VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis.

BACKGROUND: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. METHODS: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. RESULTS: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. CONCLUSIONS: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

Factors Affecting the Decision to Initiate Dialysis: A National Survey of United States Nephrologists.

INTRODUCTION: The percentage of patients initiating dialysis at an estimated glomerular filtration rate (eGFR) ≤9 mL/min/1.73 m2 decreased between 2000 and 2018 in the USA. Clinical practice guidelines recommend basing the decision to initiate dialysis primarily on uremic signs and symptoms rather than on a particular level of kidney function. However, what signs and symptoms currently practicing nephrologists consider "uremic," how they weigh eGFR and other factors in the decision to initiate dialysis have not been reported. METHODS: The study was an online survey of 255 US nephrologists, conducted between August and October 2021. RESULTS: Nearly half of respondents (49.8%) had an absolute lower eGFR (8.4 [95% CI: 7.6, 9.2] mL/min/1.73 m2) at which they would initiate dialysis in an asymptomatic patient. The top 5 symptoms that would trigger a recommendation to initiate dialysis were loss of appetite/nausea/vomiting (17%), low eGFR (10%), shortness of breath (10%), declining physical ability/function (9%), and generalized weakness (9%). Poor nutritional status and physical function decline were considered very important in the decision to initiate dialysis by 64% and 55% of respondents, respectively. Nephrologists surveyed significantly shortened the time to dialysis initiation in response to declining physical function in an otherwise asymptomatic (hypothetical) patient. CONCLUSIONS: Nearly half of nephrologists sometimes based their decision to initiate dialysis on eGFR alone. The eGFR threshold at which they did so was lower than has been examined in randomized controlled trials of dialysis initiation. Initiatives designed to safely delay dialysis through aggressive medical management could focus on modifiable factors that are the most important drivers of the decision to initiate dialysis.

Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.

BACKGROUND: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.

Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial.

BACKGROUND: Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes. METHODS: This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. RESULTS: At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001). CONCLUSIONS: Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers.

As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus.

BACKGROUND: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at µ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a µ-opioid antagonist and κ-opioid agonist. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. RESULTS: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. CONCLUSIONS: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges.

Chronic kidney disease-associated pruritus (CKD-aP) is a distressing, often overlooked condition in patients with CKD and end-stage renal disease. It affects ~40% of patients with end-stage renal disease and has been associated with poor quality of life, poor sleep, depression, and mortality. Prevalence estimates vary based on the instruments used to diagnose CKD-aP, and standardized diagnostic instruments are sorely needed. Treatment studies have often yielded conflicting results. This is likely related to studies that are limited by small sample size, flawed designs, and nonstandardized diagnostic instruments. Several large well-designed treatment trials have recently been completed and may soon influence CKD-aP management.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

BACKGROUND: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

A longitudinal study of uremic pruritus in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Although uremic pruritus (UP) is a highly prevalent complication of chronic kidney disease, it remains poorly characterized. There have been no longitudinal studies of natural history, and no health-related quality of life (HR-QOL) instruments have been developed for UP. The objectives of this study were to describe the natural history of UP, to compare rating scales of itching intensity, and to assess usefulness and validity of HR-QOL instruments for UP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The intensity, severity, and effects of pathologic itching on HR-QOL were assessed prospectively in 103 patients with UP on chronic hemodialysis. Outcome measures were obtained at scheduled intervals over 3.5 months. RESULTS: Itching daily or nearly daily was reported by 84% of patients and had been ongoing for >1 year in 59%. In 83%, pruritus involved large, nondermatomal areas with striking bilateral symmetry. Two thirds of the patients were using medications such as antihistamines, steroids, and various emollients without satisfactory relief of itching. Statistically significant associations were found among itching intensity, severity, and HR-QOL measures in domains such as mood, social relations, and sleep. Among patients with moderate-to-severe UP, changes in itching intensity of 20% or greater were associated with significant reductions in HR-QOL measures. CONCLUSIONS: This first longitudinal study of UP describes key features of UP and its effect on HR-QOL. The assessment instruments we have developed are easily used, are responsive to changes in UP intensity, and should facilitate clinical evaluation and research to meet the needs of afflicted patients.

Participation in the decision to become vaccinated against human papillomavirus by California high school girls and the predictors of vaccine status.

BACKGROUND: State and national policymakers are actively debating the merits of legally mandating the human papillomavirus (HPV) vaccine. METHODS: This was a cross-sectional pilot study designed to identify factors associated with HPV vaccination in 170 high school girls and the decision making by girls about vaccination. RESULTS: Overall, 48.4% participated in the vaccination decision making and 37.8% were vaccinated, but there were significant vaccine-related knowledge gaps. Girls often lacked basic knowledge necessary to make vaccine decisions. Vaccination was significantly associated with older age, vaccine information sources, and higher vaccine-related knowledge, but not with estimates of risk of HPV-related diseases, religion, or frequency of health care visits. CONCLUSIONS: This paper describes the first study to have identified factors associated with HPV vaccination among California high school girls and to have documented that a high percentage are participating in the vaccination decision making. These findings have implications for adolescent health education and nursing practice and provide new information relevant to the current public policy debates about mandatory vaccination.

The RegEx trial: a randomized, double-blind, placebo- and active-controlled pilot study combining regadenoson, a selective A(2A) adenosine agonist, with low-level exercise, in patients undergoing myocardial perfusion imaging.

BACKGROUND: Although vasodilator stress myocardial perfusion imaging (MPI) is increasingly performed with exercise, adenosine A(2A) receptor agonists have not been studied with exercise. OBJECTIVES: To determine the safety of administering regadenoson during exercise and, secondarily, to evaluate image quality, patient acceptance, and detection of perfusion defects. METHODS: Patients requiring pharmacologic MPI received a standard adenosine-supine protocol (AdenoSup, n = 60) and were then randomized (2:1) in a double-blind manner to low-level exercise with bolus intravenous injection of regadenoson (RegEx, n = 39) or placebo (PlcEx, n = 21). RESULTS: Adverse events occurred in 95%, 77%, and 33% of patients receiving AdenoSup, RegEx, and PlcEx, respectively. Peak heart rate was 13 beats per minute (bpm) and 21 bpm greater following RegEx compared to that following PlcEx and AdenoSup, respectively (P = .006 and <.001). Change from baseline in mean systolic blood pressure (SBP), change from baseline to nadir SBP, and percentage of patients with a decline in SBP by > or = 20 mm Hg showed no important differences between RegEx and PlcEx. No occurrences of 2nd degree or higher AV block were observed following RegEx or PlcEx; one patient developed 2nd degree AV block following AdenoSup. The mean heart-to-liver and heart-to-gut ratios were improved on RegEx vs AdenoSup: 0.85 (0.34) vs 0.65 (0.26), P < .001 and 1.1 (0.36) vs 0.97 (0.34), P < .001, respectively. Compared to AdenoSup, 70% of patients felt RegEx was much or somewhat better. CONCLUSIONS: Combining regadenoson with low-level exercise is feasible, well tolerated, and associated with fewer side effects compared to AdenoSup.

Safety of regadenoson, an adenosine A2A receptor agonist for myocardial perfusion imaging, in mild asthma and moderate asthma patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Patients with reactive airways are at risk for adenosine-induced bronchoconstriction, mediated via A(2B) and/or A(3) adenosine receptors. METHODS AND RESULTS: To examine the effects of regadenoson, a selective adenosine A(2A) receptor agonist, on airway resistance, we conducted a randomized, double-blind, placebo-controlled crossover trial in asthmatic patients with a positive adenosine monophosphate challenge test. The mean ratio of the forced expiratory volume in 1 second (FEV(1)) at each tested time point relative to the baseline FEV(1) was significantly higher after treatment with regadenoson compared with placebo from 10 to 60 minutes after treatment. One patient had a substantial but asymptomatic FEV(1) reduction (-36.2%) after regadenoson that reversed spontaneously. The most common adverse events with regadenoson were tachycardia (66%), dizziness (53%), headache (45%), and dyspnea (34%). The mean heart rate significantly increased with regadenoson (maximum of +10.4 beats/min) versus placebo. CONCLUSIONS: In this pilot safety study of 48 patients with mild or moderate asthma who had bronchial reactivity to adenosine monophosphate, regadenoson was safe and well tolerated.

High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.

BACKGROUND: The prevalence of renal dysfunction in patients hospitalized with acute decompensated heart failure remains poorly characterized. METHODS AND RESULTS: Data from 118,465 hospitalization episodes were evaluated. Glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease formula. At admission, 10,660 patients (9.0%) had normal renal function (GFR > or = 90 mL x min x 1.73 m2), 32,423 patients (27.4%) had mild renal dysfunction (GFR 60-89 mL x min x 1.73 m2), 51,553 patients (43.5%) had moderate renal dysfunction (GFR 30-59 mL.min.1.73 m2), 15,553 patients (13.1%) had severe renal dysfunction (GFR 15-29 mL x min x 1.73 m2), and 8276 patients (7.0%) had kidney failure (GFR < 15 mL x min x 1.73 m2 or chronic dialysis). Despite this, only 33.4% of men and 27.3% of women were diagnosed with renal insufficiency. Diuretic dose, inotrope use, and nesiritide use increased, whereas angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use decreased, with increasing renal dysfunction (all P < .0001 across stages). In-hospital mortality increased from 1.9% for patients with normal renal function to 7.6% and 6.5% for patients with severe dysfunction and kidney failure, respectively (P < .0001). CONCLUSIONS: The majority of patients admitted with acute decompensated heart failure have significant renal impairment, which influences treatment and outcomes.

Differential effects between intravenous and targeted renal delivery of fenoldopam on renal function and blood pressure in patients undergoing cardiac catheterization.

A randomized, controlled clinical trial demonstrated that intravenous (IV) fenoldopam did not prevent further deterioration in renal function after contrast administration in patients with chronic renal insufficiency. This lack of effect may have been a consequence of the inability to administer an effective renal dose of IV fenoldopam. This study sought to determine whether compared with IV administration, selective intrarenal (IR) fenoldopam would increase local concentration, leading to a higher glomerular filtration rate (GFR), and, because of first-pass renal elimination, result in lower systemic drug levels and less decrease in systemic blood pressure (BP). A randomized, controlled, open-label, partial crossover design trial was conducted in which 33 patients who underwent coronary angiography were randomized in a 1:2 ratio to control or fenoldopam (initially IV, then crossed over to IR through a bifurcated renal infusion catheter). Compared with IV fenoldopam, IR administration was associated with a significantly higher GFR (73.7 +/- 3.1 vs 62.6 +/- 2.5 ml/min, p = 0.0007) and renal plasma flow (537.2 +/- 34.0 vs 494.0 +/- 35.5 ml/min, p <0.01), lower fenoldopam plasma levels (3.3 +/- 0.3 vs 4.8 +/- 0.3 ng/ml, p <0.0001), and greater nadir systolic BP (125.5 +/- 3.6 vs 117.4 +/- 2.8 mm Hg, p <0.0001). Two hours after drug discontinuation after contrast administration, GFRs in the patients who received IR fenoldopam remained higher than in controls (+15.0 ml/min [+25%] vs -8.0 ml/min [-14.0%], p <0.05). In conclusion, this pilot trial demonstrates that the IR infusion of fenoldopam is safe and practical, producing greater renal effect and less reduction of BP than IV infusion. It would be appropriate to restudy this renal vasodilator for the prevention of contrast nephropathy, using selective IR delivery.

Diagnostic and therapeutic utility of B-type natriuretic peptide in patients with renal insufficiency and decompensated heart failure.

Chronic kidney disease (CKD) and congestive heart failure (CHF) are epidemiologically and pathophysiologically linked. A recent study in patients with severe CHF demonstrated that renal plasma flow was inversely correlated with pulmonary capillary wedge pressure, right atrial pressure, pulmonary pressure, and right ventricular ejection fraction. This article reviews the utility of B-type natriuretic peptide (BNP) levels in assessing cardiac function and volume status in patients with CKD and examines the safety and efficacy of BNP therapy in patients with renal insufficiency and decompensated heart failure.

The efficacy and safety of B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated congestive heart failure.

BACKGROUND: Nesiritide (B-type natriuretic peptide) reduces preload and afterload, and causes natriuresis, diuresis and suppression of norepinephrine, endothelin-1 and aldosterone. In this study, we sought to explore the safety and efficacy of nesiritide in patients with acute congestive heart failure (CHF) and renal insufficiency (RI). METHODS: We studied the effects of nesiritide in patients with RI in the VMAC trial database, a multi-centre, randomized controlled trial (n = 489) of patients with acute decompensated CHF. RESULTS: The mean serum creatinine (SCr) in nesiritide-treated patients with RI (SCr > or = 2.0 mg/dl, n = 60, range 2.0-11.1 mg/dl) and without RI (SCr < 2.0 mg/dl, n = 209) was 3.0+/-1.51 and 1.2+/-0.34 mg/dl, respectively. Pulmonary capillary wedge pressure (PCWP) was reduced significantly and similarly in both RI and no RI groups starting at 15 min into nesiritide infusion from a baseline of 29.9+/-8.1 and 26.6+/-6.0 mmHg, respectively. Addition of placebo to standard therapies yielded no further improvement in PCWP in patients with RI; in contrast, nesiritide significantly reduced PCWP at every time point during 24 h. The effects of nitroglycerin were less robust than those of nesiritide, and PCWP was not significantly reduced by nitroglycerin at the 3 h primary end-point. At 24 h, 83% of the RI patients and 91% of patients without RI treated with nesiritide reported improvements in dyspnoea. Nesiritide was well tolerated in patients with RI and no RI, and renal function was preserved in both groups. CONCLUSIONS: In patients with RI, nesiritide was safe and improved haemodynamics and dyspnoea.

Diagnostic and therapeutic utility of B-type natriuretic peptide in patients with renal insufficiency and decompensated heart failure.

Chronic kidney disease (CKD) and congestive heart failure (CHF) are epidemiologically and pathophysiologically linked. A recent study in patients with severe CHF demonstrated that renal plasma flow was inversely correlated with pulmonary capillary wedge pressure, right atrial pressure, pulmonary pressure, and right ventricular ejection fraction. This article reviews the utility of B-type natriuretic peptide (BNP) levels in assessing cardiac function and volume status in patients with CKD and examines the safety and efficacy of BNP therapy in patients with renal insufficiency and decompensated heart failure.