Faculty Bibliography

BACKGROUND:The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified. STUDY DESIGN/METHODS:Retrospective analysis of prospective randomized clinical trial. SETTING & PARTICIPANTS/METHODS:We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo. PREDICTORS/METHODS:Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR). OUTCOMES/RESULTS:Cause of death as adjudicated by a blinded committee. RESULTS:Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles. LIMITATIONS/CONCLUSIONS:Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available. CONCLUSIONS:In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone-mineral axis and anemia in the pathogenesis of chronic CRS.

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

BACKGROUND:Chronic kidney disease (CKD) is an independent risk factor for the development and severity of coronary artery disease (CHD) and endothelial dysfunction. There is an increase in the circulating angiogenesis inhibitors endostatin (END), thrombospondin-2 (TSP), angiopoietin-2 (ANG) and the nitric oxide (NO) inhibitor asymmetric dimethyl arginine (ADMA) in CKD patients. The aim of this study was to evaluate associations of the serum level of these factors and of the related angiogenesis inhibitor, endoglin (ENG), with burden of coronary atherosclerosis. METHODS:One hundred twenty-two patients undergoing coronary angiography were recruited from the cardiac catheterization lab at a single center. The total burden of coronary plaque (mm(2)) and the presence of coronary collaterals were quantified using quantitative coronary angiography (QCA). Serum levels of angiogenesis inhibitors were measured by ELISA (ENG, END, and ANG), Luminex assay (TSP), or HLPC (ADMA), respectively. Associations with plaque burden and coronary collateral supply were analyzed in multi-variable linear and logistic regression models. RESULTS:There was no significant association found between levels of circulating ADMA, ENG, END, ANG, or TSP and coronary plaque burden or collateral formation. CONCLUSIONS:Our findings suggest that associations of circulating END, ENG, TSP, and ANG with cardiovascular mortality are unlikely to be mediated via direct effects on coronary plaque formation or by inhibition of collateral formation. Whether associations of these factors with mortality are mediated via local concentrations, myocardial tissue, or intra-plaque expression of these factors or by an effect on plaque vulnerability merits additional investigation.

BACKGROUND:Acute kidney injury (AKI) and metabolic acidosis are common in the intensive care unit. The effect of bicarbonate administration on acid-base parameters is unclear in those receiving continuous venovenous hemofiltration (CVVH) and mechanical ventilatory support. METHODS:Metabolic and ventilatory parameters were prospectively examined in 19 ventilated subjects for up to 96 hours following CVVH initiation for AKI at an academic tertiary care center. Mixed linear regression modeling was performed to measure changes in pH, partial pressure of carbon dioxide (pCO2), serum bicarbonate, and base excess over time. RESULTS:During the 96-hour study period, pCO2 levels remained stable overall (initial pCO2 42.0±14.6 versus end-study pCO2 43.8±16.1 mmHg; P=0.13 for interaction with time), for those with initial pCO2≤40 mmHg (31.3±5.7 versus 35.0±4.8; P=0.06) and for those with initial pCO2>40 mmHg (52.7±12.8 versus 53.4±19.2; P=0.57). pCO2 decreased during the immediate hours following CVVH initiation (42.0±14.6 versus 37.3±12.6 mmHg), though this change was nonsignificant (P=0.052). CONCLUSIONS:We did not detect a significant increase in pCO2 in response to the administration of bicarbonate via CVVH in a ventilated population. Additional studies of larger populations are needed to confirm this finding.

AIM/OBJECTIVE:Renal dysfunction is a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). We sought to determine whether renal dysfunction was associated with measures of cardiovascular structure/function in patients with HFpEF. METHODS:We studied 217 participants from the PARAMOUNT study with HFpEF who had echocardiography and measures of kidney function. We evaluated the relationships between renal dysfunction [estimated glomerular filtration rate (eGFR) >30 and <60 mL/min/1.73 m(2) and/or albuminuria] and cardiovascular structure/function. RESULTS:The mean age of the study population was 71 years, 55% were women, 94% hypertensive, and 40% diabetic. Impairment of at least one parameter of kidney function was present in 62% of patients (16% only albuminuria, 23% only low eGFR, 23% both). Renal dysfunction was associated with abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) (adjusted P = 0.048), lower midwall fractional shortening (MWFS) (P = 0.009), and higher NT-proBNP (P = 0.006). Compared with patients without renal dysfunction, those with low eGFR and no albuminuria had a higher prevalence of abnormal LV geometry (P = 0.032) and lower MWFS (P < 0.01), as opposed to those with only albuminuria. Conversely, albuminuria alone was associated with greater LV dimensions (P < 0.05). Patients with combined renal impairment had mixed abnormalities (higher LV wall thicknesses, NT-proBNP; lower MWFS). CONCLUSION/CONCLUSIONS:Renal dysfunction, as determined by both eGFR and albuminuria, is highly prevalent in HFpEF, and associated with cardiac remodelling and subtle systolic dysfunction. The observed differences in cardiac structure/function between each type of renal damage suggest that both parameters of kidney function might play a distinct role in HFpEF.