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Introduction Low muscle mass, or sarcopenia, is commonly seen in patients with heart failure (HF). For any given level of renal function, patients with sarcopenia will have lower levels of serum creatinine because there is less muscle mass to produce creatinine. Thus, the use of creatinine to estimate glomerular filtration rate (GFR) is affected by sarcopenia. In contrast to creatinine, cystatin C is considered a better filtration marker to estimate GFR in the setting of sarcopenia because it not seclusively produced by muscle. However, it has not been demonstrated that serum cystatin C levels are independent of sarcopenia in patients with HF. Hypothesis Serum cystatin C levels will be minimally influenced by muscle mass in patients with heart failure. Methods Serum cystatin C and serum creatinine were measured in patients with decompensated heart failure. Strict timed urine collections were used to measure creatinine excretion rate. Muscle mass was estimated with a validated equation based on urine creatinine excretion (Heymsfield). Creatinine clearance was calculated and used as a surrogate for measured GFR. Results Out of the 295 patients analyzed (average age 65 ±14 years), 65% were male and 61% were obese. Baseline levels of serum creatinine were 1.5±0.6 mg/dL and cystatin C were 1.7±0.7 mg/L. In univariate analysis, serum cystatin C showed a negative correlation with muscle mass (rho -0.37, p Conclusion Serum cystatin C serum levels are strongly associated with muscle mass in patients with HF. This may lead to inaccuracies when cystatin C is used to estimate GFR.

Introduction Growth differentiation factor-15 (GDF-15) is a stress-responsive biomarker that is elevated in patients with heart failure (HF) and carries prognostic value. However, conditions other than HF can increase levels, making plasma concentration non-specific for HF. In diabetic patients, urinary GDF-15 has been associated with worse kidney function, but its role in HF remains unknown. Therefore, we sought to determine if urinary GDF-15 might provide unique cardio-renal information in patients with HF. Hypothesis Urinary GDF-15 will be associated with diuretic efficiency and survival, independently of plasma GDF-15. Methods GDF-15 was measured in 171 patients with heart failure treated with IV diuretics in the outpatient setting. Pre and post diuretic spot urinary GDF-15 (n=166) was measured using the Mesoscale Assay platform (MesoScale Diagnostics, Gaithersburg, MD, USA). Urinary GDF-15 was normalized to urine creatinine. Diuretic efficiency was defined as sodium excretion per doubling of loop diuretic dose. Results Plasma GDF-15 was weakly correlated with pre-diuretic urinary GDF-15 (r= 0.21, p=0.019) and modestly correlated with post-diuretic urinary GDF-15 (r=0.50, p Conclusion Plasma, but not urinary, GDF-15 was independently associated with diuretic efficiency and survival. This suggests that urinary GDF-15 does not provide specific cardio-renal information, likely because it is mainly filtrated from plasma rather than produced in the kidney.

Introduction Diuretic response is generally assessed using crude measures such as fluid or weight loss which are usually reported in a delayed manner (e.g. the change in weight from one day to the next). This in turn restricts clinicians’ ability to titrate diuretics. These established metrics have poor correlation with one another and they do not predict outcomes as well as cumulative sodium excretion. However, a 24h urine collection is difficult to perform even in a clinical trial, much less in routine clinical practice. It also does not address the lag time between diuretic administration and assessment of response. We previously reported proof of concept results on an equation to estimate sodium excretion based on a post-diuretic spot urine sample. Our current objective was to validate this equation in a real-world sample of patients undergoing IV diuretic therapy. Hypothesis Cumulative sodium output from a loop diuretic can be predicted using a spot urine sample. Methods The validation cohort consisted of 286 hospitalized patients receiving IV diuretics. Our equation is shown below (Figure). The validation cohort consisted of 286 hospitalized patients receiving IV diuretics. Urine collections were performed under intense supervision by a study coordinator. A spot urine was obtained at 1h, 2h post diuretic administration, and a cumulative 6h urine collection was used to determine total sodium. We used the 2h value for the equation. We defined a poor diuretic response as Results The predicted sodium equation had the best receiver operating characteristics (AUC = 0.92, 95% CI = 0.88 to 0.96, p Conclusions Our natriuretic response equation provides a faster and more accurate estimation of sodium excretion following a diuretic dose than either net fluid loss or weight change. This may aid in more rapid assessment of diuretic response and ultimately dose titration.

Introduction In the treatment of patients with acute decompensated heart failure (ADHF) estimation of the degree of volume overload is critical in guiding the goals of diuretic therapy. A “dry weight,” or the weight of a patient when they are euvolemic, is commonly used by clinicians to determine when to discontinue diuretic therapy during hospitalization. However, it is unclear how this dry weight relates to the actual weight loss achieved during hospitalization. Hypothesis Dry weight will have limited correlation with the ultimate weight loss achieved during hospitalization. Methods Patients hospitalized for ADHF with volume overload and receiving IV diuretics were enrolled. Each participant completed a clinical assessment survey that asked, “How many pounds of water weight are you above your dry weight?” We additionally extracted any dry weight that was documented in the electronic medical record (EMR) and the lowest documented weight in the EMR within the previous year. The primary comparison was to evaluate the correlation between the patients’ estimate above their dry weight and the degree of weight loss during ADHF hospitalization. Results 343 patients were enrolled and 246 (73%) were able to describe the amount of fluid above their dry weight, which was on average 15±18 lbs above ideal weight. The patient's estimate of their fluid excess correlated modestly with their actual weight loss during the admission (r= -0.38, P Conclusion Both the estimated and the EMR documented dry weight were only modestly correlated with the actual weight loss achieved during diuresis. Additional research is required to understand if the discrepancy between diuretic induced weight loss and “dry weight” is driven by inaccuracy in the “dry weight” or variability in the diuresis of these patients.

Background Fibroblast growth factor-23 (FGF-23) is a phosphaturic hormone with a primary role in the regulation of phosphate homeostasis. Recently, FGF-23 was shown to be a strong predictor of cardiovascular outcomes, and animal models have reported multiple non-phosphaturic, or off-target, effects of FGF-23. Some of the negative cardio-renal actions reported in the literature are adverse left ventricular remodeling, induction of inflammation, renal/cardiac fibrosis, and direct effects on renal sodium retention. The aim of this current investigation was to further explore the association between FGF-23 with various parameters of cardio-renal dysfunction. Hypothesis FGF-23 will be associated with cardio-renal parameters such as inflammation, neurohormonal activation, diuretic responsiveness, and survival. Methods We analyzed plasma FGF-23 levels in 199 outpatient heart failure (HF) patients who underwent diuretic administration followed by timed urine collections. Diuretic response was defined as the sodium output per doubling of the diuretic dose. Results Higher levels of FGF-23 tended to correlate with serum phosphate (r=0.21, p=0.09) but were not correlated with serum calcium (p=0.37). There were stronger correlations between FGF-23 and several parameters of cardio-renal dysfunction including lower eGFR (r=-0.42, p 0.3 for both). Higher levels of FGF-23 predicted worse diuretic responsiveness (r=-0.47, p Conclusion In patients with HF, plasma levels of FGF-23 were associated with multiple metrics of cardio-renal dysfunction, including a strong independent association with diuretic responsiveness and mortality. Additional research is warranted to understand if FGF-23 is a marker or mediator of cardio-renal dysfunction and if interventions to lower FGF-23 levels can improve outcomes.

Background The primary therapeutic objective during the treatment of acute decompensated heart failure (ADHF) is relief from volume overload. This is achieved primarily through urinary losses of sodium and water from diuretics. Urine output is a primary source of data for monitoring and titrating therapy in these patients. To our knowledge, the prevalence and natural history of bladder dysfunction in patients with ADHF undergoing diuresis has not been described. Hypothesis Bladder dysfunction will be common among patients with ADHF. Methods Patients admitted to Yale New Haven hospital with worsening heart failure requiring IV diuresis were prospectively enrolled. After a forced void, bladder ultrasounds were conducted using a Verathon® BVI 3000 bladder scanner. Three values were taken for each patient and averaged. In a subset of these patients, an ambulatory outpatient follow-up bladder scan was performed. Results 283 patients were enrolled and underwent determination of post void residual (PVR) volume. The average PVR volume was 131 ± 169 ml. Only 41% of patients had a normal PVR ( 100 ml and 23% of the patients had a PVR greater than 200 ml, which meets criteria for acute urinary retention. Surprisingly, we did not find a significant difference in the PVR retention volume between men (138 ± 166 ml) and women (118 ± 173 ml; p=0.32). There was also no difference in the prevalence of a PVR greater than 200 ml between men and women (p=0.19). Similarly, age and diabetic status were not correlated with PVR (p=NS for both) and in patients with a PVR >200 ml both the age (65 ± 15 years vs. 64 ± 13 years, p=0.62) and odds of having diabetes (OR=1.1, p=0.78) were not different. A total of 106 patients returned for an ambulatory a median of 43 days after discharge and had a repeat determination of PVR. Notably, there was a significant improvement in PVR volume post discharge with a mean 58 ± 134 ml (p 200 ml while hospitalized but only 4.7% had a PVR>200 ml at the return visit. Conclusion Significant bladder dysfunction is highly prevalent in ADHF patients and was not associated with traditional causes for bladder dysfunction. This dysfunction was largely resolved upon outpatient follow-up. Additional research is needed to understand the cause and clinical implications of the high rate of bladder dysfunction in patients with ADHF.

Introduction Glomerular filtration rate (GFR) can be estimated using serum creatinine or cystatin C. At the population level, these equations predict GFR with similar accuracy but can give substantially different results at the level of an individual patient. These within-patient differences may be explained by factors such as inflammation, as cystatin C is associated with higher levels of established inflammatory markers. We sought to determine if the discordance between the two GFR estimates could be attributed to inflammation, and furthermore to examine if this information held prognostic value. Hypothesis Discordance of estimated GFR (eGFR) using creatinine vs. cystatin C will be affected by inflammation and patients with greater discordance will have worsened survival. Methods We analyzed an outpatient cohort of patients with chronic stable heart failure (n= 162). CKDEPI-Creatinine and CKDEPI-Cystatin C equations were used to estimate GFR. Discordance of eGFR was calculated as the ratio of eGFRcreatinine to eGFRcystatin. (values higher than 1 represent eGFRcreatinine > eGFRcystatin and lower than 1 represent eGFRcystatin > eGFRcreatinine). Results In the overall population eGFRcreatinine was 54±28mL/min/m2 and the eGFRcystatin was 43±25mL/min/m2, resulting in an average ratio of 1.3±0.4. There were, however, substantial differences in individual patients with the 10th percentile ratio at 0.9 and 90th percentile a ratio of 1.7. Notably, the ratio was correlated with plasma interleukin-6 (r= 0.24), C-reactive protein (r= 0.23), and ST2 (r= 0.26); p Conclusion The discordance of eGFR with creatinine and cystatin C was associated with markers of inflammation and holds powerful independent prognostic information. Additional study into the drivers of the discordance in GFR estimates by cystatin C and creatinine is warranted.

Background Volume overload is a major driver of symptoms and organ dysfunction in heart failure. Although we typically focus on intravascular volume overload, the majority of fluid and sodium actually reside in extravascular spaces. The kidney regulates both intravascular and extravascular sodium and fluid stores. As such, markers of extravascular fluid overload may provide important cardio-renal information. Natriuretic peptides have emerged as the prototype biomarker of intravascular overload, released primarily in response to ventricular stretch. The use of carbohydrate antigen 125 (CA-125) in heart failure has also gained popularity. CA-125 is a glycoprotein produced largely from serosal epithelium such as pleura, pericardium, and peritoneum, and its increased circulation can be the result of extravascular volume retention and likely inflammation of these tissues. The goal of this analysis was to better understand the relative importance of intravascular vs. extravascular markers of volume overload on cardio-renal parameters. Methods Plasma NT-proBNP and CA-125 were measured in 199 outpatients presenting to the Yale Transition Care Center for evaluation and treatment of volume overload. Urine samples were collected before and after administration of loop diuretics, in addition to a timed urine collection. Diuretic efficiency was defined as sodium excretion per doubling of loop diuretic dose. Results The median level of CA-125 was 78 U/ml (IQR 28-187 U/ml) and the median NT-proBNP was 1860 pg/ml (IQR 607-4670 pg/ml). There was a modest correlation between these markers (r=0.40, p Conclusion Between the markers of intravascular volume overload (NT-proBNP) and extravascular volume overload (CA-125), we found that signals of intravascular volume overload appeared to have much more important effects on cardio-renal dysfunction. Additional research is warranted to better understand if this is related to the limitations of the biomarkers or the greater importance of intravascular fluid overload on cardio-renal function.

Introduction It is often assumed that diuretic delivery to the site of action is adequate if the route of administration is intravenous (IV). Although IV administration circumvents gastrointestinal bioavailability, the diuretic must be delivered and secreted into the tubular lumen induce diuresis. In ADHF, perturbations such as reduced renal perfusion and renal dysfunction may impact delivery to the tubular site of action. Hypothesis There will be substantial between-patient heterogeneity in renal diuretic delivery across hospitalized AHDF patients receiving IV diuretics. Methods ADHF patients receiving IV diuretics at Yale New Haven Hospital underwent intensively supervised timed urine collection. Renal diuretic delivery was defined as the percentage of loop diuretic recovered unchanged in the urine in the 6h after IV diuretic administration. Results 105 patients were studied after a median 80 mg (IQR 40-160mg) IV furosemide equivalents, with a median of 30 mg (12-59 mg) of unchanged loop diuretic recovered in the urine. Thus, 37% (21-54%) reached the site of action, substantially less than that reported in normal subjects (∼50-70%, p 0.1). A modest correlation between better renal filtration (eGFR r=0.23, p=0.02; creatinine clearance r=0.33, p=0.01; Cystatin C r=-0.30, p=0.003) and higher renal diuretic delivery was noted. Renal urea handling had the strongest correlation with renal diuretic delivery (fractional excretion of urea r=0.49, p= Conclusion Large variations IV loop diuretic delivered to the tubular site of action exists between hospitalized ADHF patients, and these differences relate to the ultimate diuretic response. The strongest associated factor is renal urea handling, which captures elements of renal perfusion, filtration, and solute handling. Given that patients with poor diuretic delivery may preferentially respond to loop diuretic titration, additional research is warranted to better identify patients with poor diuretic delivery.

Introduction In general, clinicians round on patients hospitalized with heart failure (HF) once per day. Additionally, the metrics commonly used to determine response to diuretics, such as fluid and weight loss, are often not recorded after each diuretic dose. Given these limitations, diuretics are generally titrated at best daily. In patients with diuretic resistance, this can translate to lost hospital days with ineffective doses of diuretics. To address this issue, we designed a protocol (herein referred to as the Yale Diuretic Pathway or YDP) to allow for rapid and safe loop diuretic escalation. Hypothesis The nurse driven auto-titrating YDP will lead to rapid dose escalation, without an excessive incidence of hypokalemia, worsening renal function, or hypotension. Methods Advanced heart failure physicians selected 51 patients, largely those who were failing traditional diuretic therapy, for this non-randomized pilot of the YDP. The provider could select the starting dose of diuretic (though the default was 2 mg of bumetanide). Additionally, providers would select safety parameters such as lowest tolerable blood pressure (default was a systolic reading of 90 mmHg or less) and largest allowable increase in creatinine (0.5 mg/dL). Diuretics were titrated based on predicted sodium excretion after each dose, which was predicted using an equation based on a spot urine sample taken 2 h after administration. Based on the predicted sodium output diuretic doses were either held, kept constant, or increased. Patients could receive up to 3 doses daily and a maximum of 12.5 mg bumetanide, equivalent to 500 mg of furosemide per dose and 1500 mg of furosemide per day. Signals for safety such as hypotension, electrolyte abnormalities, and changes in renal function were examined. Results Patients were on the YDP for an average of 3 ± 1.3 days, and the median starting dose was 80 mg of furosemide equivalents (IQR 80-160 mg). The majority of patients required the maximum daily dose of furosemide equivalents over this period (median = 1500mg, IQR 980 to 1500mg) and they reached their peak dose within 1.9 ± 0.7 days. Despite this degree of diuretic resistance, YDP still resulted in a weight loss of 4.0± 3.3 kgs total and fluid output of 9.4L ± 5.1L over the average 3 days of the protocol. With respect to safety, the average rise in creatinine was 0.1 mg/dL. No patients experienced a serum potassium below 3.0 mg/dL and only 3 patients had a serum magnesium below 1.5 mg/dL. Discontinuation of YDP for issues such as a rise in creatinine (10%) and reduction in systolic blood pressure (8%) were relatively uncommon. Conclusion The YDP lead to safe and rapid loop diuretic titration in a population comprised largely of diuretic resistant HF patients. Randomized studies are needed better characterize the safety and efficacy of the YDP.

Inferior vena cava (IVC) measurements correlate modestly with right atrial pressure (RAP). Part of this inaccuracy is due to the high compliance of the venous system where a large change in blood volume may result in only a small change in pressure. This uncoupling of pressure and volume is

Inflammatory processes play a central role in the pathophysiology of heart failure. We recently demonstrated that urine IL-6 is strongly correlated with multiple measures of cardio renal dysfunction (CRD) including diuretic responsiveness (DR), RAAS activation, and lower eGFR. TNF-α, a pleotropic