Development and validation of a general population renal risk score.

BACKGROUND AND OBJECTIVES: There is a need for prediction scores that identify individuals at increased risk for developing progressive chronic kidney disease (CKD). Therefore, this study was performed to develop and validate a "renal risk score" for the general population. Design, setting, participants, & measurements For this study we used data from the PREVEND (Prevention of Renal and Vascular ENdstage Disease) study, a prospective population-based cohort study with a median follow-up of 6.4 years. Participants with two or three consecutive estimated GFR (eGFR) measurements during follow-up were included. Participants within the group who had the most renal function decline (top 20% of the total population) and had an eGFR value <60 ml/min per 1.73 m² during follow-up were defined as having progressive CKD. Possible predictors for progressive CKD were selected on the basis of univariable logistic regression analyses. RESULTS: A final prediction model was built using backward logistic regression analysis. Besides baseline eGFR, the model contained age, urinary albumin excretion, systolic BP, C-reactive protein, and known hypertension. The area under the receiver operating characteristic (ROC) curve was 0.84. We performed internal validation by using a bootstrapping procedure. As expected, after the regression coefficients were corrected for optimism, the area under the ROC curve was still 0.84. For clinical use we divided all predictors in meaningful clinical categories to develop a score chart. The area under the ROC curve was 0.83, indicating the high discriminative value of this model. CONCLUSIONS: Given the high internal validity of this renal risk score, this score can be helpful to identify individuals at increased risk for progressive CKD.

Changes in renal risk factors versus renal function outcome during follow-up in a population-based cohort study.

BACKGROUND: Chronic kidney disease is a growing public health problem worldwide. Previous studies have identified several predictors for renal function decline. However, these studies used a single measurement of these risk factors. Therefore, the aim of this study was to investigate whether besides the baseline values of these risk factors, changes in risk factors are associated with subsequent rate of renal function loss. METHODS: Five thousand, six hundred and fifty-one participants in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) Study, a prospective, community-based cohort study, completed three screening visits during a follow-up of 6.5 years for detailed clinical and biochemical measurements. Change in renal function between the second and third screening rounds was chosen as the study parameter of interest. Changes in risk factors between the first and second screening rounds were incorporated as potential predictors for renal function loss in multivariable linear regression analyses. Based on the results of a previous study, gender-specific analyses were performed. RESULTS: In males, an increase in urinary albumin excretion (UAE), systolic blood pressure (SBP) and cholesterol was associated with a subsequent higher rate of renal function loss, whereas in females, increases in glucose levels were associated with an increase in renal function. For males, the analyses showed that both the baseline values and the change in UAE and cholesterol were significant predictors for increased rate of renal function loss during subsequent follow-up. With respect to SBP, when taking also the change in this variable into account, the baseline value was no longer a significant predictor for renal function loss. CONCLUSIONS: The results of the present study show the value of screening programs including repeated measurements of risk factors. Furthermore, these data indicate that, besides baseline values of risk factors, the changes over time in these factors should also be taken into account when developing 'Renal Risk Scores' to identify subjects in the general population who are at risk for accelerated renal function deterioration.

Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial.

BACKGROUND: Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) SETTING: 2 university medical centers in The Netherlands. PATIENTS: 114 steroid-naive current or former smokers with moderate to severe COPD. MEASUREMENTS: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. INTERVENTION: Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). RESULTS: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level. LIMITATIONS: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. CONCLUSION: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. .

High protein intake associates with cardiovascular events but not with loss of renal function.

The long-term effects of higher dietary protein intake on cardiovascular and renal outcomes in the general population are not clear. We analyzed data from 8461 individuals who did not have renal disease and participated in two or three subsequent screenings (6.4-yr follow-up) in a prospective, community-based cohort study (Prevention of Renal and Vascular ENd-stage Disease [PREVEND]). We calculated daily protein intake from 24-h urinary urea excretion (Maroni formula) and used Cox proportional hazard models to analyze the associations between protein intake, cardiovascular events, and mortality. We used mixed-effects models to investigate the association between protein intake and change in renal function over time. The mean +/- SD daily protein intake was 1.20 +/- 0.27 g/kg. Protein intake was significantly associated with cardiovascular events during follow-up. The associations seemed U-shaped; compared with intermediate protein intake, individuals with either higher or lower protein intake had higher event rates. All-cause mortality and noncardiovascular mortality also were significantly associated with protein intake; individuals with low protein intake had the highest event rates. We found no association between baseline protein intake and rate of renal function decline during follow-up. In summary, in the general population, high protein intake does not promote accelerated decline of renal function but does associate with an increased risk for cardiovascular events.

Gender differences in predictors of the decline of renal function in the general population.

We sought to identify predictors of the decline in renal function, especially those that are modifiable, in the 5488 participants of the prospective, community-based cohort study PREVEND who completed three visits during a mean follow-up of 6.5 years. The change in renal function was used as the outcome and this was calculated as the linear regression of three estimated GFR measurements obtained during follow-up. Risk factors, known to influence renal outcome in patients with primary renal diseases, were used as potential predictors in multivariate regression analyses. High systolic blood pressure and plasma glucose were found to be independent predictors for an accelerated decline in function for both genders. In males, albuminuria was the strongest independent predictor for renal function decline, whereas in females albuminuria was univariately associated only after adjustment for age. The direction of the association between cholesterol/HDL ratio and decline of renal function differed by gender. Surprisingly, in males, waist circumference was an independent predictor and positively associated with renal function outcome. These studies show that there are gender differences in the standard predictors of the decline in renal function.

Airway inflammation contributes to health status in COPD: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD. METHODS: In 114 COPD patients (99 male, age: 62 +/- 8 yr, 41 [31-55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 +/- 9% pred, FEV1/IVC: 48 +/- 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients. RESULTS: Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis. CONCLUSION: We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease.

Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is defined by progressive, irreversible airflow limitation and an inflammatory response of the lungs, usually to cigarette smoke. However, COPD is a heterogeneous disease in terms of clinical, physiologic, and pathologic presentation. We aimed to evaluate whether airflow limitation, airway responsiveness, and airway inflammation are separate entities underlying the pathophysiology of COPD by using factor analysis. A total of 114 patients (99 males/15 females, age 62 +/- 8 years, 42 pack-years smoking, no inhaled or oral steroids > 6 months) with irreversible airflow limitation (postbronchodilator FEV(1) 63 +/- 9% predicted, FEV(1)/inspiratory vital capacity [IVC] 48 +/- 9%) and symptoms of chronic bronchitis or dyspnea were studied in a cross-sectional design. Postbronchodilator FEV(1) and FEV(1)/IVC, reversibility to inhaled beta(2)-agonists, diffusing capacity, provocative concentration of methacholine required to produce a 20% drop in FEV(1), total serum IgE, exhaled nitric oxide, and induced sputum cell counts (% eosinophils, % neutrophils) were collected. Factor analysis yielded 4 separate factors that accounted for 63.6% of the total variance. Factor 1 was comprised of FEV(1), FEV(1)/IVC, and residual volume/total lung capacity. Factor 2 included reversibility, IgE, provocative concentration of methacholine required to produce a 20% drop in FEV(1,) and diffusing capacity. Factor 3 contained exhaled nitric oxide and factor 4 included sputum % neutrophils and % eosinophils. We conclude that airflow limitation, airway inflammation, and features commonly associated with asthma are separate and largely independent factors in the pathophysiology of COPD.

Sex and gender differences in lung development and their clinical significance.

Factors that affect airway growth-as early in development as in utero-seem to cause physiologic effects that can be persistent. Reduced airway function early in life does not necessarily result in persistent symptoms, but it does increase the risk of reduced lung function and the development of persistent airflow limitation in adult life, both in men and women. Normal lung growth varies with age and sex and is affected by a number of risk factors, which we have described. The importance of the various risk factors may differ depending at what point during lung growth they come into play and whether they occur in men or in women.