Anemia in chronic kidney disease: new advances.

Anemia resulting from iron and erythropoietin deficiencies is a common complication of advanced chronic kidney disease (CKD). This article covers major advances in our understanding of anemia in patients with CKD, including newly discovered regulatory molecules, such as hepcidin, to innovative intravenous iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the treatment of anemia has undergone seismic shift in the past 3 years as a result of adverse outcomes associated with targeting higher hemoglobin levels with these agents. Potential mechanisms for adverse outcomes, such as higher mortality, are discussed. Despite the disappointing experience with ESAs, there is a tremendous interest in other novel agents to treat anemia in CKD. Lastly, while awaiting updated guidelines, the authors outline their recommendations on how to best manage patients who are anemic and have CKD.

Kidney pathological changes in metabolic syndrome: a cross-sectional study.

BACKGROUND: The worldwide prevalence of metabolic syndrome is increasing and has been associated with chronic kidney disease. Kidney pathological findings in patients with metabolic syndrome have not been well described, as was explored in this study. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: We retrospectively screened clinical information for 146 patients who underwent elective nephrectomy for renal cell carcinoma between January 2005 and March 2007 at Brigham and Women's Hospital, Boston, MA. Twelve patients with metabolic syndrome were identified. Twelve age- and sex-matched patients who did not have any of the criteria for metabolic syndrome were used as controls. PREDICTOR: Presence of metabolic syndrome defined by using Adult Treatment Panel III criteria. OUTCOMES: Histological characteristics in each group, decrease in kidney function at 1-year follow-up. MEASUREMENTS: Two pathologists blinded to the clinical diagnosis independently evaluated nephrectomy specimens using Banff criteria to objectively assess histological characteristics. RESULTS: Baseline characteristics were similar between the 2 groups. On histopathologic examination, patients with metabolic syndrome compared with controls had a greater prevalence of tubular atrophy (P = 0.006), interstitial fibrosis (P = 0.001), and arterial sclerosis (P = 0.001), suggesting microvascular disease. Patients with metabolic syndrome had greater global (P = 0.04) and segmental glomerulosclerosis (P = 0.05). Glomerular volume and cross-sectional surface area were not different. The combined end point of tubular atrophy greater than 5%, interstitial fibrosis greater than 5%, and presence of arterial sclerosis was more prevalent in patients with metabolic syndrome (P = 0.003; odds ratio, 33; confidence interval, 2.9 to 374.3) than controls. After 1 year, estimated glomerular filtration rate was significantly lower in patients with metabolic syndrome compared with controls (P = 0.03). LIMITATIONS: Small sample size, retrospective design. CONCLUSIONS: We report a high prevalence of microvascular disease in patients with metabolic syndrome. There was a steeper decrease in kidney function over time in patients with metabolic syndrome, suggesting limited renal reserve. Aggressive screening and management may be warranted in patients with metabolic syndrome to protect kidney function.

Kidney disease outcomes quality initiative guidelines for bone and mineral metabolism: emerging questions.

Since their initial publication in 2003, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative clinical practice guidelines for bone and mineral metabolism have transformed the clinical approach to the management of metabolic bone disease in both dialysis and nondialysis chronic kidney disease patients. These guidelines largely were based on expert opinion rather than evidence. In the past 5 years, with the publication of several randomized controlled trials, large observational studies, and smaller clinical series, significant progress has been made in our understanding of mineral metabolism, calcium and phosphorus management, and the use of activated vitamin D irrespective of parathyroid hormone level in chronic kidney disease. More recently, fibroblast growth factor-23 and serum alkaline phosphatase have been shown to predict mortality in dialysis patients, making these attractive markers to monitor. In the wake of this progress, the bone Kidney Disease Outcomes Quality Initiative guidelines will need to be revised. Here, we review some of the issues and controversies that likely will form the basis of these revised guidelines.

Role of vitamin D in chronic kidney disease.

Decline in renal function is related directly to cardiovascular mortality. However, traditional risk factors do not fully account for the high mortality in these patients. Activated vitamin D, a hormone produced by the proximal convoluted tubule of the kidney, appears to have beneficial effects beyond suppressing parathyroid hormone (PTH). However, activated vitamin D also can cause hypercalcemia and hyperphosphatemia in chronic kidney disease. Newer agents such as vitamin D receptor activators (eg, paricalcitol) suppress PTH with reduced risk of hypercalcemia and hyperphosphatemia. Recent evidence from animal and preliminary human studies supports an association between vitamin D receptor activators and reduced risk of cardiovascular disease deaths, irrespective of PTH levels. New pathways of vitamin D regulation also have been discovered, involving fibroblast growth factor-23 and klotho. Although considerable work has been performed to advance our understanding of the effects of vitamin D in health and chronic kidney disease, more investigations and randomized trials need to be performed to elucidate the mechanistic underpinnings of these effects.

Endothelial activation markers in anemic non-dialysis chronic kidney disease patients.

BACKGROUND/AIMS: Anemia in chronic kidney disease is an independent predictor of cardiovascular disease (CVD). We explored the relationship between anemia and markers of inflammation and endothelial activation in non-dialysis chronic kidney disease (ND-CKD) patients to understand this mechanism. METHODS: Cross-sectional analysis was performed on 30 adult ND-CKD patients for markers of inflammation and endothelial activation using a multiplexed immunoassay. Data were analyzed according to the anemic status defined by the modified World Health Organization criteria. RESULTS: Seventeen patients were classified as anemic. Baseline characteristics by anemic status were similar except that anemic patients were older (p = 0.006), had lower estimated glomerular filtration rate (eGFR; p = 0.01) and higher prevalence of CVD (p = 0.02). Compared to non-anemic patients, log-transformed values of fibrinogen (p = 0.012); von Willebrand factor (vWF, p = 0.008), vascular cell adhesion molecule-1 (VCAM-1, p = 0.025) and C-reactive protein (p = 0.043) were elevated in anemic patients. Serum ferritin (p = 0.93) and serum albumin (p = 0.06) were not different. Age and eGFR-adjusted logistic regression analysis showed that anemic patients had increased odds for a composite of higher median values of fibrinogen, vWF and VCAM-1 (p = 0.01, odds ratio 8.1, 95% CI 1.08-111.0). CONCLUSION: We report the association of anemia with elevated markers of endothelial activation in ND-CKD patients. Longitudinal studies are needed to confirm our findings.

Does treatment with calcitriol improve survival in predialysis patients with chronic kidney disease?

Treatment of secondary hyperparathyroidism with activated vitamin D analogs has been associated with improved survival of dialysis-dependent patients with chronic kidney disease (CKD). Whether this treatment regimen affords similar benefits to non-dialysis-dependent patients with CKD remains unclear. In this Practice Point commentary, we discuss a study by Kovesdy et al. that reported enhanced survival in predialysis patients with CKD who received calcitriol for a median duration of 2.1 years. Despite the achievement of favorable results in these patients, the study had several limitations that could preclude generalization of the findings to other populations. These limitations included the nonrandomized, observational design, the small patient population, the exclusive enrollment of men (76.5% of whom were white), and the lack of information on cause of death. Here, we place the findings of the study into clinical context and emphasize the urgent need for large, well-designed, randomized trials that aim to assess cardiovascular and mortality end points.

Angiotensinogen genotype predicts abnormal renal hemodynamics in young hypertensive patients.

OBJECTIVE: In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype. DESIGN AND METHODS: Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril. RESULTS: Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril. CONCLUSION: The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.

Association of anemia and erythropoiesis stimulating agents with inflammatory biomarkers in chronic kidney disease.

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Is it time to reconsider subcutaneous administration of epoetin?

Anemia treatment in nondialysis chronic kidney disease (ND-CKD) and dialysis CKD patients (D-CKD) has been recently scrutinized in the literature and by the lay press. New evidence suggests that patients receiving epoetin and achieving higher hemoglobin have a higher risk of death and cardiovascular complications. Data from the Centers for Medicare & Medicaid Services demonstrate upward spiraling costs of injectables, especially epoetin, in the care of CKD patients. There is considerable literature favoring the use of subcutaneous administration of epoetin compared to intravenous route in hemodialysis patients. Evidence clearly shows that the subcutaneous route achieves the target hemoglobin level at a lower administered dose. Thus, the same clinical effect can be achieved at a lower cost. Despite the economic and evidentiary justifications for subcutaneous administration of epoetin, adoption of this strategy has been limited, especially in the United States. Reasons include: inflexibility by dialysis providers because of reduced profitability, claims that patients oppose the subcutaneous route because of pain at the site of injection, concerns regarding pure red cell aplasia associated with subcutaneous administration, and greater hemoglobin cycling with the subcutaneous route. In this article, the advantages and disadvantages of the subcutaneous route are reviewed.