Renal AA-amyloidosis in intravenous drug users - a role for HIV-infection?

Background: Chronic renal disease is a serious complication of long-term intravenous drug use (IVDU). Recent reports have postulated a changing pattern of underlying nephropathy over the last decades. Methods: Retrospective investigation including all patients with prior or present IVDU that underwent renal biopsy because of chronic kidney disease between 01.04.2002 and 31.03.2012 in the city of Frankfurt/Main, Germany. Results: Twenty four patients with IVDU underwent renal biopsy because of progressive chronic kidney disease or proteinuria. Renal AA-amyloidosis was the predominant cause of renal failure in 50% of patients. Membranoproliferative glomerulonephritis (GN) was the second most common cause found in 21%. Patients with AA-amyloidosis were more likely to be HIV infected (67 vs.17%; p=0.036) and tended to have a higher rate of repeated systemic infections (92 vs. 50%; p=0.069). Patients with AA-amyloidosis presented with progressive renal disease and nephrotic-range proteinuria but most patients had no peripheral edema or systemic hypertension. Development of proteinuria preceded the decline of GFR for approximately 1--2 years. Conclusions: AA-amyloidosis was the predominant cause of progressive renal disease in the last 10 years in patients with IVDU. The highest rate of AA-amyloidosis observed was seen in HIV infected patients with IVDU. We speculate that chronic HIV-infection as well as the associated immunosuppression might promote development of AA-amyloidosis by increasing frequency and duration of infections acquired by IVDU

Epidemiological trends in mortality, event rates and case fatality of acute myocardial infarction from 2004 to 2015: results from the KORA MI registry

AIM: This study examines epidemiological trends of acute myocardial infarction (AMI) in Germany from 2004–2015 across different age groups, using data of the population-based KORA myocardial infarction registry. METHODS: Annual age-standardised, age-group- and sex-specific mortality and event rates (incident and recurrent) per 100,000 population as well as 28-day case fatality were calculated from all registered cases of AMI and coronary heart disease deaths in 25–74-year-olds from 2004–2015 and 75–84-year-olds from 2009–2015. Average annual percentage changes (AAPC) were calculated by joinpoint regression. RESULTS: Mortality rates declined considerably among the elderly (75–84 years), in men by –6.0% annually, due to declines of case fatality by –3.0% and incidence rate by 3.4% and in women by –10.0%, driven by declines in incidence (–9.1%) and recurrence rate (–4.9%). Significant mortality declines also occurred in males, 65–74 years of age (AAPC –3.8%). Among the age groups 25–54 years and 55–64 years, there was no substantial decline in mortality, event rates or case fatality except for a decline of incidence rate in 55–64-year-old men (AAPC –1.8%). CONCLUSION: Inhomogeneous AMI trends across age-groups indicate progress in prevention and treatment for the population >64 years, while among <55-year-olds, we found no significant trend in AMI morbidity and mortality. KEY MESSAGES: Age standardised AMI mortality continued to decline from 2009 to 2015 in the study region. Declines in AMI mortality were driven by declines in event rates (both incidence and recurrence rates) and case fatality. AMI trends were inconsistent across different age groups with the strongest declines in mortality and event rates among the elderly population (75–84 years of age)

Association of obesity and long-term mortality in patients with acute myocardial infarction with and without diabetes mellitus: results from the MONICA/KORA myocardial infarction registry

Background Paradoxically, beneficial effects of overweight and obesity on survival have been found in patients after cardiovascular events such as acute myocardial infarction (AMI). This obesity paradox has not been analyzed in AMI patients with diabetes even though their cardiovascular morbidity and mortality is increased compared to their counterparts without diabetes. Therefore, the objective of this long-term study was to analyze the association between body mass index (BMI) and all-cause mortality in AMI patients with and without diabetes mellitus. Methods Included in the study were 1190 patients with and 2864 patients without diabetes, aged 28-74 years, recruited from a German population-based AMI registry. Patients were consecutively hospitalized between 1 January 2000 and 31 December 2008 with a first ever AMI and followed up until December 2011. Data collection comprised standardized interviews and chart reviews. To assess the association between BMI and long-term mortality from all causes, Cox proportional hazards models were calculated adjusted for risk factors, co-morbidities, clinical characteristics, in-hospital complications as well as medical and drug treatment. Results AMI patients of normal weight (BMI 18.5-24.9 kg/m2) had the highest long-term mortality rate both in patients with and without diabetes with 50 deaths per 1000 person years and 26 deaths per 1000 person years, respectively. After adjusting for a selection of covariates, a significant, protective effect of overweight and obesity on all-cause mortality was found in AMI patients without diabetes (overweight: hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.58-0.93; p=0.009; obesity: HR 0.64, 95% CI 0.47-0.87; p=0.004). In contrast, an obesity paradox was not found in AMI patients with diabetes. However, stratified analyses showed survival benefits in overweight AMI patients with diabetes who had been prescribed statins prior to AMI (HR 0.51, 95% CI 0.29-0.89, p=0.018) or four evidence-based medications at hospital-discharge (HR 0.52, 95% CI 0.34-0.80, p=0.003). Conclusion In contrast to AMI patients without diabetes, AMI patients with diabetes do not experience a survival benefit from an elevated BMI. To investigate the underlying reasons for these findings, further studies stratifying their samples by diabetes status are needed. &nbsp

CXCL16 and oxLDL are induced in the onset of diabetic nephropathy

Diabetic nephropathy (DN) is a major cause of end-stage renal failure worldwide. Oxidative stress has been reported to be a major culprit of the disease and increased oxidized low density lipoprotein (oxLDL) immune complexes were found in patients with DN. In this study we present evidence, that CXCL16 is the main receptor in human podocytes mediating the uptake of oxLDL. In contrast, in primary tubular cells CD36 was mainly involved in the uptake of oxLDL. We further demonstrate that oxLDL down-regulated α3-integrin expression and increased the production of fibronectin in human podocytes. In addition, oxLDL uptake induced the production of reactive oxygen species (ROS) in human podocytes. Inhibition of oxLDL uptake by CXCL16 blocking antibodies abrogated the fibronectin and ROS production and restored α3 integrin expression in human podocytes. Furthermore we present evidence that hyperglycaemic conditions increased CXCL16 and reduced ADAM10 expression in podocytes. Importantly, in streptozotocin-induced diabetic mice an early induction of CXCL16 was accompanied by higher levels of oxLDL. Finally immunofluorescence analysis in biopsies of patients with DN revealed increased glomerular CXCL16 expression, which was paralleled by high levels of oxLDL. In summary, regulation of CXCL16, ADAM10 and oxLDL expression may be an early event in the onset of DN and therefore all three proteins may represent potential new targets for diagnosis and therapeutic intervention in DN

Emulating a target trial of proton pump inhibitors and dementia risk using claims data

Background and purpose Understanding the adverse effects of proton pump inhibitors (PPIs) is important due to their widespread use, but the available evidence for an increased dementia risk amongst patients taking PPIs is inconclusive. The present study aimed to estimate the causal effect of PPIs on the risk of dementia by target trial emulation and time-varying exposure modeling. Methods Using claims data of 2,698,176 insured people of a large German statutory health insurer, a target trial was conceptualized in which individuals aged 40 years and older were classified as PPI initiators or non-initiators between 2008 and 2018, and were followed until diagnosis of dementia, death, loss to follow-up or end of study. Incidence of dementia (International Classification of Diseases 10 codes F00, F01, F03, F05.1, G30, G31.0, G31.1, G31.9 and F02.8+G31.82) was defined applying a 1-year lag window. Weighted Cox models were used to estimate the effect of PPI initiation versus non-initiation on dementia risk and weighted pooled logistic regression was used to estimate the effect of time-varying use versus non-use. Results In all, 29,746 PPI initiators (4.4%) and 26,830 non-initiators (1.3%) were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio for dementia was 1.54 (95% confidence interval 1.51-1.58). The hazard ratio for time-dependent PPI use versus non-use was 1.56 (95% confidence interval 1.50-1.63). Differentiated subtypes, including unspecified dementia, Alzheimer's disease and vascular dementia, showed increased risk by PPI initiation and time-varying PPI use. Conclusions This study suggests that PPI initiation and time-varying PPI use may increase overall dementia risk

Association of sleep disturbances within 4weeks prior to incident acute myocardial infarction and long-term survival in male and female patients: an observational study from the MONICA/KORA Myocardial Infarction Registry

Background: Sleep-related investigations in acute myocardial infarction (AMI) patients are rare. The aim of this study was to examine sex-specific associations of patient-reported sleep disturbances within 4weeks before AMI and long-term survival. Methods: From a German population-based, regional AMI registry, 2511 men and 828 women, aged 28-74years, hospitalized with a first-time AMI between 2000 and 2008 and still alive after 28days, were included in the study (end of follow-up: 12/2011). Frequency of any sleep disturbances within 4weeks before AMI was inquired by a 6-categorical item summarized to never', sometimes' and nightly'. Cox regression models were calculated.Results: Over the median follow-up time of 6.1years (IQR: 4.1) sleep disturbances were reported by 32.3% of male and 48.4% of female patients. During the observation period, 318 men (12.7%) and 131 women (15.8%) died. Men who sometimes' had sleep disturbances showed a 56% increased mortality risk compared to those without complaints in an age-adjusted model (HR 1.56;95%-CI 1.21-2.00). Additional adjustment for confounding variables attenuated the effect to 1.40 (95%-CI 1.08-1.81). Corresponding HRs among women were 0.97 (95%-CI 0.65-1.44) and 0.99 (95%-CI 0.66-1.49). HRs for patients with nightly sleep disturbances did not suggest any association for both sexes. Conclusions: Our study found that nightly sleep disturbances have no influence on long-term survival in male and female AMI patients. Contrary to women, men who reported sometimes sleep disturbances had a higher mortality. Further investigations on this topic taking into account the role of obstructive sleep apnoea are needed

Helicobacter pylori Seropositivity: Prevalence, Associations, and the Impact on Incident Metabolic Diseases/Risk Factors in the Population-Based KORA Study

Introduction:Helicobacter pylori (H. pylori) is a common infection and known risk factor for gastric cancer. We assessed cross-sectional and longitudinal associations to study the impact of H. pylori seropositivity on metabolic diseases.Methods:Helicobacter pylori seropositivity in serum samples of the KORA study was analyzed by multiplex serology. We calculated sex-specific prevalence of H. pylori seropositivity for the year 2007 based on the first follow-up survey (termed F4) of the KORA study S4. We identified factors associated with H. pylori seropositivity in the F4 survey. Further, we assessed relative risks of incident metabolic diseases/risk factors at the time of the second follow-up survey of S4 (termed FF4) and H. pylori seropositivity at the F4 survey as a determinant. Models were adjusted for age, sex, overweight status, physical activity, smoking status, education level, alcohol intake, and other metabolic diseases.Results: Based on 3,037 persons aged 32 to 82 years, the H. pylori prevalence for 2007 was 30.2% in men (n = 1,465) and 28.1% in women (n = 1,572). Increasing age, current smoking, low education and no alcohol intake were significantly associated with H. pylori seropositivity in the F4 survey. However, no association between H. pylori seropositivity and BMI, metabolic diseases (type 2 diabetes, hypertension and dyslipidemia, gout or increased uric acid) and gastrointestinal diseases (gastritis, inflammatory bowel disease, and gastric or duodenal ulcer) was observed. No significant associations between H. pylori seropositivity and one of the five investigated incident metabolic diseases/risk factors were detected in the longitudinal analysis.Conclusion: We identified associations between age, smoking, education and alcohol intake and H. pylori seropositivity but no impact of H. pylori seropositivity on incident metabolic diseases/risk factors

Lack of association between proton pump inhibitor use and brain aging: a cross-sectional study

PURPOSE Due to conflicting scientific evidence for an increased risk of dementia by intake of proton pump inhibitors (PPIs), this study investigates associations between PPI use and brain volumes, estimated brain age, and cognitive function in the general population. METHODS Two surveys of the population-based Study of Health in Pomerania (SHIP) conducted in Northeast Germany were used. In total, 2653 participants underwent brain magnetic resonance imaging (MRI) and were included in the primary analysis. They were divided into two groups according to their PPI intake and compared with regard to their brain volumes (gray matter, white matter, total brain, and hippocampus) and estimated brain age. Multiple regression was used to adjust for confounding factors. Cognitive function was evaluated by the Verbal Learning and Memory Test (VLMT) and the Nuremberg Age Inventory (NAI) and put in relation to PPI use. RESULTS No association was found between PPI use and brain volumes or the estimated brain age. The VLMT score was 1.11 lower (95% confidence interval: - 2.06 to - 0.16) in immediate recall, and 0.72 lower (95% CI: - 1.22 to - 0.22) in delayed recall in PPI users than in non-users. PPI use was unrelated to the NAI score. CONCLUSIONS The present study does not support a relationship between PPI use and brain aging