Body mass index modifies the risk of cardiovascular death in proteinuric chronic kidney disease.

BACKGROUND: In subjects with end-stage renal disease, a high body mass index (BMI) is inversely related to overall mortality, which has been coined reverse epidemiology phenomenon. This study sought to investigate this paradox as well as a possible risk modification by proteinuria on the relationship of BMI with earlier stages of chronic kidney disease (CKD) concerning cardiovascular mortality. METHODS: We used the Vienna Health Screening Initiative, a longitudinal cohort study from 1990 to 2006, including 49 398 volunteers (49.9% women, age 20-89 years): n = 2487 showed mild CKD (proteinuria and GFR >60 ml/min/1.73 m(2)) and n = 392 showed moderate CKD (GFR = 30-59 ml/min/1.73 m(2)). The follow-up period was 5.5 +/- 4.2 years; n = 148 cardiovascular deaths occurred. Exposure variables were BMI, glomerular filtration rate (GFR) and proteinuria. Cox regression models on cardiovascular mortality with adjustment for age, sex, log(cholesterol/HDL), uric acid, smoking, glucose, diabetes, mean blood pressure, hypertension and antihypertensive drug use were fitted. RESULTS: The risk factor paradox is shown in moderate CKD (GFR = 45 ml/min/1.73 m(2)): hazard ratios (HR) of BMI contrasts decreased consistently from 1.28 (95% CI 0.33-5.82) at BMI 20 kg/m(2) versus 25 kg/m(2) to 0.76 (95% CI 0.38-1.50) at BMI 30 kg/m(2) versus 25 kg/m(2) and to 0.58 (95% CI 0.13-2.64) at BMI 35 kg/m(2) versus 25 kg/m(2), thus showing an inverse relationship compared to mild CKD/healthy participants. Examining proteinuria as an effect modifier in this context showed that in moderate CKD (contrast: proteinuria versus no proteinuria) HR decreased more profoundly from 9.43 (95% CI 2.66-27.40) at BMI 25 kg/m(2) to 3.74 (95% CI 0.93-15.70) at BMI 30 kg/m(2) and to 1.95 (95% CI 0.37-22.30) at BMI 35 kg/m(2), and conversely in non-proteinuric subjects, hazards for cardiovascular mortality increased in underweight as well as in overweight/obese subjects in a U-shaped manner. CONCLUSIONS: Our results suggest that obese subjects with proteinuric CKD may not be counselled for weight reduction since a higher BMI was associated with a remarkably reduced risk of death.

Elevated uric acid increases the risk for kidney disease.

Recent epidemiologic studies suggest that uric acid predicts the development of new-onset kidney disease, but it is unclear whether uric acid is an independent risk factor. In this study, data from 21,475 healthy volunteers who were followed prospectively for a median of 7 yr were analyzed to examine the association between uric acid level and incident kidney disease (estimated GFR [eGFR] <60 ml/min per 1.73 m(2)). After adjustment for baseline eGFR, a slightly elevated uric acid level (7.0 to 8.9 mg/dl) was associated with a nearly doubled risk for incident kidney disease (odds ratio 1.74; 95% confidence interval 1.45 to 2.09), and an elevated uric acid (> or =9.0 mg/dl) was associated with a tripled risk (odds ratio 3.12; 95% confidence interval 2.29 to 4.25). These increases in risk remained significant even after adjustment for baseline eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol, blood glucose, triglycerides, and BP). In a fully adjusted spline model, the risk for incident kidney disease increased roughly linearly with uric acid level to a level of approximately 6 to 7 mg/dl in women and 7 to 8 mg/dl in men; above these levels, the associated risk increased rapidly. In conclusion, elevated levels of uric acid independently increase the risk for new-onset kidney disease.

Predictors of new-onset decline in kidney function in a general middle-european population.

BACKGROUND: Limited epidemiological data are available on predictors of new-onset kidney disease. METHODS: In this longitudinal cohort study, 17 375 apparently healthy volunteers of the general Viennese population (46.4% women, age range 20-84 years, men 20-89 years) performed a baseline examination at some time within the study period (1990-2005) and completed a median of two follow-up examinations [interquartile range (IQR) 1 to 4]; the median follow-up period was 7 years (IQR 4 to 11). The outcome of interest was the development of kidney disease, defined as a decrease of the glomerular filtration rate (GFR) <60 ml/min/1.73 m(2) at the follow-up examinations [calculated by the abbreviated modification of diet in renal disease (MDRD) equation]. Logistic generalized estimating equations were used to analyse the relationship between the covariates and the outcome variable. RESULTS: The following parameters [odds ratios (OR) with 95% confidence intervals] predicted new-onset kidney disease: Age (increase by 5 years), OR = 1.36 (1.34-1.40); National Kidney Foundation-chronic kidney disease (NKF-CKD) stage 1 with proteinuria (+), OR = 1.39 (1.10-1.75); NKF-CKD stage 1 with proteinuria (>/=++), OR = 2.07 (1.11-3.87); NKF-CKD stage 2 with proteinuria (+), OR = 2.71 (2.10-3.51); NKF-CKD stage 2 with proteinuria (>/=++), OR = 3.80 (2.29-6.31); body mass index, OR = 1.04 (1.02-1.06); current-smoker, OR = 1.20 (1.01-1.43); performing no sports, OR = 1.57 (1.27-1.95); uric acid (increase by 2 mg/dl), OR = 1.69 (1.59-1.80); HDL-cholesterol (decrease by 10 mg/dl), OR = 1.12 (1.07-1.17); hypertension stage 1, OR = 1.35 (1.08-1.67); hypertension stage 2, OR = 2.01 (1.62-2.51); diabetes mellitus, OR = 1.44 (1.07-1.93). CONCLUSIONS: Cardiovascular risk factors as well as NKF-CKD stages 1 and 2 and proteinuria, the more the higher and an entirely novel finding, performing no sports, predicted new-onset kidney disease.

The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease.

GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period. Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007). This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.

[Perspectives on treatment of hypertension in elderly patients]. / Spezifische Aspekte der Hochdruckbehandlung beim alten Menschen.

Hypertension increases in prevalence with age. Population-based studies suggest that more than 50% of people over the age of 65 years may have chronic hypertension, defined as blood pressure (BP) > or = 140/90 mmHg. Hypertension, especially systolic hypertension, is the most common, powerful, however treatable risk factor for cardiovascular morbidity and mortality in the elderly. Large randomised trials have demonstrated that treating elderly and even very old persons (age > 80 years) is highly efficacious. A recent meta-analysis, comparing active treatment with placebo in isolated systolic hypertension demonstrated highly significant benefits: stroke was reduced by 30%, coronary heart disease events by 23%, all cardiovascular events by 26%, and cardiovascular deaths by 13%. The classic strategy of an initial thiazide or thiazide-like diuretic therapy has been verified by the most recent trials. Furthermore it is not appropriate to limit the choice of initial drugs for hypertensive older individuals to a single class of agents, since so many older people have other medical problems that affect this decision and reaching the target blood pressure is the determinant factor for cardiovascular risk reduction. Therefore single drug therapy with long-acting (dihydropyridine-type) calcium-antagonists, beta-blockers, angiotensin-converting-enzyme-inhibitors or angiotensin-receptor-blockers is justified with respect to individual efficacy and comorbidity. If a combination of antihypertensive drugs is needed to reach blood pressure goal, thiazides remain the cornerstone. First line therapy with an alpha-blocker is no longer recommended, even for men with hypertension and benign prostatic hypertrophy. Today, recommended blood pressure goals are the same for younger individuals and the elderly.

The reduced release of GH by GHRH in 8 subjects aged 65-69 years is augmented considerably by rivastigmine, a drug for Alzheimer's disease.

BACKGROUND: The growth hormone (GH) secretion declines by 14% with each decade of adult life. Several attempts have been made to reverse the manifestations of the senile GH deficiency, termed somatopause, but GH substitution treatment in old age has not yet developed an established regimen. Cholinesterase inhibitors like pyridostigmine are able to elicit GH secretion when administered alone and to enhance the GH response to growth hormone releasing hormone (GHRH), but its clinical use is limited due to the strong peripheral cholinergic side effects. OBJECTIVE: The aims of our experiments were to find out whether the GH response to GHRH can be augmented by rivastigmine, a new orally applicable and well-tolerated selective inhibitor of cerebral acetylchoinesterase. METHODS: Eight healthy volunteers (age range 65-69 years) were studied. After an overnight fast, GHRH tests were done: 1 microg/kg GHRH was injected as an intravenous bolus. Blood samples for an immunoradiometric GH assay were taken at the time of GHRH injection (time 0) and after 15, 30, 45, 60, and 120 min. First, the baseline experiment was done: it consisted of two subsequent GHRH tests which were carried out within an interval of 120 min. Four weeks later the rivastigmine experiment was done identically, but 60 min before performing the second GHRH test, rivastigmine (4.5 mg) was administered orally. The GH secretory responses were expressed as areas under the curve (AUC; median, interquartile range), Wilcoxon's signed-rank test was used for statistical comparisons. RESULTS: Baseline experiment: The GH AUC of the first GHRH test was 1040 (range 420-1250) ng/ml/h. The repeated GHRH stimulation after 120 min (second GHRH test) showed a 13-fold decrease to 80 (range 60-130) ng/ml/h. Rivastigmine experiment: The GH AUC of the first GHRH test was 950 (range 540-1430) ng/ml/h and, therefore, similar to that of the baseline experiment. 60 min after ingestion of the single oral dose of rivastigmine (4.5 mg), the following GHRH stimulation (second GHRH test) nearly doubled the GH AUC to 1580 (range 860-3330) ng/ml/h. Comparing the DeltaGH AUC values (DeltaGH AUC = GH AUC of the first GHRH test minus GH AUC of the second GHRH test), baseline experiment versus rivastigmine experiment, there was a 20-fold (p = 0.018) increase in GH AUC after rivastigmine pretreatment. CONCLUSIONS: Rivastigmine is a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. Future investigations are necessary to find out whether rivastigmine can restore the senile decline of the circadian GH secretion in the long term and, therefore, has new implications for patient treatment.