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Background: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear. Methods: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Results: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P =0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6–27.7]; P =0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P =0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P =0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P =0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (−1861 versus −727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83–0.95]; P Conclusions: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04049045.

Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD.Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI.Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Supplemental Digital Content is available in the text., Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure–associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics. Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6. Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133–936]; P=0.005) and week 6 (mean difference, 545 mL [95% CI, 136–954]; P=0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, −7.85 mmol/L [95% CI, −2.43 to 6.73]; P=0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, −0.03 to 0.63]; P=0.09; week 6, 0.11% [95% CI, −0.22 to 0.44]; P>0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26–598]; P=0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6. Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.

BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m(2) from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH

Background: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. Methods: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. Results: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis ( P ≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [ P ≥0.33 for all]) or neurohormonal activation (plasma or urine renin [ P ≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis ( P =0.44). Conclusions: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.

Purpose of review: Chronic breathlessness is a troublesome symptom experienced by people with advanced malignant and nonmalignant disease. Disease-directed therapies are often insufficient in the management of chronic breathlessness. Therefore, pharmacological and nonpharmacological breathlessness-specific interventions should be considered for select patients. Recent findings: There is some evidence to support the use of low-dose opioids (

A long-acting loop diuretic, azosemide, has been shown to improve long-term prognosis in patients with heart failure compared with a short-acting loop diuretic, furosemide. However, the therapeutic advantages of azosemide over furosemide have not been clearly established. In this study, we retrospectively analyzed clinical outcomes and laboratory data in patients with congestive heart failure treated with furosemide or azosemide, and the efficacy of these agents was compared. First, we screened 1900 patients and selected 124 (furosemide group: n = 40; azosemide group: n = 84) as the total study population. From these patients, we next selected 72 patients for the propensity score-matched analysis (furosemide group: n = 36; azosemide group: n = 36). The incidence of all-cause death and rehospitalization due to worsening heart failure during 24 months of follow-up was similar between the furosemide and azosemide groups in both the total study population and the propensity score-matched population. However, in the propensity score-matched analysis, the estimated glomerular filtration rate time-dependently decreased during 36 months of follow-up in the furosemide group (56.5 ± 19.5-43.2 ± 16.3 mL/min/1.73 m), whereas it did not change in the azosemide group (58.6 ± 22.0-50.3 ± 17.8 mL/min/1.73 m) (P = 0.032). Azosemide might have some potential advantage for renal protection over furosemide in patients with congestive heart failure.

Background: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians’ clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients’ status. Methods: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. Results: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of −2.2 mg/day (−2.9 to −1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75–0.92]; P for interaction, 0.54). Conclusions: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.

In the setting of acute decompensated heart failure, decongestion has become a “holy grail,” because patients who are effectively decongested by treatment do better both from a neurohormonal standpoint and clinically. “Congestion” is variably defined, but a recent position statement from the

BACKGROUND AND OBJECTIVES: Loop diuretics are commonly used to manage nondialysis-dependent CKD. Despite benefits of augmented urine output, loop diuretics are often discontinued after dialysis initiation. Here, we assessed the association of the early decision to continue loop diuretics at hemodialysis start with clinical outcomes during the first year of dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We considered all patients on in-center hemodialysis at a large dialysis organization (2006–2013) with Medicare Part A and D benefits who had an active supply of a loop diuretic at dialysis initiation (n=11,297). Active therapy was determined on the basis of whether loop diuretic prescription was refilled after dialysis initiation and within 30 days of exhaustion of prior supply. Patients were followed under an intention-to-treat paradigm for up to 12 months for rates of death, hospitalization, and intradialytic hypotension and mean monthly values of interdialytic weight gain, serum potassium, predialysis systolic BP, and ultrafiltration rates. RESULTS: We identified 5219 patients who refilled a loop diuretic and 6078 eligible controls who did not. After adjustments for patient mix and clinical differences, continuation of loop diuretics was associated with lower hospitalization (adjusted incidence rate ratio, 0.93; 95% confidence interval, 0.89 to 0.98) and intradialytic hypotension (adjusted incidence rate ratio, 0.95; 95% confidence interval, 0.92 to 0.99) rates, no difference in death rate (adjusted hazard ratio, 0.92; 95% confidence interval, 0.84 to 1.01), and lower interdialytic weight gain (P=0.03). CONCLUSIONS: Continuation of loop diuretics after hemodialysis initiation was associated with lower rates of hospitalization and intradialytic hypotension as well as lower interdialytic weight gain, but there was no difference in mortality over the first year of dialysis.

No study has systematically evaluated the prevalence and dosages of diuretic use for patients after left ventricular assist device (LVAD) implantation. The primary objective was to characterize chronologic change in prevalence and doses of loop diuretics after LVAD placement. The secondary objective was to identify correlates of actual doses of loop diuretics. We retrospectively reviewed medical records of adult patients with LVAD implantation at the University of Kentucky. Prevalence of diuretic use and furosemide equivalent dose were assessed before LVAD implantation and at seven time points thereafter: 1 week, 1 month, 3 months, 6 months, 1 year, 18 months, and 2 years. Correlation analyses and linear mixed modeling were used to identify correlates of diuretic dose before and after LVAD implantation. Eighty-two consecutive eligible patients were reviewed. The prevalence of loop diuretic use was 95% at baseline but significantly lower than that at all subsequent time points (p < 0.048 for all). Nevertheless, more than half of patients on whom we had such follow-up data were on loop diuretics 2 years after LVAD implantation. Average furosemide equivalent dose was significantly lower at every time point after implantation compared with baseline (p < 0.006 for all). Blood urine nitrogen (BUN) was the most robust predictor of dose after LVAD implant. The prevalence and average furosemide equivalent dose were significantly reduced after LVAD implantation, but the use of loop diuretic remained more than 50% for up to 2 years. Consistent association with BUN may indirectly indicate overuse of diuretics post-LVAD implant.

Background Evidence accumulated that some glucose‐lowering medications protect against cardiovascular events ( CVEs ) in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease. The present study evaluated if and how glucose‐lowering medication prescription pattern changes in T2DM after a CVE. Methods and Results DATAFILE (Diabetes Therapy After a Cardiovascular Event) was a retrospective multicenter study conducted at 12 diabetes mellitus specialist outpatient clinics in Italy. We identified T2DM patients with an incident CVE for whom a follow‐up visit was available after the event. We selected control T2DM patients without an incident CVE , who were matched with cases for age, sex, known diabetes mellitus duration, baseline hemoglobin A 1c , kidney function, and follow‐up time. We extracted clinical variables and compared prescribed therapies at baseline and follow‐up. We included 563 patients with and 497 matched patients without an incident CVE . As expected, patients with a subsequent CVE had a higher baseline prevalence of ischemic heart disease. After a median of 9.5 months, in patients with versus those without a CVE , there was a significant increase in the prescription of beta‐blockers, loop diuretics, dual antiplatelet therapy, and, among glucose‐lowering medications, a significant decrease in metformin. Hemoglobin A 1c marginally declined only in the control group, whereas low‐density lipoprotein cholesterol decreased only in patients with CVE . Conclusions This study highlights that occurrence of a CVE in T2DM patients did not prime the prescription of glucose‐lowering medications provided with cardiovascular protective effects, even though glucose control remained poor. These data emphasize the need to optimize the therapeutic regimen of T2DM patients with established cardiovascular disease, according to updated guidelines.

Background: Currently, there are no meta-analyses evaluating the efficacy and safety of intermittent vs continuous furosemide for heart failure concomitant renal dysfunction. Our protocol is conceived to evaluate the efficacy and safety of intermittent vs continuous furosemide for heart failure concomitant renal dysfunction. Methods: We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines and the recommendations of the Cochrane Collaboration to conduct this meta-analysis. The systematic review protocol has been registered in Open Science Framework registries. The following databases including PubMed, Cochrane Library, Web of Science, and EMBASE will be searched using the key phrases “loop diuretics,” “furosemide,” “heart failure,” and “renal dysfunction” for all randomized clinical trials (RCTs) published up to May 2021. Revman 5.3 (Nordic Cochrane Centre, Denmark) will be used to complete the meta-analysis and generate forest plots. We will choose between a fixed effects and random effects model based upon the heterogeneity of included studies. Significance will be set at P

Chronic hypertension and associated cardiovascular disease are among the leading causes of maternal and perinatal morbidity and death in the United States. Chronic hypertension in pregnancy is associated with a host of adverse outcomes that include preeclampsia, cesarean delivery, cerebrovascular accidents, fetal growth restriction, preterm birth, and maternal and perinatal death. There are several key issues related to the diagnosis and management of chronic hypertension in pregnancy where data are limited and further research is needed. These challenges and recent guidelines for the management of chronic hypertension are reviewed. Well-timed pregnancies are of utmost importance to reduce the risks of chronic hypertension; long-acting reversible contraceptive options are preferred. Research to determine optimal blood pressure thresholds for diagnosis and treatment to optimize short- and long-term maternal and perinatal outcomes should be prioritized along with interventions to reduce extant racial and ethnic disparities.

OBJECTIVE Diuretic drugs have been a mainstay of hypertension treatment in the elderly however their dementia sparing effects are under-reported. The objective was to quantify dementia risk in relation to diuretic antihypertensive drugs. METHODS Electronic databases were searched until June 2015. ELIGIBILITY CRITERIA population, adults without dementia from primary care, community cohort, residential/institutionalized, or randomized controlled trial; exposure, diuretic antihypertensive drug; comparison, no diuretic drug, other or no antihypertensive drug, placebo-control; outcome, incident dementia diagnosed by standardized criteria. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were pooled in fixed-effects models with RevMan 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) and the findings rated according to The Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS A total of 15 articles were included (52 599 persons, 3444 dementia cases, median age 76.1 years) and median follow-up was 6.1 years. Diuretics were associated with reduced dementia risk (HR 0.83; 95% CI 0.76-0.91, P

Background Dapagliflozin inhibits the sodium‐glucose–linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium‐glucose–linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide. Methods and Results Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d −1 of Na + were randomized to bumetanide (1 mg·d −1 ), dapagliflozin (10 mg·d −1 ), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na + excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d −1 ; P P −1 ; P −1 ; P + excretion with dapagliflozin was 190% greater ( P −1 ), and Na + excretion with bumetanide was 36% greater ( P −1 ). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy ( P Conclusions First‐dose Na + excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na + excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide‐induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT00930865.

Furosemide has historically been the primary loop diuretic in heart failure patients despite data suggesting potential advantages with torsemide. We used the Duke Echocardiography Lab Database to investigate patients admitted with heart failure to Duke Hospital from 2000 to 2010 who were discharged on either torsemide or furosemide. We described baseline characteristics based on discharge diuretic and assessed the relationship with all-cause mortality through 5 years. Of 4580 patients, 86% (n = 3955) received furosemide and 14% (n = 625) received torsemide. Patients receiving torsemide were more likely to be female and had more comorbidities compared with furosemide-treated patients. Survival was worse in torsemide-treated patients [5-year Kaplan-Meier estimated survival of 41.4% (95% CI: 36.7-46.0) vs. 51.5% (95% CI: 49.8-53.1)]. After risk adjustment, torsemide use was no longer associated with increased mortality (hazard ratio 1.16; 95% CI: 0.98-1.38; P = 0.0864). Prospective trials are needed to investigate the effect of torsemide versus furosemide because of the potential for residual confounding.

Objective: To evaluate risk indicators for congenital and delayed onset hearing loss in a cohort of newborns who underwent newborn hearing screening, and to evaluate the impact of use of the Joint Committee on Infant Hearing (JCIH) recommendations on requirements for ongoing monitoring of infants identified as at risk for hearing loss. Patients and Methods: Cohort of 26,341 newborns entered in a prospectively collected database as part of the University of Michigan Universal Newborn Hearing Screening program, with 90 patients identified. Logistic regression analysis was used to evaluate putative risk indicators for congenital and delayed onset hearing loss. An estimate of the cost burden of ongoing monitoring imposed by the use of differing risk indicators was performed. Results: After controlling for the impact of other risk indicators, intensive care unit length of stay greater than 5 days and exposure to loop diuretics are not associated with an increased risk of congenital or delayed onset hearing loss. Inclusion of these risk indicators as a requirement for ongoing audiologic monitoring results in a high monitoring cost per additional case identified. Discussion: This study confirms that the majority of the risk indicators currently recommended by the JCIH are effective at identifying infants at increased risk of congenital and delayed onset hearing loss. However, use of neonatal intensive care unit length of stay greater than 5 days and exposure to ototoxic medications are associated with small gains in the number of infants correctly identified as at risk of hearing loss. Further evaluation of the utility of these risk indicators, preferably with a diversity of patient population and healthcare settings, is warranted. Key Words: Hearing lossVNeonatal screeningV Risk factors. Otol Neurotol 35:1839Y1843, 2014.

Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain.

Background— Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose. Methods and Results— We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r 2 ≤0.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission diuretic therapy, traditional baseline characteristics, including right heart catheterization variables, were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04−1.78; P =0.02; ESCAPE: HR, 2.86; 95% CI, 1.53−5.36; P =0.001). Conclusions— Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine (123l-MIBG) myocardial scintigraphy. We enrolled 137 hospitalized patients (62.5 ± 14.2 years old, 103 men) with LVEF < 45% who underwent 123l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using 123l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events. Cardiac events occurred in 57 patients in a follow-up period of 33.1 ± 30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P = .0042, P = .033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40 mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P = .003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60 mg/day vs 40–60 mg/day vs

Diuretics are the most commonly prescribed drugs for hypertension in the USA [1]. Diuretics modulate the reabsorption of sodium in the kidney and affect the homeostasis of water and sodium and thus the volume of blood and blood pressure. From a pharmacogenomics perspective, the most well studied drug in this class is the thiazide diuretic hydrochlorothiazide (HCT). HCT is excreted primarily by renal elimination with greater than 95% of the drug recovered unchanged in the urine [2]. Therefore, pharmacodynamic genes have been the focus for studies of the variation in response to thiazide diuretics. Thiazide diuretics act by inhibiting the sodium chloride cotransporter, NCC, coded for by SLC12A3 [3]. Also acting on sodium regulation in the kidney, loop diuretics such as furosemide, target the sodium potassium chloride cotransporter (NKCC2, SLC12A1). In addition, another subclass of diuretics, potassium-sparing diuretics like amiloride, act on the sodium channel ENac, coded for by SCNN1 family of genes. Table 1 shows the common names and their corresponding HGNC gene symbols for the key transporters. Table 1 Transporters and accessory proteins involved in diuretic pharmacodynamics and the genes that encode them This brief summary introduces the candidate genes in the pharmacodynamic pathway of diuretics (Fig. 1) and discusses the pharmacogenomic studies. Fig. 1 Graphic representation of the candidate genes involved in the pharmacodynamics of diuretics. A fully interactive version of this pathway is available online at PharmGKB (http://www.pharmgkb.org/pathway/PA165984799). Thiazide diuretics The sodium chloride cotransporter SLC12A3 is also known as the thiazide-sensitive transporter. It controls uptake of sodium accompanied by a chloride ion from the lumen into the kidney epithelial cell in the distal convoluted tubule (DCT) [4]. Sodium is then returned to the bloodstream through the ATP-dependent sodium-potassium pump, Na,K-ATPase [5] (Fig. 1). The Na,-K-ATPase is coded for by several genes of the ATPase family, which show tissue specific expression [5]. The uptake of sodium by SLC12A3 can be blocked by thiazide diuretics, or by rare, hereditary loss of function mutations in the SLC12A3 gene that result in Gitelman’s syndrome [3,4]. Thiazides inhibit the binding of chloride to SLC12A3, which then prevents the cotransport of sodium [6]. In order to have its pharmacological effect the thiazide must first be excreted into the lumen by transporters OCT1 and OCT3, coded for by SLC22A6 and SLC22A8 [PMID: 18216144]. Both the trafficking of SLC12A3 to the membrane and phosphorylation and activation of SLC12A3 is controlled by the with-no-lysine kinases (WNKs) [7]. As seen in Fig. 1, the WNKs are central to a complex regulatory network that balances the relative roles of the different transporters and ion channels in the different parts of the kidney (for a full review of the detailed signaling see Hoorn and Ellison [7]). In the DCT, WNK3 activates SLC12A3 both directly and through STK39 (also known as SPAK, or Ste20/SPS1-related kinase) [8,9]. WNK1 may also activate STK39 [7]. STK39 phosphorylates SLC12A3 in the DCT leading to its activation. STK39 can be differently spliced, with the short form or kinase defective form (KS-SPAK), which does not phosphorylate SLC12A3 or OXSR1, being expressed in the thick ascending limb of the kidney [8]. SLC12A3 is inhibited by WNK4 by promotion of its degradation via the lysosomal pathway [7], however angiotensin II (AngII) may act to counteract this by switching WNK4 to stimulate STK39 and so stimulate SLC12A3 [10]. Also a kidney specific splice variant of WNK1 inhibits SLC12A3 by inhibition of WNK1, which in turn inhibits WNK3 [7]. WNK1 can also inhibit the WNK4 effects on SLC12A3 [7]. Mutations in the WNK1 or WNK4 genes cause FHHt, familial hyperkalemic hypertension or Gordon syndrome or pseudohypoaldosteronism type II, whereby SLC12A3 is overactive and results in hypertension [11]. Patients with FHHt can have six to seven times the average response to HCT [12]. There is also regulation of SLC12A3 by aldosterone [13]. Aldosterone increases SLC12A3 protein expression by activation of SGK1, which phosphorylates NEDD4L and prevents NEDD4L binding to and inhibiting SLC12A3 [13]. Other hormones may also influence the activity of SLC12A3. Male patients with mutations in SLC12A3 tend to have more severe symptoms of Gitelman syndrome than female patients [14]. Estrogens have been shown to increase SLC12A3 density at the membrane in rats [15]. The Na,K-ATPase is formed from three subunits α, β, and γ. Several genes encode the catalytic α subunit with different tissue expression patterns. ATP1A1 is the predominant form expressed in the kidney [5]. There are also several genes for the β subunit (ATP1B1, ATP1B2, ATP1B3) [16]. The γ subunit is coded for by FXYD2 [17]. Mutations in FXYD2 result in hypomagnesemia and hypocalciuria [17]. In-vitro studies have shown that the Na,K-ATPase is regulated by phosphorylation on the α subunit by protein kinase A (PKA) and protein kinase C (PKC) [18–20]. Phosphorylation can also affect the transporters trafficking to the membrane with G-protein coupled receptor kinases (GRKs) and arrestins promoting phosphorylation and phosphatase PP2AC reversing this process [18]. The FXYD2 subunit expression is alternatively spliced and the ratios of these may be affected by the transcription factor HIF1B [21]. Variants in the ARNT gene that codes for HIF1B may therefore result in hypomagnesemia [21]. Experiments in mice showed that the epithelial Mg2+ channel transient receptor potential channel subfamily M member 6, TRPM6, is downregulated in SLC12A3 knock-out animals treated chronically with HCT [PMID: 15902302]. In addition, hypomagnesemia has been reported in patients receiving both diuretics and protonpump inhibitors, which interact with TPRM6 [PMID: 23538697]. The DCT is responsible for only around 5% of the sodium reabsorbed within the nephron therefore thiazide diuretics have only a limited capacity to change sodium balance [4]. However, these drugs are often sufficient in patients with uncomplicated hypertension and no concurrent renal disease [4]. One of the side effects of thiazides is hypokalemia, reduced serum potassium. This results from thiazides inhibiting NaCl transport along the DCT, thus increasing sodium delivery into the connecting tubule and collecting duct. These segments express the epithelial sodium chancel, ENaC, and the potassium channel, ROMK, at their apical membranes, so that potassium secretion is a consequence of enhanced sodium reabsorption through ENaC [22]. Thiazide-related potassium loss is dose dependent and at high doses can lead to arrhythmia and sudden cardiac death [22]. Therefore, rather than increase the dose, if low doses of thiazides are insufficient to reduce blood pressure a second antihypertensive drug is added, such as an ACE inhibitor or AngII receptor blocker which often reduces the renal potassium excretion as well as synergistically reducing blood pressure [22]. The mechanism for this counter-balancing is likely through AngII on WNK4 (as discussed above) [10].

Hyponatremia is the most common electrolyte disorder. With the aging of the population and the greater propensity of the elderly to develop hyponatremia, this electrolyte disorder is of increasing importance to the practicing nephrologist. In this Attending Rounds, an illustrative patient with hyponatremia is presented. The reasons for the increased incidence and prevalence of hyponatremia in the elderly are discussed, with emphasis on the effects of aging on urinary dilution, the frequently multifactorial nature of hyponatremia in this population, and the absence of a definite cause for inappropriate and persistent vasopressin release in many such patients. The rationale for treating the hyponatremia, even when apparently asymptomatic, is discussed, with attention to cognitive function, gait, and bone structure disturbances that increase the risk for fractures. The various available treatment approaches, including water restriction, demeclocycline, loop diuretics with NaCl supplementation, urea, and vasopressin antagonists are summarized, with emphasis on the efficacy and limitations of each of these therapies.

This study explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and in ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1-10 μM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 μM) and maximal rates of force development and decline (3 and 10 μM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggests that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (eg, reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

Background— Arginine vasopressin, which promotes the reabsorption of renal water is increased in chronic heart failure. Here, we compared the effects of tolvaptan, a newly developed nonpeptide V 2 receptor antagonist, with those of furosemide, a loop diuretic, and a combination of these 2 agents in rats with left ventricular dysfunction after myocardial infarction (MI). Methods and Results— After 10 weeks of MI induction, the rats were separated them into the following 6 groups adjusted to the infarct size: a vehicle group, a group treated with 15 mg·kg -1 ·day -1 of furosemide, 2 groups treated with 3 or 10 mg·kg −1 ·day −1 of tolvaptan; and 2 groups treated with 15 mg·kg −1 ·day −1 of furosemide plus 3 or 10 mg·kg −1 ·day −1 tolvaptan. Each treatment agent was administered for 4 weeks, and all groups had similar blood pressure levels and infarct size. The tolvaptan-treated groups were found to have lower levels of left ventricular end-diastolic and systolic cardiac volumes than the vehicle group did. Furthermore, the improvement in the ejection fraction in the tolvaptan-treated groups was significantly greater than those in the vehicle group. ED-1 immunostaining and Sirius red staining revealed that tolvaptan significantly repressed MI-induced macrophage infiltration and interstitial fibrosis in the left ventricle, respectively. Tolvaptan attenuated the MI-induced mRNA expressions of atrial and brain natriuretic peptides, monocyte chemotactic protein-1, transforming growth factor-β1, arginine vasopressin V 1a receptor, and endothelin-1 in the marginal infarct region. Conclusions— Tolvaptan may improve cardiac dysfunction after MI, which is partially mediated by the suppression of V 1a receptor, neurohumoral activation and inflammation.

We examined the association between the use of medications and the prevalence of urinary incontinence in gender specific analyses of a community based, representative sample.A population based epidemiological study was conducted of 5,503 men and women 30 to 79 years old residing in Boston, Massachusetts (baseline data collected from 2002 to 2005). Urological symptoms were ascertained in a 2-hour, in person interview. Urinary incontinence was defined as urine leakage occurring weekly or more often during the last year. Medications used in the last month were considered current use. Associations of 20+ medications and prevalent urinary incontinence were examined using multivariate logistic regression (ORs and 95% CIs) with adjustments for known urinary incontinence risk factors.The prevalence of urinary incontinence in the analysis sample was 9.0% in women and 4.6% in men. For women the prevalence was highest among users of certain antihistamines (28.4%) and angiotensin II receptor blockers (22.9%). For men the prevalence was highest among angiotensin II receptor blocker (22.2%) and loop diuretic (19.1%) users. After final multivariate adjustment there were significant positive associations for certain antihistamines, beta receptor agonists, angiotensin II receptor blockers and estrogens with urinary incontinence in women (all ORs greater than 1.7), and a borderline significant association for anticonvulsants (OR 1.75; 95% CI 1.00, 3.07). Among men only anticonvulsants were associated with urinary incontinence after final adjustments (OR 2.50; 95% CI 1.24, 5.03), although angiotensin II receptor blockers showed an adjusted association of borderline significance (OR 2.21; 95% CI 0.96, 5.10).Although a cross-sectional analysis cannot determine causality, our analysis suggests certain medications should be further examined in longitudinal analyses of risk to determine their influence on urological symptoms.

Salt sensitivity of blood pressure has been studied in humans with a 48-hour inpatient protocol of salt loading and depletion or with longer outpatient protocols using high- and low-salt diets. Results have been reproducible, but both methods are laborious and costly. A 6-hour protocol of intravenous salt loading and furosemide has been reported but never validated. We studied 14 normal volunteers (39±2 years old; 86% women and 21% black) with the inpatient and 6-hour protocols, separated by 30 days. Four subjects (29%) were salt sensitive in the inpatient protocol. They had higher systolic blood pressure, higher body mass index, and somewhat lower plasma renin activity than salt-resistant subjects. Baseline systolic blood pressure before both protocols was highly reproducible ( r =0.90; P r =0.09). Three salt-sensitive and 4 salt-resistant subjects were misclassified by the short protocol. Three-hour natriuresis by furosemide in the short protocol (344±15 mmol) was not different from the 12-hour natriuresis in the inpatient protocol (357±19). However, stimulation of plasma renin activity and aldosterone was significantly less in the short (+0.10±0.07 ngA I /L/sec and −61±44 pmol/L) than in the inpatient protocol (+1.80±0.60 ngA I /L/sec and +256±88 pmol/L; P

—Type 1 diabetes triggers protein kinase C (PKC)-dependent NADPH oxidase activation in the renal medullary thick ascending limb (mTAL), resulting in accelerated superoxide production. As acute exposure to superoxide stimulates NaCl transport by the mTAL, we hypothesized that diabetes increases mTAL Na + transport through PKC-dependent and NADPH oxidase–dependent mechanisms. An O 2 -sensitive fluoroprobe was used to measure O 2 consumption by mTALs from rats with streptozotocin-induced diabetes and sham rats. In sham mTALs, total O 2 consumption was evident as a 0.34±0.03 U change in normalized relative fluorescence (ΔNRF)/min per mg protein. Ouabain (2 mmol/L) reduced O 2 consumption by 69±4% and 500 μmol/L furosemide reduced O 2 consumption by 58±8%. Total O 2 consumption was accelerated in mTAL from diabetic rats (0.74±0.07 ΔNRF/min/mg protein; P 2 consumption. NADPH oxidase inhibition (100 μmol/L apocynin) reduced furosemide-sensitive O 2 consumption by mTAL from diabetic rats to values not different from sham. The PKC inhibitor calphostin C (1 μmol/L) or the PKCα/β inhibitor Gö6976 (1 μmol/L) decreased furosemide-sensitive O 2 consumption in both groups, achieving values that did not differ between sham and diabetic. PKCβ inhibition had no effect in either group. Similar inhibitory patterns were evident with regard to ouabain-sensitive O 2 consumption. We conclude that NADPH oxidase and PKC (primarily PKCα) contribute to an increase in O 2 consumption by the mTAL during type 1 diabetes through effects on the ouabain-sensitive Na + -K + -ATPase and furosemide-sensitive Na + -K + -2Cl − cotransporter that are primarily responsible for active transport Na + reabsorption by this nephron segment.

Background— Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure. Methods and Results— Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P =0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P =0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% ( P P P P P P =0.15). Conclusions— Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

Renal medullary superoxide (O 2 − ) increases in angiotensin (Ang) II–dependent hypertension. O 2 − increases thick ascending limb Na transport, but the effect of Ang II–dependent hypertension on the thick ascending limb is unknown. We hypothesized that Ang II–dependent hypertension increases thick ascending limb NaCl transport because of enhanced O 2 − production and increased protein kinase C (PKC) α activity. We measured the effect of Ang II–dependent hypertension on furosemide-sensitive oxygen consumption (a measure of Na transport), O 2 − production, and PKCα translocation (a measure of PKCα activity) in thick ascending limb suspensions. Ang II–dependent hypertension increased furosemide-sensitive oxygen consumption (26.2±1.0% versus 36.6±1.2% of total oxygen consumption; P 2 − was also increased (1.1±0.2 versus 3.2±0.5 nmol of O 2 − /min per milligram of protein; P 2 − (2.4±0.4 versus 1.2±0.2 nmol of O 2 − /min per milligram of protein; P P 2 − or furosemide-sensitive oxygen consumption in normotensive controls and did not alter systolic blood pressure. Ang II–dependent hypertension increased PKCα translocation (5.7±0.3 versus 13.8±1.4 AU per milligram of protein; P P P 2 − and PKCα activity.

To review the literature on prevention of acute kidney injury (AKI).MEDLINE- and PubMed-based review of literature published from 1965 to 2007.AKI is very common among critically ill patients. Even mild forms of AKI have significant attributable mortality. Hence, it is imperative that every effort to prevent AKI be made in clinical practice. However, there are very few interventions that have been shown to consistently prevent AKI. Measures such as adequate hydration, maintenance of adequate circulating blood volume and mean arterial pressure, and avoidance of nephrotoxins are still the mainstay of prevention. Loop diuretics and "renal-dose" dopamine have been clearly shown not to prevent AKI and may, in fact, do harm. Among the remaining pharmacologic options, N-acetylcysteine has the strongest evidence in prevention of AKI. Fenoldopam and theophylline need further investigation before being used to prevent septic AKI and contrast nephropathy, respectively. The role of prophylactic dialysis in preventing contrast nephropathy needs to be investigated further.

Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na + diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto- prostaglandin F1α was unaffected by salt loading but was dramatically increased 7- to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load.

Heart failure is one of the leading causes of hospitalizations in the United States. Concomitant and significant renal dysfunction is common in patients with heart failure. Increasingly, the syndrome of heart failure is one of cardiorenal failure, in which concomitant cardiac and renal dysfunctions exist, with each accelerating the progression of the other. One fourth of patients hospitalized for the treatment of acute decompensated heart failure will experience significant worsening of renal function, which is associated with worse outcomes. It remains unclear whether worsening renal function specifically contributes to poor outcomes or whether it is merely a marker of advanced cardiac and renal dysfunction. Diuretic resistance, with or without worsening renal function, is also common in acute decompensated heart failure, although the definition of diuretic resistance, its prevalence, and prognostic implications are less well defined. The term cardiorenal syndrome has been variably associated with cardiorenal failure, worsening renal function, and diuretic resistance but is more comprehensively defined as a state of advanced cardiorenal dysregulation manifest by one or all of these specific features. The pathophysiology of the cardiorenal syndrome is poorly understood and likely involves interrelated hemodynamic and neurohormonal mechanisms. When conventional therapy for acute decompensated heart failure fails, mechanical fluid removal via ultrafiltration, hemofiltration, or hemodialysis may be needed for refractory volume overload. While ultrafiltration can address diuretic resistance, whether ultrafiltration prevents worsening renal function or improves outcomes in patients with cardiorenal syndrome remains unclear. Evidence regarding the potential renal-preserving effects of nesiritide is mixed, and further studies on the efficacy and safety of different doses of nesiritide in heart failure therapy are warranted. Newer therapeutic agents, including vasopressin antagonists and adenosine antagonists, hold promise for the future, and clinical trials of these agents are underway.

Managing volume overload is essential for the treatment of symptomatic heart failure. Traditionally, it is achieved with oral and intravenous diuretics. Alternatively, the excess fluid can be removed via ultrafiltration. Modern technology has made this latter option more feasible than before for routine clinical practice. In this article we review the existing literature on the use of ultrafiltration for treating volume overload states in patients with heart failure.

Recovery of renal function after acute renal failure is an important clinical determinant of patient morbidity. Herein, the epidemiology of renal recovery after acute renal failure will be described, along with potential predictive factors and interventions.Renal recovery has been variably defined, most often as recovery to independence from renal replacement therapy. A recent consensus definition for acute renal failure has been published and included provisions for defining renal recovery. Renal recovery to renal replacement therapy independence occurs in the majority by hospital discharge and peaks by 90 days. All of older age, female sex, co-morbid illnesses, especially chronic kidney disease, and late initiation of renal replacement therapy or conventional intermittent renal replacement therapy have been coupled with non-recovery. Analysis of the literature suggests several interventions may influence recovery.The prognosis is generally good for recovery after acute renal failure. Most patients will be independent of renal replacement therapy by 90 days. Additional research is necessary, however, to understand recovery rates not only to independence from renal replacement therapy, but also to complete and partial recovery. Future studies need to consider the health economic implications for survival and non-recovery. Finally, questions on the role of various interventions require characterization in randomized controlled trials to determine how they may influence renal prognosis.

Metanephric organ culture has been used to determine whether embryonic kidney tubules can be stimulated by cAMP to form cysts. Under basal culture conditions, wild-type kidneys from embryonic day 13.5 to 15.5 mice grow in size and continue ureteric bud branching and tubule formation over a 4- to 5-d period. Treatment of these kidneys with 8-Br-cAMP or the cAMP agonist forskolin induced the formation of dilated tubules within 1 h, which enlarged over several days and resulted in dramatically expanded cyst-like structures of proximal tubule and collecting duct origin. Tubule dilation was reversible upon withdrawal of 8-Br-cAMP and was inhibited by the cAMP-dependent protein kinase inhibitor H89 and the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR(inh)172. For further testing of the role of CFTR, metanephric cultures were prepared from mice with a targeted mutation of the Cftr gene. In contrast to kidneys from wild-type mice, those from Cftr -/- mice showed no evidence of tubular dilation in response to 8-Br-cAMP, indicating that CFTR Cl(-) channels are functional in embryonic kidneys and are required for cAMP-driven tubule expansion. A requirement for transepithelial Cl(-) transport was demonstrated by inhibiting the basolateral Na(+),K(+),2Cl(-) co-transporter with bumetanide, which effectively blocked all cAMP-stimulated tubular dilation. For determination of whether cystic dilation occurs to a greater extent in PKD kidneys in response to cAMP, Pkd1(m1Bei) -/- embryonic kidneys were treated with 8-Br-cAMP and were found to form rapidly CFTR- and Na(+),K(+),2Cl(-) co-transporter-dependent cysts that were three- to six-fold larger than those of wild-type kidneys. These results suggest that cAMP can stimulate fluid secretion early in renal tubule development during the time when renal cysts first appear in PKD kidneys and that PKD-deficient renal tubules are predisposed to abnormally increased cyst expansion in response to elevated levels of cAMP.

Chloride (Cl-) efflux induces depolarization and contributes to contraction of cerebral arteries. We tested the effect of endothelin-1 and 5-hydroxytryptamine on isometric tension in rabbit basilar artery by inhibition of Na+-K+-2Cl- co-transporter and Cl-/HCO3- exchanger to decrease Cl-, by decreasing extracellular Cl- concentration, and by blocking Cl- channels using Cl- channel inhibitors. We have made the following observations: (i)endothelin-1 and 5-hydroxytryptamine produced contraction in the normal Cl- Krebs-Henseleit bicarbonate solution (123 mM Cl-); (ii)inhibition of Na+-K+-2Cl- co-transporter with bumetanide abolished the contractions; (iii) bicarbonate-free solution with HEPES reduced contractions to 5-hydroxytryptamine and endothelin-1; (iv) substitution of extracellular Cl- with methanesulfonate acid (MS- 113 mM, Cl- 10 mM) enhanced peak contraction to 5-hydroxytryptamine and endothelin-1 and decreased plateau contraction to 5-hydroxytryptamine, but did not affect the plateau contraction to endothelin-1 and KCl; and (v) blockade of Ca2+-dependent Cl- channel with niflumic acid and non-selective Cl- channel with 5-nitro-2-(3-phenylpropylamino) benzoic acid and indanyloxyacetic acid-94, R- (+)-methylindazone (R- (+)-IAA-94)decreased contractions to endothelin-1 and 5-hydroxytryptamine.However, removal of endothelium attenuated the effect of Cl-channel inhibitors. In conclusion, Cl- channels and Cl- flux are involved in endothelin-1-induced and 5-hydroxytryptamine-induced contraction in rabbit basilar artery. Cl- channel blockers might exert additional effects by releasing vasodilatation agents from endothelial cells.