Patient survival after renal transplantation; more than 25 years follow-up

Background: The determinators of patient survival after renal transplantation are incompletely known, and conflicting results hae been reported. This may have been influenced by time-related changes in patients selection, post-transplantation management and immunosuppressive regimens. This study was performed to evaluate in recipients of a first renal transplant the effect of patient characteristics, transplantation era, and the immunosuppressive regimen on patient survival. Method: We studied data from the Leiden Renal Transplant Database of all first renal transplantations performed between 1966 and 1994 in Leiden, the Netherlands. The effect of the following parameters on mortality was investigated: era of transplantation, sex, age at transplantation, cause of renal failure, immunosuppressive regimen, type and duration of pretransplantation dialysis, hypertension, diabetes mellitus, and smoking. In addition we analysed the causes of death. Results were expressed as crude mortality rates, relative risks of mortality, and standardized mortality ratios as compared with death rates in the Dutch population. Results: The analysis comprised 86 living donor transplant recipients and 916 cadaver transplant recipients. After adjustment for age and sex, the relative risk of morality for living donor transplant recipients compared with cadaver transplant recipients was 0.5 (95% CI 0.2 to 10.3, P=0.06). In the first cadaver kidney transplant recipients the risk of first-year mortality improved significantly with time, which coincided with the introduction of cyclosporin. The risk of mortality after the first year was higher in patients aged over 40 years at transplantation, men, smokers, and in the presence of hypertension or diabetes, but the effect of individual factors on mortality was small. We found no effect of the type of pretransplantation dialysis or the duration of pretransplantation haemodialysis on post-transplantation mortality. The standardized mortality ratio for recipients of first renal transplants was 14 times the population average in the first year after transplantation and was still four times in the remaining years. Conclusion: In the present study, time-related changes in patient management were responsible for improved patient survival in the first year after transplantation during the study period. Many individual factors contributed moderately to the risk of mortality after the first year. Compared to the general population the mortality rate of renal transplant recipients was significantly higher during the whole follow-up period.     

Hormone replacement therapy and intima-media thickness of the common carotid artery: the Rotterdam study

BACKGROUND AND PURPOSE: Observational data suggest that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular disease in healthy postmenopausal women. The mechanisms underlying this protection are not entirely clear but may include inhibition of the atherosclerotic process. METHODS: We studied the association between ever use of HRT and intima-media thickness (IMT) of the common carotid artery in 1103 naturally menopausal women, aged 55 to 80 years, in the Rotterdam Study, a community-based cohort study in a suburban area of Rotterdam, Netherlands. Mean and maximum IMT of the common carotid artery were measured noninvasively with B-mode ultrasound. RESULTS: Ever use of HRT for >/=1 year was associated with a decreased mean and maximum IMT compared with never users (mean IMT, 0.719 mm [SE 0.01] versus 0. 742 mm [SE 0.004], P=0.03; maximum IMT, 0.952 mm [SE 0.015] versus 0. 983 mm [SE 0.006], P=0.04), after adjustment for age, smoking, educational level, systolic blood pressure, and body mass index. No association was found for use <1 year (mean IMT, 0.739 mm [SE 0.013] versus 0.742 mm [SE 0.004], P=0.69; maximum IMT, 0.990 mm [SE 0.019] versus 0.983 mm [SE 0.006], P=0.75). Additional adjustment for diabetes, frequency of visits to healthcare facilities, or total and HDL cholesterol did not change these results. CONCLUSIONS: The findings of this population-based study show that ever use of HRT is associated with a decreased IMT in the common carotid artery in elderly women.     

The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM

BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes.     

Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction.

INTRODUCTION: In patients with myocardial infarction (MI)-induced heart failure, angiotensin-converting enzyme (ACE) inhibitors are proven effective therapy in inhibiting the progression towards overt heart failure. However, the prognosis in these patients is still very poor, and optimisation of therapy is warranted. The antihypertensive and renoprotective effects of ACE inhibitors (ACE-Is) can be substantially enhanced by dietary sodium restriction. In line with the latter, the aim of the present study was to explore whether dietary sodium restriction enhances the efficacy of ACE-I after MI. METHODS: Rats with MI-induced left ventricular (LV) dysfunction received ACE-I therapy with zofenopril (5.5 mg/kg/day orally), with or without dietary sodium restriction. ACE activity was measured in non-infarcted LV tissue, kidneys and plasma. Effects on cardiac hypertrophy were examined by means of organ weight/body weight ratios. After blood pressure (BP) measurements, functional consequences of therapy were evaluated as LV pressure development in isolated perfused hearts. RESULTS: Dietary sodium restriction alone had no effect on any of the measured parameters, whereas zofenopril alone significantly reduced plasma and kidney ACE activity, but not LV ACE activity, nor LV weight/body weight ratio. However, only when ACE-I therapy was combined with dietary sodium restriction was LV ACE activity significantly reduced. This effect was paralleled by inhibition of LV hypertrophy. BP was reduced after infarction, and further reduced by zofenopril, but not affected by dietary sodium. Neither treatment was associated with effects on the MI-induced reduction of LV function in vitro. CONCLUSIONS: Effects of ACE inhibition with zofenopril can be potentiated by additional dietary sodium restriction. However, these effects were tissue-specific, since LV, but not kidney or plasma, ACE activity was affected by the additional dietary sodium restriction. Effects on LV ACE activity were paralleled by reduced LV hypertrophy. Since the measured parameters did not indicate any adverse side-effects, dietary sodium restriction may provide a safe strategy to improve ACE-I efficacy in patients with infarction-induced LV dysfunction.     

Serum triiodothyronine levels and inflammatory cytokine production capacity

Increasing evidence suggests that pro-inflammatory cytokines are at play in lowering peripheral thyroid hormone levels during critical illness. Conversely, thyroid hormones have been suggested to enhance production of inflammatory cytokines. In view of these considerations, we hypothesized a mutual association between triiodothyronine and pro-inflammatory cytokines. Therefore we evaluated the relation between both circulating and induced inflammatory markers and serum thyroid function parameters in the Leiden 85-plus Study. We found that higher circulating levels of inflammatory markers were associated with lower levels of free serum triiodothyronine. In turn, higher serum free triiodothyronine levels were related to higher production capacity of pro-inflammatory cytokines after stimulation with lipopolysaccharide. By combining in vivo and ex vivo data, we were able to demonstrate for the first time the existence of a potential feedback mechanism between thyroid function and immune production capacity. We conclude that maintenance of normal thyroid function might be important for a preserved immune response in elderly human populations.     

Nonagenarian Siblings and Their Offspring Display Lower Risk of Mortality and Morbidity than Sporadic Nonagenarians: The Leiden Longevity Study

OBJECTIVES: To compare the risk of mortality of nonagenarian siblings with that of sporadic nonagenarians (not selected on having a nonagenarian sibling) and to compare the prevalence of morbidity in their offspring with that of the offsprings' partners.
DESIGN: Longitudinal (mortality risk) and cross-sectional (disease prevalence).
SETTING: Nationwide sample.
PARTICIPANTS: The Leiden Longevity Study consists of 991 nonagenarian siblings derived from 420 Caucasian families, 1,365 of their offspring, and 621 of the offsprings' partners. In the Leiden 85-plus Study, 599 subjects aged 85 were included, of whom 275 attained the age of 90 (sporadic nonagenarians).
MEASUREMENTS: All nonagenarian siblings and sporadic nonagenarians were followed for mortality (with a mean±standard deviation follow-up time of 2.7±1.4 years and 3.0±1.5 years, respectively). Information on medical history and medication use was collected for offspring and their partners.
RESULTS: Nonagenarian siblings had a 41% lower risk of mortality ( P <.001) than sporadic nonagenarians. The offspring of nonagenarian siblings had a lower prevalence of myocardial infarction (2.4% vs 4.1%, P =.03), hypertension (23.0% vs 27.5%, P =.01), diabetes mellitus (4.4% vs 7.6%, P =.004), and use of cardiovascular medication (23.0% vs 28.9%, P =.003) than their partners.
CONCLUSION: The lower mortality rate of nonagenarian siblings and lower prevalence of morbidity in their middle-aged offspring reinforce the notion that resilience against disease and death have similar underlying biology that is determined by genetic or familial factors.     

Basal cerebral blood flow is dependent on the nitric oxide pathway in elderly but not in young healthy men

OBJECTIVE: Brain perfusion is tightly regulated over a wide range of blood pressures by local regulation of cerebral blood flow (CBF). Ageing is associated with impaired CBF and impaired nitric oxide mediated vasodilator responses. The role of nitric oxide in the regulation of basal CBF in young and older subjects was investigated, using the nitric oxide synthase inhibitor L-NMMA as pharmacological tool. METHODS: We used a gradient echo phase-contrast magnetic resonance imaging technique to investigate the role of nitric oxide in the regulation of cerebral blood flow in young (25+/-7.1 years; n=8) and old (78+/-6.6 years; n=7) volunteers. The study was performed in a double-blinded fashion and consisted of two study days. On one day the effects of the intravenously infused L-NMMA on CBF and blood pressure was measured and on the other day the effects of a matching placebo. RESULTS: Basal CBF was significantly lower in old compared to young subjects (590+/-20 vs 704+/-20 ml/min), while the cerebral vascular resistance (CVR) levels were significantly higher (0.15+/-0.01 (arbitrary units) vs 0.12+/-0.01, respectively). Infusion of L-NMMA significantly increased mean arterial pressure in both groups (2.8+/-1.2 mmHg; p=0.02 in the young and in the old subjects 5.6+/-1.1 mmHg; p<0.001). Infusion of L-NMMA significantly decreased CBF (49+/-12 ml/min; p<0.001) and increased CVR (0.02+/-0.004; p<0.001) in the old subjects but did not significantly influence cerebral circulation in the young subjects. CONCLUSION: We conclude that compared to young subjects, in old people CBF is impaired, and dependent on the intactness of the nitric oxide pathway.     

Common chronic diseases and general impairments as determinants of walking disability in the oldest-old population

OBJECTIVES: Walking disability affects older people's autonomy and well-being. We investigated the relative effect of common chronic diseases and general impairments on walking disability in the general oldest-old population. DESIGN: Population-based cohort study. SETTING: Leiden 85-plus Study, the Netherlands. PARTICIPANTS: Five hundred ninety-nine persons aged 85, response rate 87%. MEASUREMENTS: Walking disability was assessed using a 6-meter walking test. Persons with a walking time below the 25th percentile and those who were physically unable to perform the walking test were categorized as having a walking disability. Information on common chronic diseases was obtained from records of subjects' general practitioners and pharmacies. General impairments were assessed with functional tests and standardized questions during face-to-face interviews. We expressed the effect of common chronic diseases and general impairments as the population attributable risk (PAR), indicating how much disability can be prevented when the identified risk factor is eliminated from the population. RESULTS: One hundred ninety-two persons (33%) had a walking disability. This disability was highly associated with poor mobility in daily life, recurrent falls, and poor well-being (all P <.001). Of the common chronic diseases, stroke, angina pectoris, diabetes mellitus, and hip fracture but not arthritis contributed most (PARs from 6% to 15%) to walking disability in the population at large. General impairments had higher prevalence rates and higher PARs than common chronic diseases. Cognitive impairment, depressive symptoms, and dizziness upon rising contributed most (PARs between 22 to 27%) to walking disability. In multivariate regression analyses of all common chronic diseases and general impairments, associations remained significant. CONCLUSION: Within the general oldest-old population, general impairments contribute more substantially to walking disability than do common chronic diseases. The diagnosed diseases did not explain the impairments that led to walking disability. Especially in the oldest old, clinicians should focus not merely on common chronic diseases but particularly on general impairments as targets for diagnostic analysis and treatment to decrease walking disability.