Can Serum Gdf-15 be Associated with Functional Iron Deficiency in Hemodialysis Patients?

Functional iron deficiency (FID) incidence is gradually increasing in hemodialysis (HD) patients. Recently, high levels of GDF-15 supressed the iron regulatory protein hepcidin and GDF-15 expression increased in iron-deficient patients. The relationship between FID, GDF-15, and hepcidin is currently unknown. The present study aimed to evaluate the association between GDF-15, hepcidin, and FID in chronic HD patients. Serum GDF-15 and hepcidin concentrations were measured in 105 HD patients and 40 controls. FID is defined as serum ferritin >800 ng/mL, TSAT <25 %, Hb levels <11 g/dL, and reticulocyte haemoglobin content (CHr) <29 pg. Serum GDF-15 and hepcidin levels were increased significantly in HD patients with FID, compared to HD patients without anemia and controls. GDF-15 correlated with ferritin, hepcidin, and CRP in the entire cohort. GDF-15 was related to ferritin and CRP in HD patients with FID. GDF-15 is better diagnostic marker than hepcidin for detection of FID [AUC = 0.982 (0.013) versus AUC = 0.921 (0.027); P = 0.0324]. GDF-15 appears to be a promising tool for detection of FID. High levels of ferritin and CRP correlated with GDF-15. Our results support GDF-15 as a new mediator of FID via hepcidin, chronic inflammation, or unknown pathways.     

OPPORTUNITY?: A Randomized Clinical Trial of Growth Hormone on Outcome in Hemodialysis Patients

Background: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY™ Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients.Hypothesis: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile.Design/Measurements: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 μg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V ≥1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy.Conclusions: The OPPORTUNITY™ Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.Adult end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (MHD) experience high mortality and morbidity with diminished quality of life (1,2). Death and hospitalization rates in MHD patients correlate strongly with indicators of low protein mass, as indicated by low serum albumin and decreased fat-free, edema-free body mass (i.e., lean body mass [LBM]), as well as chronic inflammation (3,4). This is an important association because protein-energy wasting (PEW) occurs in approximately 40% of MHD patients (5). The possibility that improved measures of PEW may lead to decreased mortality or morbidity was recently underscored by several cross-sectional and longitudinal evaluations of cohorts containing up to 58,000 MHD patients who were followed for up to 2 yr. These studies showed that both higher serum albumin and body weight and an increase in these measures are strongly associated with greater survival (6,7). However, there are no prospective, randomized, clinical trials (RCTs) that have confirmed or even assessed whether a pharmacologic intervention that improves indicators of PEW prolongs survival and/or reduces morbidity, including hospitalization, in MHD patients. Thus, major unmet medical needs and important questions exist concerning whether PEW causes mortality and morbidity in MHD patients and whether a treatment that reduces PEW will reduce their high mortality and morbidity.Growth hormone (GH) has extensive metabolic and, in particular, protein anabolic effects (8), a number of which have also been demonstrated in MHD or chronic peritoneal dialysis patients (9–23). Most of these studies were performed on small numbers of patients. A recent phase 2 RCT involving 139 MHD patients indicated that the GH-treated patients underwent improvement in LBM, serum transferrin, exercise capacity, and a tendency (P = 0.076) for serum albumin to rise (9). Based on these data, a decision was made to conduct a more definitive prospective RCT in hypoalbuminemic MHD patients.     

Assessment of Myeloperoxidase and Oxidative α1-Antitrypsin in Patients on Hemodialysis

Background and objectives: The present study assesses the effects of the oxidative stress marker, myeloperoxidase (MPO), and the possible MPO-related oxidative stress marker, oxidative α₁-antitrypsin (oxAT), on carotid intima-media thickness (CIMT) and protein-energy wasting (PEW) in patients on hemodialysis (HD).Design, setting, participants, & measurements: Blood samples were obtained from 383 patients before HD to measure WBC count, serum albumin, lipids, high-sensitivity C-reactive protein (CRP), α₁-antitrypsin (AT), interleukin-6, oxidative LDL-C, MPO, and oxAT. We assessed both CIMT and the geriatric nutritional risk index (GNRI) in this cross-sectional competitive study.Results: Levels of MPO and oxAT correlated. Myeloperoxidase was associated with max-CIMT, and oxAT correlated with max-CIMT and GNRI. Multivariate linear regression models showed that MPO and oxAT were independent predictors of increasing max-CIMT, whereas oxAT, but not MPO, independently correlated with GNRI. In four combined MPO and oxAT groups classified according to median values, a multinomial logistic regression model showed that high MPO together with high oxAT was independently associated with increased max-CIMT. Moreover, the OR for max-CIMT with positive PEW and high MPO was significantly increased in the four groups with combined MPO and PEW.Conclusions: High MPO with high oxAT and high MPO with PEW seem to contribute to plaque formation in patients on HD, whereas elevated MPO or oxAT alone might not predict increasing CIMT. In contrast, a high oxAT value seems to be an independent predictor of PEW in patients on HD.Ahigh prevalence of cardiovascular disease (CVD) events and of protein-energy wasting (PEW) is significantly associated with increased mortality and morbidity among patients undergoing hemodialysis (HD) (1). The progression of atherosclerosis and PEW in such patients is accelerated by various factors, in particular oxidative stress and inflammation. Oxidative stress is closely associated with advancing atherosclerosis (2) and is a principal risk factor for cardiovascular mortality in patients on HD (3). Such patients develop uremic syndrome per se or factors associated with uremia and an excessively inflamed state with marked hypoalbuminemia (4). Increased oxidative stress and higher levels of C-reactive protein (CRP) and pro-inflammatory cytokines contribute to increased protein catabolism in these states.Myeloperoxidase (MPO) is a hemoprotein that is secreted during the activation of neutrophils and of reactive species-generating enzyme, which acts in host defense by catalyzing the production of hypochloric acid (HOCl) (5). Neutrophil-derived MPO induces vascular injury responses such as endothelial dysfunction and thus MPO might play an important role in vascular injury and atherogenesis (6). Elevated levels of MPO are associated with coronary heart disease and predict risk in patients with acute coronary syndromes (7,8). Myeloperoxidase influences atherosclerosis not only in nonuremic patients, but also in patients with end-stage renal disease (ESRD), especially when under HD therapy. During HD sessions, MPO might be released in association with biocompatibility factors such as deleterious effects induced in the blood during dialysis (9). A high MPO value, as well as hepatic acute phase proteins and increased expression of pro-inflammatory interleukins, is associated with CVD among patients on HD (10), and increased levels of MPO are closely linked to mortality in such patients (11). Moreover, MPO influences PEW in patients on HD (12).However, MPO levels are not associated with atherosclerosis progression in nonuremic patients (13), which suggests that serum MPO levels do not always reflect MPO catalysis of HOCl.Free radicals released from activated neutrophils oxidize the 52-kD acute-phase protein α₁-antitrypsin, which is a typical serine proteinase inhibitor (14). Thus, oxidized α₁-antitrypsin (oxAT) is a potential marker of activated neutrophil-associated oxidation including MPO catalyzing HOCl production (15).The present competitive study was designed to estimate MPO and oxAT values to predict carotid intima-media thickness (CIMT) and PEW in patients on HD.     

How Can I Manage Thrombocytopenia in Hemodialysis Patient? A Review

Hemodialysis (HD) is the most important treatment for patients with end‐stage renal disease (ESRD). Thrombocytopenia is a potential treatment complication related to dialysis. Under normal circumstances, the platelet count would slightly decrease within the first hour of HD, but get restored towards the end of procedure. In most patients, the platelet count can be maintained within the normal range, and the occurrence of thrombocytopenia is relatively rare in clinical practice. Therefore, the possibility of thrombocytopenia in HD patients is often ignored. Moreover, thrombocytopenia might be misdiagnosed and mistreated. At present, almost all articles on the subject, apart from some case reports, focus on pseudothrombocytopenia and heparin‐induced thrombocytopenia. In this review, we summarized various underlying causes, mechanisms, and diagnostic approaches to thrombocytopenia in HD patients. The review aims to provide a guide for clinicians interested in the causes and adequate treatment of thrombocytopenia.     

Colorectal Cancer Localization in Young Patients: Should We Expand the Screening Program?

We sought to investigate the frequency and distribution of colorectal cancer (CRC) in patients by age and to evaluate whether there is a difference between young (<40 years of age) and older patients (≥40 years of age) with regard to cancer localizations. From a total of 5165 colonoscopies, 314 (6.0%) cases were identified to have colorectal carcinoma. Forty-one (13%) of 314 CRC patients were young, with a mean age of 31.1±5.7 years. When cancer localizations were compared with reference to age, it was seen that CRCs in young patients were mostly localized at the right colon, versus at the left colon and rectum (P=013) in patients >40 years of age. Tumor localizations in colon cancer patients change with age. In our study, young patients tended to have right-sided colon tumors, but those in patients >40 years of age were frequently localized at the left colon and rectum.     

Endogenous Testosterone and Mortality in Male Hemodialysis Patients: Is It the Result of Aging?

Background and objectives: Low serum testosterone levels in hemodialysis (HD) patients have recently been associated with cardiovascular risk factors and increased mortality. To confirm this observation, we investigated the predictive role of serum total testosterone levels on mortality in a large group of male HD patients from Turkey.Design, settings, participants, & measurements: A total of 420 prevalent male HD patients were sampled in March 2005 and followed up for all-cause mortality. Serum total testosterone levels were measured by ELISA at baseline and studied in relation to mortality and cardiovascular risk profile.Results: Mean testosterone level was 8.69 ± 4.10 (0.17 to 27.40) nmol/L. A large proportion of patients (66%) had testosterone deficiency (<10 nmol/L). In univariate analysis, serum testosterone levels were positively correlated with creatinine and inversely correlated with age, body mass index, and lipid parameters. During an average follow-up of 32 months, 104 (24.8%) patients died. The overall survival rate was significantly lower in patients within the low testosterone tertile (<6.8 nmol/L) compared with those within the high tertile (>10.1 nmol/L; 64 versus 81%; P = 0.004). A 1-nmol/L increase in serum testosterone level was associated with a 7% decrease in overall mortality (hazard ratio 0.93; 95% confidence interval 0.89 to 0.98; P = 0.01); however, this association was dependent on age and other risk factors in adjusted Cox regression analyses.Conclusions: Testosterone deficiency is common in male HD patients. Although testosterone levels, per se, predicted mortality in this population, this association was largely dependent on age.Low serum testosterone levels have been associated with several components of metabolic syndrome, including cardiovascular disease (CVD), hypertension, abdominal obesity, insulin resistance, and inflammatory markers in male individuals without uremia, independent of age decline (1,2). Also, it has been shown that low endogenous testosterone levels are associated with increased risk for both all-cause and cardiovascular mortality (3–12). Evidence from short-term studies indicated that testosterone replacement therapy may improve some specific cardiovascular risk factors, such as visceral obesity, insulin resistance, lipid and inflammatory profiles, and exercise-induced cardiac ischemia (13).Testosterone deficiency is a common finding in hemodialysis (HD) patients, most probably as a result of altered sex-hormone metabolism (14); however, the prevalence of male hypogonadism and the involvement of testosterone deficiency in the risk profile of HD patients are not well explored. In a small study that included male HD patients without diabetes, low testosterone levels were associated with endothelial dysfunction and atherosclerosis (15). Interestingly, Carrero et al. (16) recently demonstrated in a Swedish HD cohort that low serum testosterone levels were significant predictors of mortality, irrespective of age and inflammation, but this was abolished after correction for serum creatinine, used there as a surrogate of muscle mass (16). In light of the exceedingly elevated (cardiovascular) mortality of HD patients (17), this possibility is an attractive and therapeutically modifiable idea. We aimed in this study to investigate the prevalence of testosterone deficiency as well as its impact on overall outcome in a large prospective cohort of prevalent male Turkish patients who were undergoing HD.     

Do Income Level and Race Influence Survival in Patients Receiving Hemodialysis?

Background

Residence in a lower-income area has been associated with higher mortality among patients receiving dialysis. We sought to determine whether these differences persist and whether the effect of income-area on mortality is different for African Americans versus patients of other races.

Methods

We evaluated relationships between lower- and higher-income versus middle-income area residence and mortality to 5 years after adjusting for differences in baseline clinical, dialysis facility, and socioeconomic characteristics in 186,424 adult patients with end-stage renal disease initiating hemodialysis at stand-alone facilities between 1996 and 1999. We also compared mortality differences between race and income level groups using non-African Americans residing in middle-income areas as the reference group.

Results

Patients with end-stage renal disease who reside in lower-income areas were younger and more frequently African American. After adjustment, there were no mortality differences among income level groups. However, African Americans in all income level groups had lower adjusted mortality compared with the reference group (lower-income hazard ratio [HR] = 0.771, 95% confidence interval [CI], 0.736-0.808; middle-income HR = 0.755, 95% CI, 0.730-0.781; higher-income HR = 0.809, 95% CI, 0.764-0.857), whereas adjusted mortality was similar among non-African-American income level groups (lower-income HR = 1.019, 95% CI, 0.976-1.064; higher-income HR = 1.003, 95% CI, 0.968-1.039).

Conclusion

Adjusted survival for patients receiving hemodialysis in all income areas was similar. However, this result masks the paradoxically higher survival for African American versus patients of other race and demonstrates the need to adjust for differences in demographic, clinical, provider, and socioeconomic status characteristics.     

Acute HCV: Will IL28B Testing Change the Paradigm?

HCV infection will spontaneously resolve in 30% to 50% of patients. Patients with beneficial IL28B genotypes are more likely to clear spontaneously, while other are unlikely to, with less than 15% clearance rate. These patients would therefore be very likely to benefit from immediate treatment with pegylated interferon. In delayed treatment, ribavirin might be required to achieve similar results, making the delayed treatment also from the cost perspective only attractive in those likely to clear spontaneously: Patients with beneficial IL28B genotype and jaundiced patients with the intermediate IL28B genotype.