Advanced Glycation End Products and β(2)-Microglobulin as Predictors of Carpal Tunnel Syndrome in Hemodialysis Patients

Background/Aims: Carpal tunnel syndrome (CTS) is a common clinical presentation of dialysis-related amyloidosis. It was determined whether β(2)-microglobulin (β2M) and advanced glycation end products in serum are predictors of CTS in dialysis patients. Methods: A total of 385 hemodialysis patients were screened for CTS. β2M in serum was determined by a competitive enzyme-linked immunoassay, CML by a competitive enzyme-linked immunosorbent assay and total pentosidine by reverse-phase high-performance liquid chromatography. Results: 127 patients (33%) were treated with biocompatible membranes, 174 (45%) with high-flux dialysis. 122 patients (31.7%) had clinical signs of CTS. Significant predictors of CTS were: age, female gender, serum β2M, total protein, dialysis with non-biocompatible high-flux dialysis compared to non-biocompatible low-flux dialysis, Kt/V and serum concentration of CML (OR 2.47 for the 3rd vs. 1st quartile, 95% CI 1.229-4.961, p = 0.011). Conclusion: The prevalence of CTS as a possible manifestation of dialysis-related amyloidosis is still high. Serum concentration of CML may be a predictor of CTS besides β2M and malnutrition.     

Atrial Fibrillation and Heart Failure: Cause or Effect?

Atrial fibrillation (AF) and heart failure (HF) are two epidemics of the century that have a close and complex relationship. The mechanisms underlying this association remain an area of ongoing intense research. In this review, we will describe the relationship between these two public health concerns, the mechanisms that fuel the development and perpetuation of both, and the evolving concepts that may revolutionize our approach to this dual epidemic.     

Hypertension in CKD Pregnancy: a Question of Cause and Effect (Cause or Effect? This Is the Question)

Chronic kidney disease (CKD) is increasingly encountered in pregnancy, and hypertension is frequently concomitant. In pregnancy, the prevalence of CKD is estimated to be about 3 %, while the prevalence of chronic hypertension is about 5–8 %. The prevalence of hypertension and CKD in pregnancy is unknown. Both are independently related to adverse pregnancy outcomes, and the clinical picture merges with pregnancy-induced hypertension and preeclampsia. Precise risk quantification is not available, but risks linked to CKD stage, hypertension, and proteinuria are probably multiplicative, each at least doubling the rates of preterm and early preterm delivery, small for gestational age babies, and related outcomes. Differential diagnosis (based upon utero-placental flows, fetal growth, and supported by serum biomarkers) is important for clinical management. In the absence of guidelines for hypertension in CKD pregnancies, the ideal blood pressure goal has not been established; we support a tailored approach, depending on compliance, baseline control, and CKD stages, with strict blood pressure monitoring. The choice of antihypertensive drugs and the use of diuretics and of erythropoiesis-stimulating agents (ESAs) are still open questions which only future studies may clarify.     

Advanced glycosylation end products (AGE): new toxins?

Advanced glycation end-products (AGEs) are found in excess during diabetes mellitus, uremia and aging. Non enzymatique glycation, glycoxidation with glucose auto-oxidation and the polyol pathway are involved in the production of AGEs. Tissue accumulation of AGEs and their binding to cell receptors are critical steps in the deleterious consequences of AGE excess. AGE-receptor interaction altered endothelial cells, macrophages, mesangial and mesothelial cell functions. AGEs appear to be involved in the genesis of diabetic micro but also macro-angiopathy. Reduction of AGE clearance and permanent oxidative stress are responsible for AGE excess during uremia. High-flux hemodialysis and peritoneal dialysis reduce AGE level but kidney transplantation is the best treatment to restore homeostasis. New drugs are tested to reduce AGEs or AGE deleterious effects but the best treatment remains the prevention of AGE formation by a strict glycemic control.     

Inflammation and C-Reactive Protein in Atrial Fibrillation: Cause or Effect?

Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.     

Contrast-Induced Nephropathy and Long-Term Adverse Events: Cause and Effect?

Background and objectives: The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs.Design, setting, participants, & measurements: We obtained long-term (≥1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a χ² test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions.Results: The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs.Conclusions: The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.Contrast-induced nephropathy (CIN), a form of acute kidney injury (AKI), has received increasing attention in the past few years as a result of new knowledge regarding its pathogenesis, the proliferation of innovative approaches to its prevention, and recognition that CIN is associated with long-term adverse events (AEs) (1–5). The increased incidence of AEs after CIN is derived primarily from retrospective analyses of large databases (2,4,5) or observational studies (3) of patients who have undergone coronary angiography and/or percutaneous coronary intervention. A cause-and-effect relationship cannot be determined from such data. Patients with an increased burden of cardiovascular risk factors before contrast medium exposure may be more likely to develop CIN and independent of the occurrence of CIN have more long-term AEs. Alternatively, the occurrence of CIN may in some as-yet-undefined manner alter the future likelihood of AEs (i.e., CIN is on a pathophysiologic pathway that leads to AEs).Randomized, prospective trial designs provide an opportunity to explore causal relationships. If CIN is causally related to long-term AEs, then a strategy that prevents CIN should reduce long-term AEs, as long as the strategy itself does not alter any other risk factors for those AEs. In a randomized trial of two different treatments, the assumption is that the baseline risk factors for long-term AEs will be equally distributed between the two treatments being tested. Differences in the incidence of CIN between treatments, if paralleled by differences in long-term AEs, would suggest that CIN is on a pathophysiologic pathway that leads to those AEs.The Cardiac Angiography in Renally Impaired Patients (CARE) Study was a large, multicenter, prospective, double-blind, randomized clinical trial of patients who had moderate to severe chronic kidney disease and were undergoing cardiac angiography (6). The primary end point was the incidence of CIN. Patients were randomly assigned to two different treatments represented by two different contrast media: The low-osmolar, nonionic monomer iopamidol (Isovue; Bracco Diagnostics Inc., Princeton, NJ) and the iso-osmolar, nonionic dimer iodixanol (Visipaque; GE Healthcare, Princeton, NJ). Neither contrast medium has any known effect on the baseline risk factors that might contribute to long-term AEs. In this report, follow-up data were collected on 294 of the original participants of the CARE trial approximately 12 mo after entry into the trial. To explore whether a causal link exists between CIN and long-term AEs, we studied the differences in the incidence of CIN and long-term AEs between the two treatments (contrast media). Since the results of the CARE study were published, new definitions of AKI and thus CIN have been suggested (7). These new definitions increase the incidence of CIN and thus enhance the statistical power to detect associations with long-term outcomes.     

Late Drug-eluting Stent Thrombosis and Erythropoietin: Cause and Effect?

A case of late thrombosis of a sirolimus-eluting stent, 16 months after implantation, is described. Two weeks prior to presentation with stent thrombosis the patient had a 50% dose increase of longterm erythropoietin. The prothrombotic effect of erythropoietin may have precipitated the thrombotic event.     

Autoantibodies and Cardiovascular Dysfunction: Cause or Consequence?

There has been a long history of the exploration into autoimmunity as a possible pathogenic factor of cardiovascular diseases from unknown cause represented by dilated cardiomyopathy (DCM). Autoantibodies (AAbs) have emerged either as humoral responses provoked by the release of “self-antigens” due to tissue damage or dysregulated humoral immunity itself. The pathogenic roles of some AAbs have been suggested by the findings from basic research using in vitro and in vivo disease models as well as clinical studies including immunoadsorption studies removing AAbs from patients with DCM. In this context, the importance of AAbs belonging to IgG3 subclass has also been implicated. In this review article, we summarize the findings accumulated to date regarding AAbs which have been considered to be involved in the pathology of DCM or pregnancy-related cardiovascular disease. Furthermore, we discuss the significance of AAbs as a possible cause of DCM and their potential roles as a novel therapeutic target.     

Diabetes: Statins, fibrates, or both?

Cardiovascular disease is the leading cause of mortality in patients with type 2 diabetes. Among the many factors that are involved in the pathogenesis of atherosclerosis in diabetic patients, dyslipidemia plays a major role. It is characterized by an increase in triglycerides, a decrease in high-density lipoprotein cholesterol and normal or mildly elevated low-density lipoprotein cholesterol. The management of patients with diabetic dyslipidemia is difficult because we lack studies specifically designed for diabetic patients. Thus, strategy has to rely on post hoc analyses of landmark intervention trials, which usually include only a small number of diabetic patients, or on rare trials enrolling small cohorts of diabetic patients. When lifestyle changes fail, monotherapy should be tried first with either a statin or a fibrate, depending on triglyceride level. If lipid target values are not reached, a combination therapy can then be initiated, with close follow-up of potential side effects.