Chronic inflammation in end-stage renal disease and dialysis.

Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as chronic kidney disease, inflammation becomes maladaptive, uncontrolled and persistent. Systemic persistent inflammation has, for almost 20 years, been recognized as a major contributor to the uraemic phenotype (such as cardiovascular disease, protein energy wasting, depression, osteoporosis and frailty), and a predictor of cardiovascular and total mortality. Since inflammation is mechanistically related to several ageing processes (inflammageing), it may be a major driver of a progeric phenotype in the uraemic milieu. Inflammation is likely the consequence of a multifactorial aetiology and interacts with a number of factors that emerge when uraemic toxins accumulate. Beside interventions aiming to decrease the production of inflammatory molecules in the uraemic milieu, novel strategies to increase the removal of large middle molecules, such as expanded haemodialysis, may be an opportunity to decrease the inflammatory allostatic load associated with retention of middle molecular weight uraemic toxins.

Visceral Adipose Tissue and Leptin Hyperproduction Are Associated With Hypogonadism in Men With Chronic Kidney Disease.

OBJECTIVE: Hypogonadism is a common endocrine disorder in men with chronic kidney disease (CKD), but its pathophysiology is poorly understood. We here explore the plausible contribution of abdominal adiposity and leptin hyperproduction to testosterone deficiency in this patient population. DESIGN: Cross-sectional analysis with all men included the Malnutrition, Inflammation and Vascular Calcification cohort, which enrolled consecutive nondialyzed patients with CKD stages 3-5. SUBJECTS: A total of 172 men with CKD stages 3-5 nondialysis (median age 61 [45-75] years, median glomerular filtration rate 24 [9-45] mL/min/1.73 m2). In them, serum levels of total testosterone, estrogen, sex hormone binding globulin, and leptin were quantified, together with visceral adipose tissue (VAT) by thoracic and abdominal CT scan. INTERVENTION: None, observational study. MAIN OUTCOME MEASURE: Total testosterone, hypogonadism. RESULTS: The median level of total testosterone was 11.7 (7.3-18.4) nmol/L, with hypogonadism (<10 nmol/L) present in 52 (30%) patients. Testosterone-deficient patients presented with significantly higher body mass index, waist circumference, and VAT. An inverse correlation between testosterone and VAT (rho = -0.25, P = .001) or waist circumference (rho = -0.20, P = .008) was found, also after multivariate adjustment including sex hormone binding globulin and estrogen. Total testosterone was inversely correlated with serum leptin (rho = -0.22, P = .003), and the ratio of leptin/VAT, an index of leptin hyperproduction, was strongly and independently associated with the prevalence of hypogonadism in multivariable regression analyses. CONCLUSION: Visceral adiposity independently associated with lower testosterone levels among men with CKD stage 3-5 nondialysis. The observed link between hyperleptinemia and hypogonadism is in line with previous evidence on direct effects of leptin on testosterone production.

Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis.

Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications.

C-reactive Protein: Repeated Measurements will Improve Dialysis Patient Care.

Systemic inflammation is a common feature in the uremic phenotype and associates with poor outcomes. The awareness regarding the importance of inflammation assessment in chronic kidney disease (CKD) patients has risen in recent years, and despite the development of novel biomarkers, C-reactive protein (CRP) is still the most measured inflammatory parameter. Notwithstanding, the possible weak points of CRP determination, this biomarker has demonstrated being useful both for guidance in clinical practice and for risk estimation. In addition, regular determination of CRP among dialysis patients has been associated with better outcomes in different dialysis facilities. Because persistent inflammation may be a silent reflection of various pathophysiologic alterations in CKD, it is crucial that inflammatory markers are regularly monitored and therapeutic attempts be made to target this inflammation.

Glomerulonephritis and cryoglobulinemia: first manifestation of visceral leishmaniasis.

Visceral leishmaniasis due to Leishmania Infantum is an endemic parasitic infection in the Mediterranean area. Since 2009, Europe's largest outbreak of Leishmaniasis has been reported in the region of Madrid (Spain). Renal involvement is an unusual complication. Different forms of renal disease have been described: interstitial, glomerular, and vascular damage. Direct invasion of renal parenchyma by the parasite has been described as a mechanism of kidney damage, especially in the immunocompromised. Immune complex deposition and T cells adhesion molecules activation have demonstrated that a pathogenic role in glomerulonephritis related to visceral leishmaniasis. The association between mixed cryoglobulinemia and visceral leishmaniasis has been previously reported in six patients. Renal involvement is only described in one of them. From July 2009 to October 2012, 4 patients with membranoproliferative glomerulonephritis and mixed cryoglobulinemia with negative serology for hepatitis B and C were diagnosed in our hospital. Serology of Leishmania in serum bank samples was performed; it was positive in 3 patients. Leishmania parasite was confirmed by other tests. We present 3 patients with mixed cryoglobulinemia and membranoproliferative glomerulonephritis as first clinical manifestation of visceral leishmaniasis.

Geriatric assessment for therapeutic decision-making regarding renal replacement in elderly patients with advanced chronic kidney disease.

UNLABELLED: In patients older than 75 years with advanced chronic kidney disease (CKD), the decision between treatment with dialysis [intention to treat with dialysis (ITD)] or conservative care (CC) is a challenge. Geriatric assessment can be helpful. The aim was to identify which factors had had an influence on decision-making. METHODS: We recruited 56 patients. At baseline we analyzed age, frailty (defined following the criteria of Fried et al. [J Gerontol A Biol Sci Med Sci 2001;56:146-156]), dependence for activities of daily living (ADL), cognitive impairment, depression, comorbidity, cardiovascular disease, and diabetes. After full information about prognosis and treatment options, the preferences of the patients and families were taken into consideration as determinants in the decision-making process. During the follow-up, we evaluated clinical and laboratory parameters, hospitalization, mortality and reevaluated frailty. RESULTS: Twenty patients opted for CC, and 36 patients opted for ITD. On univariate analysis, the predictive factors of the election of CC were age, prefrailty, cognitive impairment, and dependence for ADL. In the multivariate analysis, age and prefrailty remained as predictors for the choice of CC. Hospitalizations were more frequent in CC. Survival was similar in both groups (p = 0.098). CONCLUSIONS: Frailty assessment could be useful for decision-making about the treatment in elderly patients with CKD. CC may be a good treatment option.

Lower plasma sodium is associated with a microinflammatory state among patients with advanced chronic kidney disease.

BACKGROUND/AIMS: Lower serum sodium levels have been associated with increased mortality among patients with chronic kidney disease (CKD). Our aim was to analyze the independent factors associated with lower sodium levels among nondialysis patients with advanced CKD and to evaluate the evolution of these patients in comparison to those with higher plasma sodium over a 1-year period. METHODS: We included 72 patients with CKD stages 4 and 5 without clinically evident cardiopathy or liver disease. Bioelectrical impedance and echocardiography were performed to analyze the possible relation between plasma sodium and volume status and subclinical left ventricular (LV) dysfunction. During follow-up, we compared the evolution of patients with lower baseline plasma sodium (low quartile: <138 mEq/l) with that of patients with higher levels over a 1-year period. RESULTS: At baseline, the independent predictors of lower plasma sodium were C-reactive protein (CRP; OR 0.96; 95% CI 0.91-0.99) and body mass index (OR 0.89; 95% CI 0.78-0.99). An inverse correlation between plasma sodium and CRP was observed (r = -0.32; p = 0.01). Plasma sodium did not correlate with extracellular water and was not different between patients with or without echocardiographic data of LV dysfunction (p = 0.7). During follow-up, patients with lower sodium at baseline showed persistently lower sodium values (p = 0.04), higher CRP (p = 0.05), lower serum albumin (p < 0.01) and higher erythropoietin-stimulating agent resistance index (p = 0.05). CONCLUSIONS: Our results suggest an association between lower plasma sodium and a microinflammatory state among patients with advanced CKD. Inflammation could be an underlying confounding factor explaining the increased mortality in these patients.

Role of Uremic Toxins in Early Vascular Ageing and Calcification.

In patients with advanced chronic kidney disease (CKD), the accumulation of uremic toxins, caused by a combination of decreased excretion secondary to reduced kidney function and increased generation secondary to aberrant expression of metabolite genes, interferes with different biological functions of cells and organs, contributing to a state of chronic inflammation and other adverse biologic effects that may cause tissue damage. Several uremic toxins have been implicated in severe vascular smooth muscle cells (VSMCs) changes and other alterations leading to vascular calcification (VC) and early vascular ageing (EVA). The above mentioned are predominant clinical features of patients with CKD, contributing to their exceptionally high cardiovascular mortality. Herein, we present an update on pathophysiological processes and mediators underlying VC and EVA induced by uremic toxins. Moreover, we discuss their clinical impact, and possible therapeutic targets aiming at preventing or ameliorating the harmful effects of uremic toxins on the vasculature.

Inflammation and Protein-Energy Wasting in the Uremic Milieu.

Inflammation is normally a protective and physiological response to harmful stimuli, but typically becomes an uncontrolled, maladaptive, and persistent process in patients with end-stage renal disease (ESRD). Through a deleterious cascade of poorly controlled reactions mediated by biologically active molecules (also called middle molecular weight uremia retention solutes), inflammation associates with a range of complications including cardiovascular disease and protein-energy wasting (PEW). Persistent inflammation, which is central to the conceptual etiological models of PEW and the malnutrition, inflammation, and atherosclerosis syndrome, induces and reignites processes leading to PEW in a number of ways including stimulation of both direct and indirect mechanisms of muscle proteolysis. Similar to other chronic diseases, inflammation in the uremic milieu is the consequence of multiple factors including comorbidities, such as infections. In addition, inflammation is further aggravated in ESRD by uremic immune dysfunction, inadequate renal removal of cytokines, and inflammatory responses to dialysis. It is plausible that only by disrupting this vicious circle(s) by acting on several levels of the inflammatory cascade rather than targeting single causes of inflammation will it be possible to improve the prognosis in ESRD patients. Accordingly, treatment of uremic inflammation and PEW require an integrated approach. In addition to lifestyle modifications, nutritional supplements, and drugs with anti-inflammatory potential, improved dialysis therapy using high retention onset membranes has emerged recently. This novel dialysis technique, also called expanded hemodialysis (HDx), may provide a more efficient removal of middle molecules involved in the cascade of inflammatory mediators with selectivity against albumin losses. Plausibly, the implementation of HDx, integrated with strategies blocking an excessive secretion of inflammatory mediators, may offer a new therapeutic approach to chronic inflammation and PEW in ESRD.

Hypogonadism associated with muscle atrophy, physical inactivity and ESA hyporesponsiveness in men undergoing haemodialysis.

BACKGROUND: Testosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA). METHODS: Single-center cross-sectional study of 57 male haemodialysis patients. None of the patients was undergoing testosterone replacement therapy. Total testosterone was measured in serum. Body composition (by bioelectrical impedance analysis) and physical activity (by the use of pedometers) were assessed. Patients with testosterone levels below the normal range were considered hypogonadal. RESULTS: Mean testosterone level was 321±146ng/dL; 20 patients (35%) were hypogonadal. Hypogonadal patients were older and had lower mean arterial blood pressure, higher interleukin-6 levels, lower lean body mass and higher fat body mass. A negative association between testosterone and normalized ESA dose was found in uni- and multivariate regression analyses. Testosterone levels directly correlated with lean body mass regardless of confounders. Hypogonadal patients had lower physical activity than their counterparts [2753±1784 vs. 4291±3225steps/day (p=0.04)]. The relationship between testosterone and physical activity was independent of age, comorbidities and inflammatory markers, but dependent on the proportion of muscle mass. CONCLUSION: Hypogonadism is common in our male haemodialysis population and is associated with higher ESA doses, reduced muscle mass and lower physical activity. The link between low testosterone levels and physical inactivity may conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis.

Echocardiographic findings in haemodialysis patients according to their state of hydration.

BACKGROUND: Chronic fluid overload is frequent in hemodialysis patients (P) and it associates with hypertension, left ventricular hypertrophy (LVH) and higher mortality. Moreover, echocardiographic data assessing fluid overload is limited. Our aim was to evaluate the relationship between fluid overload measured by bioimpedance spectroscopy (BIS) and different echocardiographic parameters. METHODS: Cross-sectional observational study including 76 stable patients. Dry weight was clinically assessed. BIS and echocardiography were performed. Weekly time-averaged fluid overload (TAFO) and relative fluid overload (FO/ECW) were calculated using BIS measurements. RESULTS: Based on TAFO three groups were defined: A- dehydrated, TAFO <-0.25 L 32 P (42%); B- normohydrated, TAFO between -0.25 and 1.5 l: 26 (34%); C- overhydrated, TAFO>1.5 l: 18 (24%). We found significant correlation between TAFO and left atrial volume index (LAVI) (r: 0.29; p=0.013) but not with FO/ECW (r 0.06; p=0.61). TAFO, but not FO/ECW kept a significant relationship with LAVI (p=0.03) using One-Way ANOVA test and linear regression methods. LVH was present in 73.7% (concentric 63.2%, eccentric in 10.5%). No differences between groups in the presence of LVH or left ventricular mass index were found. CONCLUSIONS: We found that left atrial volume index determined by echocardiographic Area-length method, but not left ventricle hypertrophy or dimensions of cavities, are related on hydration status based on bioimpedance measured time-averaged fluid overload (TAFO), and not with FO/ECW.

Clinical determinants of reduced physical activity in hemodialysis and peritoneal dialysis patients.

OBJECTIVES: The phenotype associated to reduced physical activity (PA) in dialysis patients is poorly documented. We here evaluate weekly PA in two independent cohorts. METHODS: Cross-sectional study with PA assessed by the number of steps/day measured by pedometer in two cohorts of prevalent dialysis patients: (1) peritoneal dialysis (PD) patients (n = 64; 62 ± 14 years; 70 % men) from Stockholm, Sweden using the pedometer for 7 consecutive days; (2) hemodialysis (HD) patients (n = 78; 63 ± 12 years; 65% men) from a single center in Madrid, Spain using the pedometer for 6 consecutive days: 2 HD days, 2 non-HD midweek days and 2 non-HD weekend days. In both cohorts, comorbidities, body composition, nutritional status, and related biomarkers were assessed. Cohorts were not merged; instead data were analyzed separately serving as reciprocal replication analyses. RESULTS: Most patients (63% of PD and 71% of HD) were considered sedentary (<5,000 steps/day). PD patients had on average 4,839 ± 3,313 steps/day. HD patients had 3,767 ± 3,370 steps/day on HD-free days, but fewer steps/day on HD days (2,274 ± 2,048 steps/day; p < 0.0001). In both cohorts, and across increasing PA tertiles, patients were younger and had less comorbidities. Higher PA was also accompanied by better nutritional status (depicted by albumin, pre-albumin, creatinine and normalized protein catabolic rate in HD, and by albumin and subjective global assessment [SGA] in PD), higher lean body mass, and lower fat body mass (bioimpedance and/or dual-energy X-ray absorptiometry [DEXA]). Higher levels of PA were accompanied by lower levels of C-reactive protein in PD. Age and lean body mass were the strongest multivariate predictors of PA in both cohorts. CONCLUSION: There is a high prevalence of sedentary behavior in dialysis patients. Better physical activity was consistently associated with younger age, lower presence of comorbidities and better nutritional status. Pedometers represent a simple and inexpensive tool to objectively evaluate physical activity in this patient population.

Cystatin C as a predictor of mortality and cardiovascular events in a population with chronic kidney disease.

Background. We examine whether cystatin C, a surrogate marker of renal function, could identify patients with chronic kidney disease (CKD) with an increased risk of renal disease progression, death, or cardiovascular events. Methods. Data were obtained for 180 patients, with a diagnosis of chronic renal failure based on serum creatinine estimated glomerular filtration rate (eGFRcreat) <90 mL/min/1.73 m(2). This population was grouped in tertiles according to cystatin C and creatinine values at baseline. Cardiovascular events and overall mortality were estimated for each tertile. Predictors of overall mortality and for the development of renal disease progression were analyzed. Results. The median age was 75 years (interquartile range 69-82) and the median eGFRcreat 38 mL/min m(2) (interquartile range 33-49). Overall mortality was lower on the first and on the second tertiles of cystatin C than on the third one (HR = 0.060; 95% CI: 0.008-0.447 and HR = 0.094; 95% CI: 0.022-0.406, resp.). Deaths related to the creatinine tertiles followed the same pattern, but differences were not as large. Cardiovascular mortality was lower on the second than on the third cystatin C tertile (HR = 0.198; 95% CI: 0.040-0.987), but it did not show differences on the first and the second creatinine tertiles compared with the third one (HR = 0.126; 95% CI: 0.013-1.265 and HR = 0.403; 95% CI: 0.093-1.740). The only independent predictors of mortality during followup were baseline cystatin C (OR = 0.100; 95% CI: 0.021-0.463) and baseline uric acid (OR = 1.377; 95% CI: 1.070-1.773). Conclusion. Cystatin C may be an alternative to creatinine for detecting a high risk of death and cardiovascular events in a population with CKD.

Lack of influence of serum magnesium levels on overall mortality and cardiovascular outcomes in patients with advanced chronic kidney disease.

Background. Low serum magnesium has been associated with an increased cardiovascular risk in the general population and in dialysis patients. Our aim was to analyze the influence of serum magnesium on overall mortality and cardiovascular outcomes in patients with advanced CKD not yet on dialysis. Methods. Seventy patients with CKD stages 4 and 5 were included. After a single measurement of s-magnesium, patients were followed a mean of 11 months. Primary end-point was death of any cause, and secondary end-point was the occurrence of fatal or nonfatal CV events. Results. Basal s-magnesium was within normal range (2.1 ± 0.3 mg/dL), was lower in men (P = 0.008) and in diabetic patients (P = 0.02), and was not different (P = 0.2) between patients with and without cardiopathy. Magnesium did not correlate with PTH, calcium, phosphate, albumin, inflammatory parameters (CRP), and cardiac (NT-proBNP) biomarkers but correlated inversely (r = -0.23; P = 0.052) with the daily dose of loop diuretics. In univariate and multivariate Cox proportional hazard models, magnesium was not an independent predictor for overall mortality or CV events. Conclusions. Our results do not support that serum magnesium can be an independent predictor for overall mortality or future cardiovascular events among patients with advanced CKD not yet on dialysis.