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1.
Comparative efficacy of terlipressin and norepinephrine for treatment of hepatorenal syndrome-acute kidney injury: A systematic review and meta-analysis
Olson, J. C., Subramanian, R. M.
PloS one. 2024;19(1):e0296690
Abstract
The treatment of choice for hepatorenal syndrome-acute kidney injury (HRS-AKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. In the absence of larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine, meta-analysis of smaller studies can provide insights needed to understand the comparative effects of these medications. Additionally, recent changes in the HRS diagnosis and treatment guidelines underscore the need for newer analyses comparing terlipressin and norepinephrine. In this systematic review, we aimed to assess reversal of hepatorenal syndrome (HRS) and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRS-AKI. We searched literature databases, including PubMed, Cochrane, Clinicaltrials.gov, International Clinical Trials Registry Platform, Embase, and ResearchGate, for randomized controlled trials (RCTs) published from January 2007 to June 2023 on June 26, 2023. Only trials comparing norepinephrine and albumin with terlipressin and albumin for the treatment of HRS-AKI in adults were included, and trials without HRS reversal as an endpoint or nonresponders were excluded. Pairwise meta-analyses with the random effects model were conducted to estimate odds ratios (ORs) for HRS reversal and 1-month mortality as primary outcomes. Additional outcomes assessed, included HRS recurrence, predictors of response, and incidence of adverse events (AEs). We used the Cochrane risk of bias assessment tool for quality assessment. We included 7 RCTs with a total of 376 subjects with HRS-AKI or HRS type 1. This meta-analysis showed numerically higher rates of HRS reversal (OR 1.33, 95% confidence interval [CI] [0.80-2.22]; P = 0.22) and short-term survival (OR 1.50, 95% CI [0.64-3.53]; P = 0.26) with terlipressin, though these results did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with a reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Limitations of this analysis included small sample size and study differences in HRS-AKI diagnostic criteria. As more studies using the new HRS-AKI criteria comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge.
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2.
Furosemide and albumin for the treatment of nephrotic edema: a systematic review
Hedin E, Bijelić V, Barrowman N, Geier P
Pediatric nephrology (Berlin, Germany). 2022
Abstract
BACKGROUND Edema is one of the cardinal clinical features of nephrotic syndrome (NS). It may vary from mild periorbital edema to severe generalized edema (anasarca). In patients where edema does not improve with prednisone therapy, the most common supportive medications are diuretics and albumin. However, due to the complex pathophysiology of edema formation in NS patients resulting in intravascular normovolemia or hypovolemia, optimal therapy for edema is still debated. We conducted a systematic review with the objective of evaluating the change in urine volume and urine sodium excretion after treatment with furosemide only versus furosemide with albumin in edematous patients with NS. OBJECTIVES (1) To evaluate efficacy of furosemide alone versus furosemide with albumin in the treatment of nephrotic edema in adults and children. (2) To compare the harms and benefits of different doses of furosemide for treating nephrotic edema. SEARCH METHODS The search included all randomized or quasi-randomized controlled trials in English and French using MEDLINE, Embase, and CENTRAL Trials Registry of the Cochrane Collaboration using the Ovid interface. ClinicalTrials.gov and the International Clinical Trials Registry Platform were also searched. SELECTION CRITERIA We included all RCTs and randomized cross-over studies in which furosemide and furosemide plus albumin are used in the treatment of children or adults with nephrotic edema. We excluded patients with hypoalbuminemia of non-renal origin and severe chronic kidney disease (CKD) with a glomerular filtration rate below 30 ml/min/1.74 m(2) and patients with congenital NS. DATA COLLECTION AND ANALYSIS All abstracts were independently assessed by at least two authors to determine which studies met the inclusion criteria. Information on study design, methodology, and outcome data (urine volume, urine sodium excretion, adverse effects) from each identified study was entered into a separate data sheet. The differences in outcomes between the types of therapy were expressed as standardized mean difference (SMD) with 95% confidence intervals (CI). RESULTS The search yielded 525 records, and after screening, five studies were included in the systematic review and four of those studies in the meta-analysis. One study had high risk of bias and the remaining three studies were deemed to have some concerns. Urine excretion was greater after treatment with furosemide and albumin versus furosemide (SMD 0.85, 95% CI = 0.33 to 1.38). Results for sodium excretion were inconclusive (SMD 0.37, 95%CI = - 0.28 to 1.02). AUTHORS' CONCLUSIONS The current evidence is not sufficient to make definitive conclusions about the role of albumin in treating nephrotic edema. High-quality randomized studies with adequate samples sizes are needed. Including an assessment of intravascular volume status may be helpful. TRIAL REGISTRATION Prospero: CRD4201808979. https://www.crd.york.ac.uk/PROSPERO A higher resolution version of the Graphical abstract is available as Supplementary information.
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3.
Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome
Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, Gonzalez SA, Mumtaz K, Lim N, Simonetto DA, et al
The New England journal of medicine. 2021;384(9):818-828
Abstract
BACKGROUND The vasoconstrictor terlipressin is used for type 1 hepatorenal syndrome (HRS-1) in many parts of the world and is part of the clinical practice guidelines in Europe. METHODS We conducted a phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-1. The patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days; in both groups, concomitant use of albumin was strongly recommended. The primary end point was verified reversal of HRS, defined as two consecutive serum creatinine measurements of 1.5 mg per deciliter or less at least 2 hours apart and survival without renal-replacement therapy for at least 10 days after the completion of treatment. Four prespecified secondary end points were analyzed with the Hochberg procedure to account for multiple comparisons. RESULTS A total of 300 patients underwent randomization - 199 were assigned to the terlipressin group and 101 to the placebo group. Verified reversal of HRS was reported in 63 patients (32%) in the terlipressin group and 17 patients (17%) in the placebo group (P = 0.006). With respect to the prespecified secondary end points, HRS reversal, defined as any serum creatinine level of 1.5 mg per deciliter or less during the first 14 days, was reported in 78 patients (39%) in the terlipressin group and 18 (18%) in the placebo group (P<0.001); HRS reversal without renal-replacement therapy by day 30, in 68 (34%) and 17 (17%), respectively (P = 0.001); HRS reversal among patients with systemic inflammatory response syndrome (84 patients in the terlipressin group and 48 patients in the placebo group), in 31 (37%) and 3 (6%), respectively (P<0.001); and verified reversal of HRS without recurrence by day 30, in 52 (26%) and 17 (17%), respectively (P = 0.08). At day 90, liver transplantations had been performed in 46 patients (23%) in the terlipressin group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) and 45 (45%), respectively. More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the terlipressin group and 2 patients (2%) in the placebo group. CONCLUSIONS In this trial involving adults with cirrhosis and HRS-1, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. (Funded by Mallinckrodt Pharmaceuticals; CONFIRM ClinicalTrials.gov number, NCT02770716.).
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4.
Hyperoncotic Albumin Solution in Continuous Renal Replacement Therapy Patients
O'Brien Z, Finnis M, Gallagher M, Bellomo R
Blood purification. 2021;:1-10
Abstract
AIM: The aim of this study was to investigate the association of hyperoncotic (20%) human albumin solution (HAS) with outcomes among critically ill patients receiving continuous renal replacement therapy (RRT). METHODS Analysis of the Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data. RESULTS Of 1,508 patients, 771 (51%) received albumin. Of these, 345 (45%) received 4% HAS only, 155 (20%) received 20% HAS only, and 271 (35%) received both. Patients who received combined 4% and 20% HAS were more severely ill, received more days of RENAL trial therapy and required mechanical ventilation for longer. Mean daily fluid balance was -288 mL (-904 to 261) with 20% HAS only versus 245 mL (-248 to 1,050) with 4% HAS only (p < 0.001). On Cox proportional hazards regression, 20% HAS exposure was not associated with greater 90-day mortality (odds ratio 1.12, 95% confidence interval [CI]: 0.77-1.62; p = 0.55) or longer recovery to RRT independence (sub-hazard ratio 1.04, 95% CI: 0.84-1.30; p = 0.70) compared to those who received 4% HAS only. CONCLUSIONS RENAL trial patients commonly received albumin in varying concentrations. The administration of 20% HAS was associated with a more negative fluid balance but was not independently associated with increased mortality or RRT dependence when compared to 4% HAS only.
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5.
A randomized trial of albumin infusion to prevent intradialytic hypotension in hospitalized hypoalbuminemic patients
Macedo E, Karl B, Lee E, Mehta RL
Critical care (London, England). 2021;25(1):18
Abstract
BACKGROUND Intradialytic hypotension (IDH) is a frequent complication of intermittent hemodialysis (IHD), occurring from 15 to 50% of ambulatory sessions, and is more frequent among hospitalized patients with hypoalbuminemia. IDH limits adequate fluid removal and increases the risk for vascular access thrombosis, early hemodialysis (HD) termination, and mortality. Albumin infusion before and during therapy has been used for treating IDH with the varying results. We evaluated the efficacy of albumin infusion in preventing IDH during IHD in hypoalbuminemic inpatients. METHODS A randomized, crossover trial was performed in 65 AKI or ESKD patients with hypoalbuminemia (albumin < 3 g/dl) who required HD during hospitalization. Patients were randomized to receive 100 ml of either 0.9%sodium chloride or 25% albumin intravenously at the initiation of each dialysis. These two solutions were alternated for up to six sessions. Patients' vital signs and ultrafiltration removal rate were recorded every 15 to 30 min during dialysis. IDH was assessed by different definitions reported in the literature. All symptoms associated with a noted hypotensive event as well as interventions during the dialysis were recorded. RESULTS Sixty-five patients were submitted to 249 sessions; the mean age was 58 ([Formula: see text] 12), and 46 (70%) were male with a mean weight of 76 ([Formula: see text] 18) kg. The presence of IDH was lower during albumin sessions based on all definitions. The hypotension risk was significantly decreased based on the Kidney Disease Outcomes Quality Initiative definition; (15% with NS vs. 7% with albumin, p = 0.002). The lowest intradialytic SBP was significantly worse in patients who received 0.9% sodium chloride than albumin (NS 83 vs. albumin 90 mmHg, p = 0.035). Overall ultrafiltration rate was significantly higher in the albumin therapies [NS - 8.25 ml/kg/h (- 11.18 5.80) vs. 8.27 ml/kg/h (- 12.22 to 5.53) with albumin, p = 0.011]. CONCLUSION In hypoalbuminemic patients who need HD, albumin administration before the dialysis results in fewer episodes of hypotension and improves fluid removal. Albumin infusion may be of benefit to improve the safety of HD and achievement of fluid balance in these high-risk patients. ClinicalTrials.gov Identifier: NCT04522635.
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6.
Early Treatment with Human Albumin Solution in Continuous Renal Replacement Patients
O'Brien Z, Finnis M, Gallagher M, Bellomo R
Blood purification. 2020;:1-9
Abstract
AIMS: To study the impact of early human albumin solution (HAS) in continuous renal replacement therapy (RRT) patients. METHODS Analysis of Randomized Evaluation of Normal versus Augmented Level (RENAL) RRT trial data. RESULTS Of 1,464 patients, 500 (34%) received early albumin. These patients had higher illness severity scores, greater use of mechanical ventilation, and 90-day mortality (51 vs. 41%; p < 0.001). However, early albumin carried similar RRT dependence risk among survivors at day 90 (4.9 vs. 5.8%; p = 0.62). On Cox proportional hazards regression, with standardized inverse probability of treatment weighting, early albumin was not associated with increased mortality (hazard ratio [HR]: 1.23, 95% CI: 0.97-1.55; p = 0.09) or recovery to RRT independence (HR: 0.92, 95% CI: 0.78-1.10; p = 0.38). CONCLUSIONS Early albumin was administered to one-third of RENAL trial patients and in those with greater illness severity. Early albumin was not independently associated with mortality risk or rate of recovery to RRT independence.
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7.
Human albumin infusion for treating oedema in people with nephrotic syndrome
Ho JJ, Adnan AS, Kueh YC, Ambak NJ, Van Rostenberghe H, Jummaat F
The Cochrane database of systematic reviews. 2019;7:Cd009692
Abstract
BACKGROUND Oedema is a common clinical symptom in people with nephrotic syndrome and human albumin has been widely used in the treatment of oedema by increasing vascular volume and this inducing diuresis. It may be used with or without diuretics such as furosemide. However, the quantitative contribution of human albumin in treating oedema is not fully understood. If human albumin were found to be effective and safe in the treatment of oedema, it could help clinicians to develop therapeutic strategies to improve the management of diuretic resistance associated with nephrotic syndrome. OBJECTIVES This review aimed to examine the benefits and harms of human albumin infusion for treating oedema associated with nephrotic syndrome. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 23 June 2019 through contact with the Information Specialists using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs evaluating the effect of human albumin infusion compared with placebo or no intervention, human albumin with diuretics compared with diuretic alone, human albumin compared with diuretics and other treatments, clinical outcomes, death, quality of life, kidney function and adverse effects in people with nephrotic syndrome. We excluded cross-over studies but data for the first period was to be included if available. DATA COLLECTION AND ANALYSIS Standard methods of the Cochrane Collaboration were used. Two authors independently assessed eligibility, risk of bias, study quality and extracted data. We calculated mean difference (MD) for continuous data with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. MAIN RESULTS One study met our inclusion criteria (26 children with minimal change nephrotic syndrome) and 11 were excluded (nine cross-over studies, one where albumin was not used for nephrotic syndrome and one where authors did not state whether the children had oedema). Risk of bias for the included study was unclear for selection bias, high for performance and detection bias, low for attrition bias, and high for selective reporting. The included study compared albumin plus furosemide with an equal volume of dextrose. Of our prespecified outcomes, the authors reported clinical improvement as weight change, serum sodium and adverse outcomes (blood pressure). The authors reported a greater weight loss in the albumin treated group initially but no difference overall at 10 days. However, the data in the text and the figures were inconsistent so we could not confirm the authors statements (very low certainty evidence). It is uncertain whether albumin infusion improves serum sodium when compared with an equal volume of dextrose (MD 2.00 mEq/L, 95% CI -0.09 to 4.09), systolic blood pressure (MD 2.00 mmHg, 95% CI -3.52 to 7.52) or diastolic blood pressure (MD 2.00 mmHg, 95%CI -4.29 to 8.29). Death, quality of life, and kidney function were not reported. AUTHORS' CONCLUSIONS We identified only one small study that was relevant to our review, therefore we are unable to draw any conclusions regarding the use of human albumin with or without diuretics in nephrotic syndrome. More RCTs are needed.
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8.
The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study
Phakdeekitcharoen B, Boonyawat K
BMC Nephrology. 2012;13:92.
Abstract
BACKGROUND Chronic kidney disease (CKD) with edema is a common clinical problem resulting from defects in water and solute excretion. Furosemide is the drug of choice for treatment. In theory, good perfusion and albumin are required for the furosemide to be secreted at the tubular lumen. Thus, in the situation of low glomerular filtration rate (GFR) and hypoalbuminemia, the efficacy of furosemide alone might be limited. There has been no study to validate the effectiveness of the combination of furosemide and albumin in this condition. METHODS We conducted a randomized controlled crossover study to compare the efficacy of diuretics between furosemide alone and the combination of furosemide plus albumin in stable hypoalbuminemic CKD patients by measuring urine output and sodium. The baseline urine output/sodium at 6 and 24 hours were recorded. The increment of urine output/sodium after treatment at 6 and 24 hours were calculated by using post-treatment minus baseline urine output/sodium at the corresponding period. RESULTS Twenty-four CKD patients (GFR = 31.0+/-13.8 mL/min) with hypoalbuminemia (2.98+/-0.30 g/dL) were enrolled. At 6 hours, there were significant differences in the increment of urine volume (0.47+/-0.40 vs 0.67+/-0.31 L, P<0.02) and urine sodium (37.5+/-29.3 vs 55.0+/-26.7 mEq, P<0.01) between treatment with furosemide alone and with furosemide plus albumin. However, at 24 hours, there were no significant differences in the increment of urine volume (0.49+/-0.47 vs 0.59+/-0.50 L, P = 0.46) and urine sodium (65.3+/-47.5 vs 76.1+/-50.1 mEq, P = 0.32) between the two groups. CONCLUSION The combination of furosemide and albumin has a superior short-term efficacy over furosemide alone in enhancing water and sodium diuresis in hypoalbuminemic CKD patients. TRIAL REGISTRATION The Australian New Zealand Clinical Trials Registration (ANZCTR12611000480987).
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9.
Co-administration of albumin-furosemide in patients with the nephrotic syndrome
Ghafari A, Mehdizadeh A, Alavi-Darazam I, Rahimi E, Kargar C, Sepehrvand N
Saudi Journal of Kidney Diseases and Transplantation. 2011;22((3):):471-5.
Abstract
Generalized edema is one of the most important complications in patients with nephrotic syndrome. Diuretics like furosemide are the first choice for reducing the edema. Hypo-albuminemia reduces the effect of furosemide, and thus, this drug is co-administered with albumin to reinforce the therapeutic effect and for the correction of reduced oncotic pressure. The aim of this study was to compare urine volume and 24-hour sodium levels after using furosemide alone versus using furosemide along with albumin in patients with nephrotic syndrome. In a randomized clinical trial, ten patients with nephrotic syndrome were chosen and were randomly allocated into four groups. Three therapeutic protocols were chosen, and at the end, each patient had received all three protocols randomly. Data were gathered and analyzed using non-parametric tests in SPSS software. The average urine volume after receiving albumin alone, furosemide alone and albumin plus furosemide were 742 mL (SD = 528), 1707 mL (SD = 745) and 2175 mL (SD = 971), respectively (P = 0.015); the fractional excretion of sodium was 1.96 (SD = 0.251), 3.18 (SD = 0.25), and 4.77 (SD = 8.45), respectively (P = 0.000); the 24-hour urinary sodium levels were 18.3 (SD = 6.68), 208.4 (SD = 5.27) and 206 (SD = 8.45), respectively; while the glomerular filtration rate (GFR) was 104.5, 96.6 and 106.6 (P = 0.021), respectively, in the three therapy groups. Our study shows that albumin administration alone and with furosemide in patients with nephrotic syndrome who had normal kidney function, results in different urine volumes and sodium levels. Co-administration of albumin and furosemide increased the urine volume and sodium level, which is due to increase in the GFR as well as the diuretic effects of furosemide.
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10.
Human albumin for intradialytic hypotension in haemodialysis patients
Fortin PM, Bassett K, Musini VM
Cochrane Database of Systematic Reviews. 2010;((11):):CD006758.
Abstract
BACKGROUND Intradialytic hypotension (IDH) occurs in 20% to 55% of haemodialysis sessions and is more frequent among patients on long-term haemodialysis. Symptomatic IDH is generally defined as a decrease in systolic blood pressure (BP) of at least 10 mm Hg or a systolic BP less than 100 mm Hg, with symptoms such as cramps, nausea, vomiting, and dizziness. IDH is managed acutely by volume expansion through the intravenous administration of fluids. OBJECTIVES To compare the benefits and harms of volume expansion with human albumin, alone or in combination with crystalloid or non-protein colloids, for treating IDH in haemodialysis patients. SEARCH STRATEGY The Cochrane Renal Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 9) MEDLINE (1966 to Oct 2009), and EMBASE (1980 to Oct 2009) were searched. SELECTION CRITERIA Randomised controlled trials (RCTs), quasi-RCTs as well as randomised crossover studies were to be included. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed trial quality. Relative risk (RR) was to be used to analyse dichotomous variables and mean difference (MD) used to analyse continuous variables. MAIN RESULTS One double blind randomised crossover trial met the inclusion criteria and compared 5% albumin to normal saline in patients with a previous history of IDH. Results from 45 assessable participants did not lead to rejection of the null hypothesis of no difference between 5% albumin and normal saline in the primary outcome measure of percentage target ultrafiltration achieved, nor in 11/12 secondary outcomes. Additional (unblinded) saline was given less often when 5% albumin was used compared with saline (16% versus 36%, P = 0.04). However, the volume of additional fluid administered was similar in both groups. There were no significant differences in the nursing time required to treat IDH and the time to restore BP. AUTHORS' CONCLUSIONS No randomised or controlled trial was identified comparing albumin to crystalloids (other than normal saline) or non-protein colloids, or a combination of both, in the treatment of symptomatic hypotension during dialysis.One double blind crossover RCT in 45 assessable patients showed that 5% albumin is not superior to normal saline for the treatment of symptomatic hypotension in maintenance haemodialysis patients with a previous history of IDH. Given the cost and relative rarity of albumin use compared to saline, saline should be first line of therapy for treatment of IDH in stable dialysis patients.