Aldo J. Peixoto

Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure

The kidney not only regulates fluid and electrolyte balance but also functions as an endocrine organ. For instance, it is the major source of circulating erythropoietin and renin. Despite currently available therapies, there is a marked increase in cardiovascular morbidity and mortality among patients suffering from end-stage renal disease. We hypothesized that the current understanding of the endocrine function of the kidney was incomplete and that the organ might secrete additional proteins with important biological roles. Here we report the identification of a novel flavin adenine dinucleotide-dependent amine oxidase (renalase) that is secreted into the blood by the kidney and metabolizes catecholamines in vitro (renalase metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine). In humans, renalase gene expression is highest in the kidney but is also detectable in the heart, skeletal muscle, and the small intestine. The plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects. Renalase infusion in rats caused a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as what we believe to be a novel amine oxidase that is secreted by the kidney, circulates in blood, and modulates cardiac function and systemic blood pressure.

Kidney Biomarkers and Differential Diagnosis of Patients With Cirrhosis and Acute Kidney Injury

Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase‐associated lipocalin (NGAL), interleukin‐18 (IL‐18), kidney injury molecule‐1 (KIM‐1), liver‐type fatty acid binding protein (L‐FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step‐wise with the number of biomarkers above optimal diagnostic cutoffs. Conclusion: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS. (Hepatology 2014;60:622–632)

Methods of assessment of volume status and intercompartmental fluid shifts in hemodialysis patients: implications in clinical practice.

Determining dry weight and assessing extracellular fluid volume in hemodialysis (HD) patients is one of the greatest challenges to practicing nephrologists. The clinical examination has limited accuracy, so different strategies have been investigated to aid in this evaluation. Biochemical markers of volume overload (ANP, BNP, cGMP) are fraught with excessive variability and poor correlation with volume status. Inferior vena cava ultrasound is effective, but cumbersome and costly. Bioimpedance measurements of intra‐ and extracellular water have significant shortcomings when used as isolated measurements, but can be useful in following trends over time and have been shown to improve intradialytic symptoms and blood pressure control. Continuous blood volume monitoring is helpful in preventing intradialytic hypotension and may help identify patients who are volume overloaded and need increased ultrafiltration. In this review we discuss these different techniques and other developments in the evaluation of dry weight and volume status, which may enhance our ability to improve patient stability and well‐being during HD sessions.

Out-of-office blood pressure monitoring in chronic kidney disease.

Blood pressure (BP) control is vital to the management of patients with chronic kidney disease (CKD) yet most treatment decisions use BPs obtained in the clinic. The purpose of this report is to review the importance of self-measured and automatic ambulatory BPs in the management of patients with CKD. Compared with clinic-obtained BPs, self-measured BP more accurately defines hypertension in CKD. Masked hypertension seems to be associated with higher risk of end-stage renal disease in CKD patients. Conversely, white-coat hypertension seems to be associated with better renal outcomes than those who have persistent hypertension. Ambulatory BP monitoring is the only tool to monitor BP during sleep, diagnose nondipping, and, as self-measured BPs, have greater prognostic power in CKD compared with clinic BP. In hemodialysis patients, self-measured BP, but not pre/post-dialysis BP, shares the combination of high sensitivity and high specificity of greater than 80% to make a diagnosis of hypertension with the reference standard of ambulatory BP monitoring. In addition, self-measured and ambulatory BPs seem to be better correlates of left-ventricular hypertrophy and mortality in hemodialysis patients compared with pre/post-dialysis BP. Emerging data suggest that out-of-office BP monitoring is superior to BP obtained in the clinic when predicting target-organ damage and prognosis. Out-of-office BP monitoring is recommended for the management of hypertension in all stages of CKD.

Long-term stability of serum sodium in hemodialysis patients.

Background: A direct relationship between dialysate-to-plasma sodium gradient, blood pressure and interdialytic weight gain exists in hemodialysis (HD) patients. The aim of this study was to delineate the long-term variability of serum sodium in HD patients. Methods: We performed a retrospective cohort analysis of serum sodium and other analytes routinely evaluated in 100 stable chronic HD patients observed for 12 months. Results: Individual levels across the cohort varied from 122 to 145 mM, but 12-month intraindividual coefficients of variation for sodium were low (pre-HD = 1.6%; post-HD = 1.8%) with overall variability similar to that related to laboratory assay variability especially when compared with other analytes (3.1–30.8%). Pre-HD serum sodium had a trend toward hyponatremia (mean 136 ± 0.8 mM). Conclusion: Serum sodium is stable over time in HD patients. Pre-HD serum sodium may be used as a parameter for individualizing dialysate sodium prescription.

Renalase in hypertension and kidney disease

Renalase, a recently discovered flavoprotein, which is strongly expressed in the kidney and heart, effectively metabolizes catecholamines. It was discovered during the search to identify proteins secreted by the kidney that could help explain the high incidence of cardiovascular disease in patients with chronic kidney disease. Recent advances have led to more detailed knowledge of its biology, structure, enzymatic activity, mechanisms of action, associations with human disease states and potential therapeutic value. In this study, we review these advances with a focus on hypertension and kidney disease.

Human renalase: a review of its biology, function, and implications for hypertension.

Renalase is a novel flavoprotein, highly expressed in kidney and heart, which metabolizes catecholamines and catecholamine-like substances via a superoxide (O2(-))-dependent mechanism using nicotinamide adenine dinucleotide (NADH) as a cofactor. Its mechanism of action is distinct from that of monoaminooxidases A and B, because it oxidizes catecholamines (epinephrine>>L-DOPA>dopamine = norepinephrine) to aminochrome, and the reaction rate increases ∼4- to 6-fold in presence of NADH. Tissue and plasma renalase levels are decreased in animal models of chronic kidney disease, and renalase deficiency is associated with increased blood pressure and elevated circulating catecholamines. Renalase plasma levels, measured by enzyme-linked immunosorbent assay, are reported to be ∼ 5-fold higher in patients with end-stage renal disease than in normal control subjects. They were also increased in kidney and heart transplant recipients, and inversely correlated with estimated glomerular filtration rate. Renalase has potential therapeutic applications. Experimental models demonstrate that the chronic administration of renalase decreases ambulatory blood pressure and prevents the development of cardiac hypertrophy in rats, and that its acute administration decreases ischemic acute kidney injury in mice. Here we provide a detailed review of renalase biology including its mechanism of action, secretion into blood, interaction with the renal dopamine and epinephrine system, and early studies evaluating its association with outcomes related to hypertension and target-organ injury.

Processes of Care Associated With Acute Stroke Outcomes

BACKGROUND Many processes of care have been proposed as metrics to evaluate stroke care. We sought to identify processes of stroke care that are associated with improved patient outcomes after adjustment for both patient characteristics and other process measures. METHODS This retrospective cohort study included patients 18 years or older with an ischemic stroke or transient ischemic attack (TIA) onset no more than 2 days before admission and a neurologic deficit on admission. Patients were excluded if they resided in a skilled nursing facility, were already admitted to the hospital at stroke onset, or were transferred from another acute-care facility. The combined outcome included in-hospital mortality, discharge to hospice, or discharge to a skilled nursing facility. Seven processes of stroke care were evaluated: fever management, hypoxia management, blood pressure management, neurologic evaluation, swallowing evaluation, deep vein thrombosis (DVT) prophylaxis, and early mobilization. Risk adjustment included age, comorbidity (medical history), concomitant medical illness present at admission, preadmission symptom course, prestroke functional status, code status, stroke severity, nonneurologic status, modified APACHE (Acute Physiology and Chronic Health Evaluation) III score, and admission brain imaging findings. RESULTS Among 1487 patients, the outcome was observed in 239 (16%). Three processes of care were independently associated with an improvement in the outcome after adjustment: swallowing evaluation (adjusted odds ratio [OR], 0.64; 95% confidence interval [CI], 0.43-0.94); DVT prophylaxis (adjusted OR, 0.60; 95% CI, 0.37-0.96); and treating all episodes of hypoxia with supplemental oxygen (adjusted OR, 0.26; 95% CI, 0.09-0.73). CONCLUSION Outcomes among patients with ischemic stroke or TIA can be improved by attention to swallowing function, DVT prophylaxis, and treatment of hypoxia.

Derivation and Validation of a Clinical System for Predicting Pneumonia in Acute Stroke

Aims: We derived and validated a clinical prediction rule that can be used to predict post-stroke pneumonia. Methods: We conducted a retrospective cohort study of patients admitted to hospital with a stroke. The cohort was subdivided into a derivation group and a validation group. Within the derivation group, a point scoring system was developed to predict pneumonia based on a logistic regression model. The point scoring system was then tested within the validation group. Results: Of the 1,363 patients with stroke, 10.5% of patients experienced new pneumonia. The most points were assigned for abnormal swallowing result and history of pneumonia (4 points), followed by greater NIHSS score (3 points), patient being ‘found down’ at symptom onset (3 points), and age >70 years (2 points). A 3-level classification system was created denoting low, medium and high risks of pneumonia, which accurately predicted pneumonia in the validation group. The discriminatory accuracy of the 3-level clinical prediction rule exceeded the acceptable range in both the derivation group (c statistic: 0.78) and validation group (c statistic: 0.76). Conclusion: A simple scoring system was derived and validated. This clinical scoring system may better identify stroke patients who are at high risk of developing new pneumonia.

Profile of interdialytic blood pressure in hemodialysis patients.

Background and Methods: Hypertension is a common problem in hemodialysis (HD). However, its behavior during the interdialytic period is not completely known and is infrequently monitored in clinical practice. Thus, for better understanding of interdialytic blood pressure (BP), we analyzed the interdialytic blood pressure profile using 44-hour ambulatory blood pressure monitoring (ABPM) data in 71 unselected, stable HD patients. Results: There was an increase in BP during the interdialytic period (awake day 1: 135/84 ± 23/14 mm Hg; awake day 2: 140/86 ± 22/15 mm Hg, p < 0.05; sleep day 1: 130/77 ± 24/15 mm Hg; sleep day 2: 136/80 ± 24/15 mm Hg, p < 0.05). The correlation between the average 44-hour BP and interdialytic weight gain (IDWG) was not significant (r = –0.07 for systolic BP and r = –0.09 for diastolic BP). The number of non-dipper patients was high, 77% on interdialytic day 1 and 83% on interdialytic day 2 for systolic BP. Uncontrolled hypertension (average 44 h BP ≧135/85 mm Hg) was diagnosed in 58 (55%) patients. Patients with uncontrolled hypertension had higher pre- and posthemodialysis BP, higher BP on each interdialytic day and night, and higher night/day diastolic BP ratio on the second interdialytic day. These patients were also taking a greater number of vasoactive medications (1.5 vs. 0.6 in those with controlled BP, p = 0.001). There were no significant differences related to kt/V, hematocrit, or weekly erythropoietin dose between patients with controlled or uncontrolled BP. Hemodialysis shift assignment (morning or afternoon) did not impact on BP levels or diurnal profile. Conclusion: In HD patients, interdialytic BP is often poorly controlled, there is a progressive rise in BP, and a trend toward loss of nocturnal decline in BP as the interdialytic period progresses. Further research is needed to determine whether treatment directed to interdialytic BP changes can alter outcomes in HD patients.