1.06; p = 0.02) and baseline albuminuria (OR 5.71; p<0.001). Based on these findings a risk score was made to estimate a subject's risk for progressive albuminuria. CONCLUSION: A high baseline albuminuria is by far the most important predictor of progressive albuminuria. Thus, screening for baseline albuminuria will be more important than screening for cardiovascular risk factors in order to identify subjects at risk for progressive albuminuria.

Isolated microalbuminuria indicates a poor medical prognosis.

BACKGROUND: Microalbuminuria is often regarded as a sign of end-organ damage due to diabetes and/or hypertension, and as such to be associated with an increased risk for cardiovascular events. It has been questioned whether isolated microalbuminuria, that is microalbuminuria in the absence of a cardiovascular disease (CVD) history, hypertension and diabetes has clinical relevance. METHODS: Included were 8356 subjects who participated in the first four screening rounds of the PREVEND study, a prospective, community-based, observational cohort study. Isolated microalbuminuria was defined as microalbuminuria (30-300 mg/24 h), in the absence of a CVD history, hypertension (blood pressure<140/90 mmHg, not using blood pressure-lowering drugs) and diabetes (fasting glucose<7.0 mmol/L, not using glucose-lowering drugs). RESULTS: Three hundred subjects met the definition of isolated microalbuminuria, in which 2250 person-years of follow-up were available. In subjects with isolated microalbuminuria, the incidence rates of cardiovascular events and mortality, hypertension and diabetes were 15.3, 28.9 and 8.9 per 1000 person-year follow-up, respectively. Subjects with isolated microalbuminuria had an increased risk for cardiovascular events and mortality [crude HR 2.23 (1.63-3.07); P<0.001], hypertension [OR 1.95 (1.47-2.59); P<0.001] and diabetes [OR 4.69 (2.92-7.51); P<0.001] compared with subjects without microalbuminuria, CVD history, hypertension and/or diabetes. This increased risk remained significant after adjustment for age and gender. The relative risk held by isolated microalbuminuria was similar to the relative risk held by microalbuminuria in subjects that did have a CVD history, hypertension and/or diabetes. CONCLUSIONS: Isolated microalbuminuria indicates a poor prognosis and warrants medical attention.

Glomerular and tubular damage markers in individuals with progressive albuminuria.

BACKGROUND AND OBJECTIVES: Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as "progressors" if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. RESULTS: After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. CONCLUSIONS: These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable.

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.

AIMS: 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. METHODS AND RESULTS: We included 8121 subjects from the PREVEND study with both values of hsTnT and NT-pro-BNP available. High-sensitive troponin T >0.01 µg/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. CONCLUSION: 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.

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-µmol/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 <10 mg/d and 1.18 (confidence interval, 1.07-1.29) among those 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.

Influence of urine creatinine on the relationship between the albumin-to-creatinine ratio and cardiovascular events.

BACKGROUND AND OBJECTIVES: In the albumin-to-creatinine ratio (spot-ACR), urine creatinine corrects for tonicity but also reflects muscle mass. Low muscle mass is associated with cardiovascular disease (CVD). We hypothesized that the spot-ACR would be higher in women, lower-weight persons, and older individuals, independent of timed urine albumin excretion (24hr-UAE), and accordingly, that spot-ACR would be more strongly associated with CVD events than 24hr-UAE in these subgroups. DESIGN, SETTING, PARTICIPANTS, & METHODS: 2627 PREVEND (Prevention of Renal and Vascular End-stage Disease) participants with 24hr-UAE <30 mg/d were followed for CVD events for 11 years. Cox regression evaluated associations of spot-ACR and 24hr-UAE with CVD events by sex, weight, and age. RESULTS: Female sex (26%), lower weight (2% per 5 kg), and older age (4% per 5 years) were associated with higher spot-ACR independent of 24hr-UAE (P<0.001). Spot urine albumin concentration (hazard ratio [HR], 1.26 per ln-SD higher) and 1/spot urine creatinine concentration (HR, 1.16 per ln-SD higher) were associated with CVD events. Spot-ACR was more strongly associated with CVD events than either component of the ratio (HR, 1.41 per ln-SD higher). Associations of spot-ACR ≥10 mg/g versus less (HR, 2.33) and 24hr-UAE ≥10 mg/d versus less (HR, 2.09) with CVD events were similar, and there were no significant differences across subgroups (P for interactions >0.06). CONCLUSIONS: In community-living individuals with 24hr-UAE <30 mg/d, spot-ACR is higher in women, older persons, and lower-weight persons, independent of 24hr-UAE. Low spot urine creatinine is associated with CVD risk, but high urine albumin is a stronger determinant of the association of spot-ACR with CVD than is low urine creatinine.

Renal histology in the elderly: indications and outcomes.

BACKGROUND: Renal disease is being increasingly diagnosed in the elderly. However, reports on biopsy-confirmed renal disease in this population are limited. The aim of this study was to give an overview of the most important indications, diagnoses and outcomes of renal biopsies in the elderly in our center. METHODS: This was a retrospective review of all elderly renal biopsies over 5 years. Patients were eligible for inclusion if they were aged ≥65 years and had had a native kidney biopsy performed. The data recorded included age, sex, indications for biopsy, histological diagnoses and outcomes. RESULTS: During this time, 1,372 native renal biopsies were performed. Of these, 236 (17%) were in patients aged ≥65 years; 150 male (64%) and 86 female (36%). The most common indications for biopsy were acute renal failure and nephrotic syndrome. Common diagnoses included pauci-immune crescentic glomerulonephritis, tubulointerstitial nephritis, membranous nephropathy, IgA nephropathy and chronic thrombotic microangiopathy. Long-term follow-up of 3 years was available for 102 patients; median serum creatinine at the time of biopsy was 427 µmol/L (interquartile range 204-702) and at 3 years post biopsy had fallen to 192 µmol/L (interquartile range 152-408). CONCLUSIONS: In our center, 17% of native kidney biopsies are performed in elderly patients aged ≥65 years. In our experience, this procedure was safe and had a 97% diagnostic rate. The available follow-up data of patients suggest that renal histology is not only of benefit in diagnosis but also of potential value in terms of prognosis and treatment.