Obesity in chronic kidney disease: good or bad?

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in chronic kidney disease (CKD) patients. As traditional risk factors cannot alone explain the high prevalence and incidence of CVD in this high-risk population, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as important non-traditional risk factors. Recent studies show that the adipose tissue is a complex organ with functions far beyond the mere storage of energy. Indeed, it has recently been shown that fat tissue secretes a number of adipokines - including leptin, adiponectin and retinol-binding protein, as well as cytokines such as resistin, visfatin, tumor necrosis factor and interleukin-6. Adipokine serum levels are furthermore markedly elevated in CKD, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and putatively CVD. As fat tissue is also a storage depot for energy, much needed in the catabolic milieu of uremia, further research is still needed to elucidate the likely complex interactions between these signaling networks, vascular health and outcome in this high-risk population.     

Severe community-acquired pneumonia: what's in a name?

PURPOSE OF REVIEW: Formerly, patients with community-acquired pneumonia admitted to an intensive care unit were considered as having the severe form of the disease. Recently, guidelines have distinguished severe and non-severe community-acquired pneumonia based on clinical definitions. In this review, we describe the different definitions of severe community-acquired pneumonia, and whether a differentiation based on these definitions reflects variation in etiology, risk factors, diagnostic approaches and treatment. RECENT FINDINGS: New definitions do not seem to accurately identify patients with high risks of mortality; patients not admitted to an intensive care unit could also be diagnosed as having severe community-acquired pneumonia. Host-factors, such as genetic factors and underlying diseases, can influence severity of presentation of community-acquired pneumonia. Distribution of pathogens in severe and non-severe disease forms is comparable. Initial antibiotic therapy in patients with severe disease should provide coverage of Streptococcus pneumoniae and Legionella pneumophila, as delay is associated with worse outcomes. However, recent studies also suggested an additional benefit of atypical coverage in non-severe disease. As a result, initial therapy with a beta-lactam plus a macrolide or an anti-pneumococcal fluoroquinolone is recommended for all patients with community-acquired pneumonia. Furthermore, the value of vaccination against pneumococci to prevent episodes of severe disease is yet unknown. SUMMARY: As current guidelines do not adequately identify patients with high risk of mortality and intensive care unit admittance, clinical judgment remains important. Based on distribution of pathogens, investigational procedures and therapy recommended in recent guidelines, differentiation between severe and non-severe community-acquired pneumonia does not seem useful. Whether atypical coverage indeed has additional value in non-severe or pneumococcal CAP, however, remains to be determined. In addition, the preventive benefit of influenza and pneumococcal vaccination for development of SCAP awaits further evidence.     

Steatosis in chronic hepatitis C: why does it really matter?

Hepatic steatosis is a common histological feature of chronic hepatitis C. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, diabetes type II, and hyperlipidaemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In humans, hepatitis C virus (HCV) genotype 3 is more commonly associated with steatosis. In vitro studies and the transgenic mouse model have suggested that the HCV core protein (genotype 1) can induce lipid accumulation within hepatocytes. However, what is the relevance of steatosis in chronic hepatitis C? It seems that in certain populations, steatosis may be associated with fibrosis progression and this may be genotype specific. The mechanisms underlying this association are unknown; neither is it clear whether this holds true for all patients or only a subgroup. Indeed, after antiviral treatment, virus related steatosis disappears whereas the host associated steatosis remains unaffected. This review describes and discusses the basic and clinical aspects of the relationship between steatosis and progression of fibrosis, and response to treatment in patients with chronic hepatitis C.     

Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: Cause or association?

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease (CVD); a graded inverse relationship between estimated glomerular filtration rate (eGFR) and cardiovascular event rates has emerged from large-scale observational studies. Chronic kidney disease is also associated with endothelial dysfunction (ED) although the precise relationship with GFR and the "threshold" at which ED begins are contentious. Abnormal endothelial function is certainly present in late-stage CKD but data in early-stage CKD appear confounded by disease states such as diabetes and hypertension which themselves promote ED. Thus, the direct effect of a reduction in GFR on endothelial function and, therefore, cardiovascular (CV) risk is far from completely established. In human studies, the precise duration of kidney impairment is seldom known and the onset of CVD often insidious, making it difficult to determine exactly when CVD first appears in the context of CKD. Kidney donors provide a near-ideal experimental model of CKD; subjects undergo an acute change from normal to modestly impaired renal function at the time of nephrectomy and lack the confounding co-morbidity that has made observational studies of CKD patients so challenging to interpret. By examining changes in endothelial function in living kidney donors before and after nephrectomy, useful insight might be gained into the pathophysiology of CVD in CKD and help determine whether targeting ED or the renal disease itself has the potential to reduce CV risk.     

Where does albuminuria come from in diabetic kidney disease?

The classic mechanism to explain albumin excretion in diabetes has been permeability defects in the glomerular filter. However, a new concept has emerged that albuminuria can be explained by the two major pathways the proximal tubular cell uses to process filtered albumin. Specifically, albumin permeability through the glomerular filter is only governed by size selectivity. Most of the filtered albumin is retrieved by the proximal tubular cell and returned to the peritubular blood supply. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-β1, whose production is stimulated by hyperglycemic environments. Dysfunction in this degradation pathway may lead to albuminuria below the nephrotic range.     

Cytokine dysregulation in chronic kidney disease: how can we treat it?

As the kidney is the major site for elimination of many cytokines, the delicate equilibrium of pro-inflammatory cytokines and their inhibitors is clearly dysregulated in chronic kidney disease (CKD) patients. The consequences of the altered immune response in uremia lead to a state of persistent inflammation which is highly prevalent among CKD patients and is linked to complications such as the development of protein-energy wasting and atherosclerotic vascular disease. The present review aims at reviewing this complex orchestration of uremic cytokines beyond the well-studied interleukin-6 and tumor necrosis factor-alpha. Finally, we update our current understanding on anti-inflammatory treatment strategies in CKD patients, including nutritional and lifestyle measurements, pharmacological intervention and specific anticytokine strategies targeting the dialytic procedure.     

Obesity--the risk factor of cardiovascular disease in patients with chronic kidney disease?

In general population obesity is regarded as a predisposing factor for chronic disease such as type 2 diabetes and cardiovascular disease. Obesity increases the risk of kidney disease and adversely affects the progress of kidney disease among patients with diagnosed kidney disease. The main reason of mortality in chronic kidney disease patients is cardiovascular disease, however, the real meaning of obesity as a risk factor of cardiovascular diseases is still uncertain. While in a general population obesity causes higher cardiovascular mortality, many studies reflect inverse association in chronic kidney disease patients. Obesity is associated with better survival, contrary to general population obesity appears to be a protective factor of cardiovascular disease. The name of this phenomenon is "reverse epidemiology" or "obesity paradox", in dialysis patients known as a "risk-factor-paradox". Some studies do not confirm this paradox association in patients with chronic kidney disease.     

Telomeres and cardiovascular disease: does size matter?

Telomeres-the specialized DNA-protein structures at the ends of eukaryotic chromosomes-are essential for maintaining genome stability and integrity and for extended proliferative life span in both cultured cells and in the whole organism. Telomerase and additional telomere-associated proteins are necessary for preserving telomeric DNA length. Age-dependent telomere shortening in most somatic cells, including vascular endothelial cells, smooth muscle cells, and cardiomyocytes, is thought to impair cellular function and viability of the aged organism. Telomere dysfunction is emerging as an important factor in the pathogenesis of hypertension, atherosclerosis, and heart failure. In this Review, we discuss present studies on telomeres and telomere-associated proteins in cardiovascular pathobiology and their implications for therapeutics.     

Administration of first hospital antibiotics for community-acquired pneumonia: does timeliness affect outcomes?

PURPOSE OF REVIEW: Associations between processes of care for hospitalized community-acquired pneumonia patients and clinical outcomes are important because of the high incidence of such admissions and substantial related mortality. Several studies have examined these associations. RECENT FINDINGS: Large retrospective studies of older patients have demonstrated associations between time to first dose as short as 4 h and length of stay and mortality during and after hospitalization. Results of smaller studies have been less consistent. The association appears to be strongest among older patients who have not received antibiotics prior to arrival at the hospital. SUMMARY: A significant and causal relationship appears to exist between antibiotic timing and improved outcomes, especially among older patients. Even modest improvements in timeliness of antibiotic administration could impact a substantial number of lives because of the high incidence of community-acquired pneumonia hospitalization.     

Does treating obesity stabilize chronic kidney disease?

Background

Much epidemiological evidence suggests that hydrocarbon exposure may induce glomerulonephritis and worsen its course in many patients. The mechanisms are unknown, however, no specific microscopic pattern has been identified, and it has also been argued that hydrocarbon exposure causes tubular damage mainly. Studying experimental animals may best answer these questions, and as no systematic review of glomerulonephritis produced experimentally by hydrocarbon exposure has been performed previously, I found it relevant to search for and analyse such studies.

Methods

Animal experiments having mimicked human glomerulonephritis by hydrocarbon exposure were sought on Medline and Toxnet

Results

Twenty-six experiments using thirteen different hydrocarbons were identified. Several human subtypes were observed including IgA nephritis, mesangial, proliferative and extracapillary glomerulonephritis, focal and focal-segmental sclerosis, minimal change nephropathy, anti-GBM and anti-TBM nephritis, and glomerulonephritis associated with peiarteritis nodosa. Glomerular proteinuria was seen in 10/12 experiments that included urine analyses, and renal failure in 5/8 experiments that included measurements of glomerular function. All experiments resulted in various degrees of tubular damage as well. In most studies, where the animals were examined at different times during or after the exposure, the renal microscopic and functional changes were seen immediately, whereas deposits of complement and immunoglobulins appeared late in the course, if at all.

Conclusion

These experiments are in accord with epidemiological evidence that hydrocarbon exposure may cause glomerulonephritis and worsen renal function. Probable mechanisms include an induction of autologous antibodies and a disturbance of normal immunological functions. Also, tubular damage may increase postglomerular resistance, resulting in a glomerular deposition of macromolecules. In most models a causal role of glomerular immune complex formation was unlikely, but may rather have been a secondary phenomenon. As most glomerulonephritis subgroups were seen and as some of the hydrocarbons produced more than one subgroup, the microscopic findings in a patient cannot be used as a clue to the causation of his disease. By the same reason, the lack of a specific histological pattern in patients with glomerulonephritis assumed to have been caused by hydrocarbon exposure is not contradictive.