Malnutrition-inflammation-cachexia Syndrome Research Articles

Novel Protein to Phosphorous Ratio Score Predicts Mortality in Hemodialysis Patients

Lowering serum phosphorus in people on hemodialysis may improve their survival. However, prior studies have shown that restricting dietary protein intake, a major source of phosphorus, is associated with higher mortality. We hypothesized that a novel metric that incorporates both these values commensurately can improve survival prediction. We used serum phosphorous and normalized protein catabolic rate (nPCR), a surrogate of dietary protein intake, to form a new metric R that was used to examine the associations with mortality in 63,016 people on hemodialysis (HD) of oneyear after treatment initiation. Survival models were adjusted for case-mix, malnutrition-inflammation cachexia syndrome (MICS), and residual kidney function (RKF). Individuals treated with hemodialysis were divided into five groups in accordance with R value. Group 1 included sick individuals with high phosphorous and low nPCR. Group 5 included individuals with low phosphorous and high nPCR. After 1-year follow-up, survival difference between the groups reflected R value, where an increase in R was associated with improved survival. The association of R with mortality was strengthened by adjustment in demographic variables and attenuated after adjustment to MICS. Mortality associations in accordance with R were not influenced by residual kidney function (RKF). The novel protein to phosphorus ratio score R predicts mortality in people on dialysis, probably reflecting both nutrition and inflammation state independent of RKF. The metric enables better phosphorus monitoring, although adequate dietary protein intake is ensured and may improve the prediction of outcomes in the clinical setting.

Racial and Ethnic Differences in Mortality Associated with Serum Potassium in a Large Hemodialysis Cohort

Background: Hyperkalemia is observed in chronic kidney disease patients and may be a risk factor for life-threatening arrhythmias and death. Race/ethnicity may be important modifiers of the potassium-mortality relationship in maintenance hemodialysis (MHD) patients given that potassium intake and excretion vary among minorities. Methods: We examined racial/ethnic differences in baseline serum potassium levels and all-cause and cardiovascular mortality using Cox proportional hazard models and restricted cubic splines in a cohort of 102,241 incident MHD patients. Serum potassium was categorized into 6 groups: ≤3.6, >3.6 to ≤4.0, >4.0 to ≤4.5 (reference), >4.5 to ≤5.0, >5.0 to ≤5.5, and >5.5 mEq/L. Models were adjusted for case-mix and malnutrition-inflammation cachexia syndrome (MICS) covariates. Results: The cohort was composed of 50% whites, 34% African-Americans, and 16% Hispanics. Hispanics tended to have the highest baseline serum potassium levels (mean ± SD: 4.58 ± 0.55 mEq/L). Patients in our cohort were followed for a median of 1.3 years (interquartile range 0.6-2.5). In our cohort, associations between higher potassium (>5.5 mEq/L) and higher mortality risk were observed in African-American and whites, but not Hispanic patients in models adjusted for case-mix and MICS covariates. While in Hispanics only, lower serum potassium (<3.6 mEq/L) levels were associated with higher mortality risk. Similar trends were observed for cardiovascular mortality. Conclusions: Higher potassium levels were associated with higher mortality risk in white and African-American MHD patients, whereas lower potassium levels were associated with higher death risk in Hispanics. Further studies are needed to determine the underlying mechanisms for the differential association between potassium and mortality across race/ethnicity.

Association of estimated glomerular filtration rate with all-cause and cardiovascular mortality: the role of malnutrition-inflammation-cachexia syndrome.

BackgroundPrevious studies have demonstrated that high estimated glomerular filtration rate (eGFR) is paradoxically associated with an increased risk of mortality, and the association becomes more predominant in older people. However, the role of malnutrition–inflammation–cachexia syndrome (MICS) in the association between eGFR and mortality has never been explored.MethodsWe conducted a community‐based cohort study using data from the Taipei City Elderly Health Examination Database, collected during the period 2001–10. All participants aged ≥65 years were included and stratified by the absence or presence of MICS, which is defined as the presence of at least one of the following markers: body mass index <22 kg/m2, serum albumin <3.0 mg/dL, or Geriatric Nutritional Risk Index (GNRI) <98. The study endpoints were all‐cause and cardiovascular mortality.ResultsA total of 131 354 participants were identified and categorized according to the chronic kidney disease stage based on eGFR. Compared with the reference eGFR of 60–89 mL/min/1.73 m2, the overall and cardiovascular mortality risks were markedly high in the groups with eGFR of <30 mL/min/1.73 m2 [overall: adjusted hazard ratio (aHR), 1.86; 95% confidence interval (CI), 1.72–2.00; cardiovascular: aHR, 1.87; 95% CI, 1.60–2.19] and ≥90 mL/min/1.73 m2 (overall: aHR, 1.23; 95% CI, 1.13–1.34; cardiovascular: aHR, 1.28; 95% CI, 1.06–1.54). In the absence of MICS, high eGFR was associated with lower mortality risk (aHR, 0.71; 95% CI, 0.62–0.80), and the U‐shaped relationship disappeared. Subgroup analyses produced consistent results.ConclusionsMICS could influence the association observed between high eGFR and mortality in older people, particularly in those with low body mass index, albumin level, GNRI, and very low serum creatinine level.

High platelet count as a link between renal cachexia and cardiovascular mortality in end-stage renal disease patients

It is not clear why cardiac or renal cachexia in chronic diseases is associated with poor cardiovascular outcomes. Platelet reactivity predisposes to thromboembolic events in the setting of atherosclerotic cardiovascular disease, which is often present in patients with end-stage renal disease (ESRD). We hypothesized that ESRD patients with relative thrombocytosis (platelet count >300 × 10(3)/μL) have a higher mortality rate and that this association may be related to malnutrition-inflammation cachexia syndrome (MICS). We examined the associations of 3-mo-averaged platelet counts with markers of MICS and 6-y all-cause and cardiovascular mortality (2001-2007) in a cohort of 40,797 patients who were receiving maintenance hemodialysis. The patients comprised 46% women and 34% African Americans, and 46% of the patients had diabetes. The 3-mo-averaged platelet count was 229 ± 78 × 10(3)/μL. In unadjusted and case-mix adjusted models, lower values of albumin, creatinine, protein intake, hemoglobin, and dialysis dose and a higher erythropoietin dose were associated with a higher platelet count. Compared with patients with a platelet count of between 150 and 200 × 10(3)/μL (reference), the all-cause (and cardiovascular) mortality rate with platelet counts between 300 and <350, between 350 and <400, and ≥400 ×10(3)/μL were 6% (and 7%), 17% (and 15%), and 24% (and 25%) higher (P < 0.05), respectively. The associations persisted after control for case-mix adjustment, but adjustment for MICS abolished them. Relative thrombocytosis is associated with a worse MICS profile, a lower dialysis dose, and higher all-cause and cardiovascular disease death risk in hemodialysis patients; and its all-cause and cardiovascular mortality predictability is accounted for by MICS. The role of platelet activation in cachexia-associated mortality warrants additional studies.

Association between vitamin D receptor gene polymorphisms and iron indices in HIV-negative patients with malnutrition-inflammation-cachexia syndrome

Malnutrition-inflammation-cachexia syndrome (MICS) is a frequent complication of end-stage AIDS. Malnutrition, with its associated adverse effects on immunocompetence contributes to the progression of AIDS independently of HIV. Iron indices are considered reliable prognostic factors because of their association with inflammation and malnutrition. Since the active form of vitamin D has immunomodulatory effects, and considering that allelic variants of the vitamin D receptor (VDR) are associated with the rates of progression to AIDS in HIV-positive patients (J Steroid Biochem Mol Biol. 2004 89-90:199-207), here we evaluated the association between VDR polymorphisms and iron indices in HIV-negative patients with MICS. 38 HIV-negative patients treated at the Unit of Clinical and Artificial Nutrition, Misericordia e Dolce Hospital, Prato (Italy) for at least 12 months were studied. The mean age of the patients (22 men and 16 women) included in this study was 65 ± 10 years. Genomic DNA was extracted from peripheral blood leucocytes and amplified by polymerase chain reaction (PCR). PCR products were digested with the respective restriction enzymes in order to identify VDR polymorphisms. Absence or presence of the BsmI, ApaI, TaqI, and FokI restriction sites were denominated B and b, A and a, T and t, F and f respectively. Serum transferrin levels showed significant association with BsmI, ApaI and TaqI polymorphisms, i.e. those polymorphisms that are located in a regulatory site at the 3’ end of the VDR gene and are in linkage disequilibrium. Patients harbouring the BB, AA and tt genotypes showed significantly higher levels of serum transferrin compared with bb, Aa, aa, TT and Tt respectively. These results are consistent with those previously obtained in HIV-positive patients (J Steroid Biochem Mol Biol. 2004 89-90:199-207; J Infect Dis. 2008 197:405-10) and highlight an inverse correlation between vitamin D signalling and AIDS progression to MISC. These results also provide a link between VDR alleles and nutritional markers which are highly predictive variables of MICS. Since MICS is one of the leading causes of mortality in AIDS patients, the determination of VDR polymorphisms could help identifying those AIDS patients with a greater risk of developing MICS, a syndrome that appears to be independent of HIV serostatus or viral load.

Abstract 3149: Greater Fluid Retention is Associated with Increased Cardiovascular Death Risk in 34,003 CKD Patients on Hemodialysis

Background: Patients with chronic kidney disease (CKD) stage 5 who undergo hemodialysis (HD) treatment have striking similarities to heart failure (HF) patients, in that both populations retain fluid frequently, have excessively high mortality, and exhibit an obesity paradox. We hypothesized that in HD patients greater interdialytic fluid retention is associated with poor cardiovascular (CV) survival. Methods: We examined the 2-year (7/2001– 6/2003) CV mortality in 34,003 HD patients across the United States, who had an averaged weight gain of at least 0.5 kg above their end-dialysis dry weight by the time the subsequent HD treatment started. The 3-month averaged interdialytic weight gain was divided into 8 categories of 0.5 kg increments (up to &gt;= 4.0 kg). Results : In unadjusted analyses, higher weight gains were associated with better nutritional status (higher protein intake, serum albumin and body mass index) and tended to be linked to greater survival. However after multivariate adjustment for demographics (case-mix) and also surrogates of malnutrition-inflammation-cachexia syndrome (MICS), higher weight gain increments were associated with increased CV death risk. [Figure ] Conclusions: In HD patients greater fluid retention between two subsequent HD treatment sessions is associated with higher CV death risk. The mechanisms by which fluid retention influences survival in HD may be similar to HF patients and warrants further research.

Inverse Association between Lipid Levels and Mortality in Men with Chronic Kidney Disease Who Are Not Yet on Dialysis

High total cholesterol is associated with lower mortality in dialysis patients, but the relationship between lipid levels and mortality in patients who have chronic kidney disease (CKD) and are not yet on dialysis is poorly described. This study examined the association between lipid levels and all-cause and cardiovascular mortality in 986 male patients (age 67.4 +/- 10.9 yr; race 23.7% black) who had CKD and were not yet on dialysis. Associations were determined in fixed-covariate and time-dependent Cox models, before and after adjustment for components of case mix and surrogates for malnutrition-inflammation-cachexia syndrome (MICS). Lower total cholesterol quartiles were associated with higher all-cause mortality in a fixed-covariate model that was adjusted for age, race, and body mass index (hazard ratio [95% confidence interval] for cholesterol <153, 153 to 182, and 183 to 215 versus >215 mg/dl: 1.91 [1.35 to 2.69], 1.36 [0.96 to 1.92], 1.10 [0.78 to 1.57]; P < 0.001 for trend), but this association was attenuated after adjustment for case mix (P = 0.023 for trend) and abolished after additional adjustment for MICS (P = 0.14 for trend), with time-dependent Cox models showing similar results. Similar tendencies also were detected in the association between levels of LDL cholesterol with total and cardiovascular mortality and triglycerides with all-cause mortality in both fixed-covariate and time-dependent analyses. Lower lipid levels are associated with higher mortality in patients who have moderate and advanced CKD and are not yet on dialysis. This inverse association is explained in part by case-mix characteristics and the presence of surrogates for MICS.

Diagnostic Discordance for Hepatitis C Virus Infection in Hemodialysis Patients

Hepatitis C virus (HCV) infection is associated with an increase in proinflammatory cytokine levels. Similar changes are seen in maintenance hemodialysis patients with malnutrition-inflammation-cachexia syndrome (MICS), which is associated with poor clinical outcomes in this population. We hypothesized that HCV transcription-mediated amplification (TMA), a sensitive qualitative molecular test for HCV RNA, may identify maintenance hemodialysis patients with HCV infection not detected by means of antibody enzyme immunoassay (EIA), particularly in those with MICS. We evaluated HCV status in 314 maintenance hemodialysis patients by using HCV antibody EIA (version 2.0; Abbott Laboratories, Abbott Park, IL) and HCV TMA (Bayer Diagnostics Laboratories, Berkeley, CA). Twenty-five patients (8%) were EIA positive (EIA+)/TMA+; 4 patients (1%), EIA+/TMA negative (TMA-), and 22 patients (7%), EIA-/TMA+. In the 47 TMA+ patients, the sensitivity of EIA for HCV infection was only 53%. TMA+ patients had lower albumin levels and higher tumor necrosis factor alpha and serum glutamic oxaloacetic transaminase levels than TMA- patients. EIA+/TMA+ patients were more likely than EIA-/TMA+ or EIA-/TMA- patients to have hypoalbuminemia and higher iron and transaminase levels. Of all TMA+ patients, EIA- patients were more likely to have diabetes, be on dialysis therapy longer, and have lower liver enzyme levels and higher proinflammatory cytokine levels, including tumor necrosis factor alpha and interleukin 6. Maintenance hemodialysis patients infected with HCV according to TMA have clinical features suggestive of MICS. In this population, HCV EIA appears to have a low sensitivity for the identification of HCV infection, which may be caused by the confounding effect of MICS or other demographic or clinical factors. These apparently false-negative HCV antibody test results are seen in persons with a longer time on hemodialysis therapy, mirroring observations in other populations with serious progressive conditions, such as human immunodeficiency virus infection.

Time-Dependent Associations between Iron and Mortality in Hemodialysis Patients

The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.