Juan Jesus Carrero

Emerging Biomarkers for Evaluating Cardiovascular Risk in the Chronic Kidney Disease Patient: How Do New Pieces Fit into the Uremic Puzzle?

Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.

ESPEN Guidelines on Parenteral Nutrition: adult renal failure.

Among patients with renal failure, those with ARF and critical illness represent by far the largest group undergoing artificial nutrition. ARF, especially in the ICU, seldom occurs as isolated organ failure but rather is a component of a much more complex metabolic environment, in the setting of the multiple organ failure. Nutritional programs for ARF patients must consider not only the metabolic derangements peculiar to renal failure and with the underlying disease process/associated complications, but also the relevant derangements in nutrient balance due to renal replacement therapies, especially when highly efficient renal replacement therapies (RRT) are used, such as continuous veno-venous hemofiltration (CVVH), or prolonged intermittent modalities such as sustained low-efficiency dialysis (SLED). Finally it is to be taken into account that nutrient requirements can change considerably during the course of illness itself (see also guidelines on PN in intensive care). From a metabolic point of view, patients with CKD or on chronic HD who develop a superimposed acute illness should be considered to be similar to patients with ARF. The same principles in respect of PN should therefore be applied.

Etiology of the Protein-Energy Wasting Syndrome in Chronic Kidney Disease: A Consensus Statement From the International Society of Renal Nutrition and Metabolism (ISRNM)

Protein-energy wasting (PEW), a term proposed by the International Society of Renal Nutrition and Metabolism (ISRNM), refers to the multiple nutritional and catabolic alterations that occur in chronic kidney disease (CKD) and associate with morbidity and mortality. To increase awareness, identify research needs, and provide the basis for future work to understand therapies and consequences of PEW, ISRNM provides this consensus statement of current knowledge on the etiology of PEW syndrome in CKD. Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contribute, other highly prevalent factors are required for the full syndrome to develop. These include uremia-induced alterations such as increased energy expenditure, persistent inflammation, acidosis, and multiple endocrine disorders that render a state of hypermetabolism leading to excess catabolism of muscle and fat. In addition, comorbid conditions associated with CKD, poor physical activity, frailty, and the dialysis procedure per se further contribute to PEW.

Inflammation in End‐Stage Renal Disease—What Have We Learned in 10 Years?

The first reports connecting uremic inflammation with a wasted and atherogenic phenotype and poor outcome initiated in the late 1990s. Since then, about 3500 publications appear on Medline, reflecting the exponential interest that this topic has evoked in nephrology. What was described as a “novel” risk factor 10 years ago has now evolved into an established finding in patients with end‐stage renal disease (ESRD). The purpose of this review is to summarize the main advances contributing to our current understanding of the complex inflammatory processes present in ESRD. Causes and consequences of inflammation, genetic heritability of the inflammatory response, implications on outcome prognostication, and contemporary therapeutic evidence are some of the various topics discussed.

Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients

BACKGROUND & AIMS Muscle wasting is considered the best marker of protein-energy wasting in end-stage renal disease (ESRD). We tested the usefulness of a simple observer subjective muscle atrophy (MA) grading in relation to morbidity and mortality in ESRD patients. METHODS In two different ESRD cohorts (265 incident patients starting dialysis and 221 prevalent hemodialysis patients), each patients degree of MA was visually graded by a trained nurse on a scale from 1 to 4 as part of the subjective global assessment. This score was confronted with inflammatory and nutritional indexes as well as objective measurements of muscle atrophy. Patients were then prospectively followed for up to four or six years, depending on the cohort. RESULTS Thirty percent of the incident and 39% of the prevalent patients presented signs of MA. Across worsening MA scale, nutritional and anthropometric markers of muscle loss were incrementally poorer. Inflammation markers as well as the proportion of women became progressively higher. Female sex, presence of cardiovascular disease, inflammation and low insulin-like growth factor-1 levels were associated with increased significant odd ratios of MA in each cohort. After adjustment for age, sex, inflammation, diabetes, cardiovascular disease, glomerular filtration rate and/or time on hemodialysis, the hazard ratio of death for moderate/severe MA was 2.62 (95% CI: 1.34, 5.13; p=0.001) and 3.04 (95% CI: 1.61, 5.71; p=0.0001) in the incident and prevalent cohorts respectively. CONCLUSION Increased MA is more common in female dialysis patients and associated with inflammation, poor nutritional and anthropometric status, as well as a 3-fold increased 4-6 year mortality. Our data support the use of frequent MA and/or nutritional assessments in the clinical practice.

Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients

Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.

Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease

Abstract.  Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P, Heimbürger O, Suliman ME, Alvestrand A, Lindholm B, Stenvinkel P (Karolinska Institutet, Stockholm; and Karo Bio AB, Novum, Huddinge; Sweden). Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007; 262: 690–701.

Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients.

Introduction.  Chronic kidney disease (CKD) predisposes to a 10‐ to 20‐fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk.

Short-Term Treatment with Sevelamer Increases Serum Fetuin-A Concentration and Improves Endothelial Dysfunction in Chronic Kidney Disease Stage 4 Patients

BACKGROUND AND OBJECTIVES Vascular calcification and endothelial dysfunction contribute to the development of cardiovascular disease in patients with chronic kidney disease (CKD). Sevelamer, a non-calcium-based phosphate binder, has been shown to attenuate cardiovascular calcification in CKD patients, although the exact mechanism has not been clarified. This study was designed to investigate the effect of short-term sevelamer treatment on both serum fetuin-A concentrations and endothelial dysfunction seen in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty nondiabetic stage 4 CKD patients whose phosphate levels were > or =5.5 mg/dl were enrolled in this 8-wk randomized prospective study. Thirty-six healthy volunteers served as matched controls. Patients were treated with either sevelamer (n = 25, 12 males) or calcium acetate (n = 25, 13 males). Fetuin-A, high-sensitivity C-reactive protein, Ca x PO4 product, flow-mediated dilation (FMD), insulin, and homeostasis model assessment (HOMA) were obtained at baseline and after the treatment period. RESULTS As expected, CKD patients had significantly lower levels of fetuin-A and FMD, and significantly higher levels of intact parathyroid hormone, Ca x PO4 product, and high-sensitivity C-reactive protein than controls (P < 0.001 for all). The use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in FMD, whereas no significant difference was observed in the calcium acetate group. In a multiple regression analysis, FMD levels were independently related to fetuin-A both before (beta = 0.63, P < 0.001) and after (beta = 0.38, P = 0.004) treatment. CONCLUSIONS This small, randomized, prospective study shows that short-term sevelamer treatment significantly increases fetuin-A levels and improves FMD in nondiabetic stage 4 CKD patients.

Abdominal fat deposition is associated with increased inflammation, protein–energy wasting and worse outcome in patients undergoing haemodialysis

OBJECTIVE The role of obesity in promoting or preventing the complications of haemodialysis patients remains unclear, with several studies suggesting that obesity may even be beneficial. We tested the hypothesis that abdominal fat deposition in HD patients is a risk factor associated with both increased inflammation and protein-energy wasting (PEW), as well as elevated mortality risk. METHODS A cross-sectional study with mortality follow-up [median 41 (interquartile range 25-47) months] of haemodialysis patients [n = 173, 100 men, aged 65 (51-74) years]. Abdominal fat deposition was assessed by means of a conicity index (Ci), which estimates fat accumulation in the abdomen as the deviation of body shape from a cylindrical towards a double-cone shape (i.e. two cones with a common base at the waist level). The Ci was studied with regard to baseline inflammatory, anthropometric and nutritional markers, including subjective global assessment (SGA). RESULTS Across increasing tertiles of the Ci, patients were older, fatter and more inflamed (P < 0.01 for all). At the same time, they presented a higher prevalence of PEW (SGA >1), reduced handgrip strength and lower S-creatinine (P < 0.01 for all). An increased abdominal fat deposition was associated with worse outcome independently of age, sex, comorbidities and dialysis vintage [Cox HR 1.93 (95% CI = 1.06-3.49)], but the predictive value disappeared following adjustment for interleukin-6 (IL-6) and PEW. CONCLUSION Abdominal fat deposition in haemodialysis patients is linked to both inflammation and PEW, resulting in an increased mortality risk. Our results support the idea that regional differences in adiposity accumulation may have diverse implications on patient outcome.