Javier A. Neyra

Association of Hyperchloremia with Hospital Mortality in Critically Ill Septic Patients

Objectives:Hyperchloremia is frequently observed in critically ill patients in the ICU. Our study aimed to examine the association of serum chloride (Cl) levels with hospital mortality in septic ICU patients. Design:Retrospective cohort study. Setting:Urban academic medical center ICU. Patients:ICU adult patients with severe sepsis or septic shock who had Cl measured on ICU admission were included. Those with baseline estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or chronic dialysis were excluded. Interventions:None. Measurements and Main Results:Of 1,940 patients included in the study, 615 patients (31.7%) had hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission. All-cause hospital mortality was the dependent variable. Cl on ICU admission (Cl0), Cl at 72 hours (Cl72), and delta Cl (&Dgr;Cl = Cl72 – Cl0) were the independent variables. Those with Cl0 greater than or equal to 110 mEq/L were older and had higher cumulative fluid balance, base deficit, and Sequential Organ Failure Assessment scores. Multivariate analysis showed that higher Cl72 but not Cl0 was independently associated with hospital mortality in the subgroup of patients with hyperchloremia on ICU admission (adjusted odds ratio for Cl72 per 5 mEq/L increase = 1.27; 95% CI, 1.02–1.59; p = 0.03). For those who were hyperchloremic on ICU admission, every within-subject 5 mEq/L increment in Cl72 was independently associated with hospital mortality (adjusted odds ratio for &Dgr;Cl 5 mEq/L = 1.37; 95% CI, 1.11–1.69; p = 0.003). Conclusions:In critically ill septic patients manifesting hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission, higher Cl levels and within-subject worsening hyperchloremia at 72 hours of ICU stay were associated with all-cause hospital mortality. These associations were independent of base deficit, cumulative fluid balance, acute kidney injury, and other critical illness parameters.

Contrast-induced acute kidney injury following coronary angiography: a cohort study of hospitalized patients with or without chronic kidney disease

BACKGROUND Contrast-induced acute kidney injury (CIAKI) has been linked to unfavorable consequences. In routine clinical practice, small increases in serum creatinine (SCr) following coronary angiography tend to be underestimated, especially in patients without chronic kidney disease (CKD). METHODS We conducted a retrospective observational cohort study to analyze in-hospital and long-term outcomes of CIAKI following coronary angiography in patients with or without CKD (eGFR ≥ 60 mL/min/1.73 m(2)) from January 2008 through December 2009. CIAKI was defined as SCr either ≥ 25% or ≥ 0.5 mg/dL from baseline within 72 h after contrast exposure. Multivariable logistic regression for in-hospital mortality and Cox proportional hazards calculations for long-term mortality and requirement for dialysis were performed. RESULTS A total of 1160 patients were included in the study. CIAKI occurred in 19% of CKD patients and in 18% of non-CKD patients. In CKD and non-CKD patients, CIAKI was more frequent in patients requiring mechanical ventilation or inotropes or in those given furosemide, and it was associated with adverse in-hospital (prolonged hospitalization, acute dialysis and mortality) and long-term (increased creatinine, initiation of dialysis and mortality) outcomes. In multivariable analysis, CKD patients had greater in-hospital mortality if they developed CIAKI (adjusted OR 8, 95% CI 1.9-34.5, P = 0.005), and non-CKD patients had greater long-term mortality if they developed CIAKI (adjusted HR 2.2, 95% CI 1.2-4.1, P = 0.016). CONCLUSIONS CIAKI following coronary angiography was associated with adverse in-hospital and long-term outcomes in both CKD and non-CKD patients.

Klotho, stem cells, and aging.

Aging is an inevitable and progressive biological process involving dysfunction and eventually destruction of every tissue and organ. This process is driven by a tightly regulated and complex interplay between genetic and acquired factors. Klotho is an antiaging gene encoding a single-pass transmembrane protein, klotho, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy, and modulation of many signaling pathways, including insulin-like growth factor and Wnt. Klotho deficiency activates Wnt expression and activity contributing to senescence and depletion of stem cells, which consequently triggers tissue atrophy and fibrosis. In contrast, the klotho protein was shown to suppress Wnt-signaling transduction, and inhibit cell senescence and preserve stem cells. A better understanding of the potential effects of klotho on stem cells could offer novel insights into the cellular and molecular mechanisms of klotho deficiency-related aging and disease. The klotho protein may be a promising therapeutic agent for aging and aging-related disorders.

Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients With Hypertension

Background: It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients with hypertension and whether reducing the risk of LVH explains the reported cardiovascular disease (CVD) benefits of intensive BP lowering in this population. Methods: This analysis included 8164 participants (mean age, 67.9 years; 35.3% women; 31.2% blacks) with hypertension but no diabetes mellitus from the SPRINT trial (Systolic Blood Pressure Intervention Trial): 4086 randomly assigned to intensive BP lowering (target SBP <120 mm Hg) and 4078 assigned to standard BP lowering (target SBP <140 mm Hg). Progression and regression of LVH as defined by Cornell voltage criteria derived from standard 12-lead ECGs recorded at baseline and biannually were compared between treatment arms during a median follow-up of 3.81 years. The effect of intensive (versus standard) BP lowering on the SPRINT primary CVD outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, and CVD death) was compared before and after adjustment for LVH as a time-varying covariate. Results: Among SPRINT participants without baseline LVH (n=7559), intensive (versus standard) BP lowering was associated with a 46% lower risk of developing LVH (hazard ratio=0.54; 95% confidence interval, 0.43–0.68). Similarly, among SPRINT participants with baseline LVH (n=605, 7.4%), those assigned to the intensive (versus standard) BP lowering were 66% more likely to regress/improve their LVH (hazard ratio=1.66; 95% confidence interval, 1.31–2.11). Adjustment for LVH as a time-varying covariate did not substantially attenuate the effect of intensive BP therapy on CVD events (hazard ratio of intensive versus standard BP lowering on CVD, 0.76 [95% confidence interval, 0.64–0.90] and 0.77 [95% confidence interval, 0.65–0.91] before and after adjustment for LVH as a time-varying covariate, respectively). Conclusions: Among patients with hypertension but no diabetes mellitus, intensive BP lowering (target systolic BP <120 mm Hg) compared with standard BP lowering (target systolic BP <140 mm Hg) resulted in lower rates of developing new LVH in those without LVH and higher rates of regression of LVH in those with existing LVH. This favorable effect on LVH did not explain most of the reduction in CVD events associated with intensive BP lowering in the SPRINT trial. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.Background:It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients w...

Potential application of klotho in human chronic kidney disease

The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.

Effect of Intensive Blood Pressure Lowering on Left Ventricular Hypertrophy in Patients with Hypertension: The Systolic Blood Pressure Intervention (SPRINT) Trial

Background: It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients with hypertension and whether reducing the risk of LVH explains the reported cardiovascular disease (CVD) benefits of intensive BP lowering in this population. Methods: This analysis included 8164 participants (mean age, 67.9 years; 35.3% women; 31.2% blacks) with hypertension but no diabetes mellitus from the SPRINT trial (Systolic Blood Pressure Intervention Trial): 4086 randomly assigned to intensive BP lowering (target SBP <120 mm Hg) and 4078 assigned to standard BP lowering (target SBP <140 mm Hg). Progression and regression of LVH as defined by Cornell voltage criteria derived from standard 12-lead ECGs recorded at baseline and biannually were compared between treatment arms during a median follow-up of 3.81 years. The effect of intensive (versus standard) BP lowering on the SPRINT primary CVD outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, and CVD death) was compared before and after adjustment for LVH as a time-varying covariate. Results: Among SPRINT participants without baseline LVH (n=7559), intensive (versus standard) BP lowering was associated with a 46% lower risk of developing LVH (hazard ratio=0.54; 95% confidence interval, 0.43–0.68). Similarly, among SPRINT participants with baseline LVH (n=605, 7.4%), those assigned to the intensive (versus standard) BP lowering were 66% more likely to regress/improve their LVH (hazard ratio=1.66; 95% confidence interval, 1.31–2.11). Adjustment for LVH as a time-varying covariate did not substantially attenuate the effect of intensive BP therapy on CVD events (hazard ratio of intensive versus standard BP lowering on CVD, 0.76 [95% confidence interval, 0.64–0.90] and 0.77 [95% confidence interval, 0.65–0.91] before and after adjustment for LVH as a time-varying covariate, respectively). Conclusions: Among patients with hypertension but no diabetes mellitus, intensive BP lowering (target systolic BP <120 mm Hg) compared with standard BP lowering (target systolic BP <140 mm Hg) resulted in lower rates of developing new LVH in those without LVH and higher rates of regression of LVH in those with existing LVH. This favorable effect on LVH did not explain most of the reduction in CVD events associated with intensive BP lowering in the SPRINT trial. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.Background:It is currently unknown whether intensive blood pressure (BP) lowering beyond that recommended would lead to more lowering of the risk of left ventricular hypertrophy (LVH) in patients w...

Cumulative Fluid Balance and Mortality in Septic Patients With or Without Acute Kidney Injury and Chronic Kidney Disease.

Objective:Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients. Design:Retrospective cohort study. Setting:Urban academic medical center ICU. Patients:ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or receiving chronic dialysis were excluded. Interventions:None. Measurements and Main Results:A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04–1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03–1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05–1.13] for acute kidney injury–/chronic kidney disease+; 1.05 [1.03–1.08] for acute kidney injury+/chronic kidney disease–; and 1.07 [1.02–1.11] for acute kidney injury–/chronic kidney disease–). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9 L for acute kidney injury+/chronic kidney disease+; 3.8 L for acute kidney injury–/chronic kidney disease+; 4.3 L for acute kidney injury+/chronic kidney disease–; and 1.5 L for acute kidney injury–/chronic kidney disease–. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury. Conclusions:Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease.

Extracellular Volume Overload and Increased Vasoconstriction in Patients With Recurrent Intradialytic Hypertension

Background/Aims: Intradialytic hypertension (IH) occurs frequently in some hemodialysis patients and increases mortality risk. We simultaneously compared pre-dialysis, post-dialysis and changes in extracellular volume and hemodynamics in recurrent IH patients and controls. Methods: We performed a case-control study among prevalent hemodialysis patients with recurrent IH and hypertensive hemodialysis controls. We used bioimpedance spectroscopy and impedance cardiography to compare pre-dialysis, post-dialysis, and intradialytic change in total body water (TBW) and extracellular water (ECW), as well as cardiac index (CI) and total peripheral resistance index (TPRI). Results: The ECW/TBW was 0.453 (0.05) pre-dialysis and 0.427 (0.04) post-dialysis in controls vs. 0.478 (0.03) and 0.461 (0.03) in IH patients (p=0.01 post-dialysis). The ECW/TBW change was -0.027 (0.03) in controls and -0.013 (0.02) in IH patients (p=0.1). In controls, pre- and post-dialysis TPRI were 3254 (994) and 2469 (529) dynes/sec/cm2/m2 vs. 2983 (747) and 3408 (980) dynes/sec/cm2/m2 in IH patients (p=0.002 post-dialysis). There were between-group differences in TPRI change (0=0.0001), but not CI (p=0.09). Conclusions: Recurrent intradialytic hypertension is associated with higher post-dialysis extracellular volume and TPRI. Intradialytic TPRI surges account for the vasoconstrictive state post-dialysis, but intradialytic fluid shifts may contribute to post-hemodialysis volume expansion.

Fibroblast growth factor 23 and acute kidney injury

Fibroblast growth factor 23 (FGF23), which is produced in bone, participates in the maintenance of phosphate metabolism and can serve as a biomarker for adverse cardiovascular outcomes in patients with chronic kidney disease and end-stage renal disease. Circulating FGF23 rapidly increases after acute kidney injury (AKI), preceding other known markers such as neutrophil gelatinase-associated lipocalin and serum creatinine. The increase in FGF23 in AKI appears to be independent of parathyroid hormone, vitamin D signaling pathways, and dietary phosphate. The potential mechanisms include: (1) increased production of FGF23 in the bone by yet-to-be-identified factors; (2) ectopic production of FGF23 by injured renal tubules; and (3) decreased renal clearance of circulating FGF23. Circulating FGF23 determined by intact FGF23 enzyme-linked immunosorbent assay (ELISA) is a more reliable biomarker of AKI than FGF23 C-terminal ELISA (a mixed readout of C-terminal fragment and intact FGF23). Given that FGF23 can be ectopically expressed in differentiated renal tubules and iron modulates FGF23 metabolism, an effect of iron on FGF23 expression in renal tubules is conceivable but remains to be confirmed. More clinical and experimental studies are required to validate the use of circulating FGF23 as a biomarker for the early identification of AKI and prediction of short- and long-term adverse outcomes post-AKI. More importantly, the biologic effect of increased FGF23 in AKI needs to be defined.

Comparison of Ambulatory Blood Pressure Patterns in Patients With Intradialytic Hypertension and Hemodialysis Controls.

Background/Aims: Intradialytic hypertension (IH) patients have higher mortality risk than other hemodialysis patients and have been shown to have higher ambulatory blood pressure (BP). We hypothesized that interdialytic BP patterns would differ in IH patients and hypertensive hemodialysis controls. Methods: We consecutively screened hemodialysis patients at our university-affiliated units. Based on pre and post-HD BP measurements during the prior 2 week period, we identified IH patients and demographically matched hemodialysis controls. We measured ambulatory interdialytic BP, flow-mediated vasodilation, and intradialytic endothelin-1 (ET-1). Using linear mixed-models, we compared BP slopes during the following intervals: 1-24 hours post-dialysis, 25-44 hours post-dialysis, and 1-44 hours post-dialysis. Results: There were 25 case subjects with IH and 24 controls. Systolic BP during hours 1-44, 1-24, and 25-44 were 143.1 (16.5), 138.0 (21.2), and 150.8 (22.3) mmHg in controls. For IH subjects, they were 155.4 (14.2), 152.7 (22.8), and 156.5 (20.8) mmHg (p=0.008, 0.02, 0.4). In controls, the slopes were +0.6, +0.6, and +0.4 mmHg/hr. In IH subjects, they were +0.1, -0.3, and +0.3 mmHg/hr. The IH 1-24 hour slope differed from the IH 25-44 hour slope (p=0.001) and the control 1-24 hour slope (p=0.002). The change in ET-1 from pre to post dialysis was 0.5 (1.5) pg/mL in controls and 1.0 (2.3) pg/mL in IH patients (p=0.4). In a univariate model, there was an association with screening BP and BP slope (p=0.002 for controls and p=0.1 for IH patients). Conclusions: Interdialytic BP patterns differ in IH patients and hemodialysis controls. The elevated post dialysis blood pressure persists for many hours in IH patients contributing to the overall increased BP burden.