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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 3  |  Page : 471-475
Co-administration of albumin-furosemide in patients with the nephrotic syndrome


1 Department of Nephrology, Imam-Khomeini Training Hospital, Urmia University of Medical Sciences, Urmia, Iran
2 Department of Internal Medicine, Imam-Khomeini Training Hospital, Urmia University of Medical Sciences, Urmia, Iran
3 Department of Infectious Disease, Shahid-Beheshti University of Medical Sciences, Tehran, Iran
4 Department of Internal Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
5 Students' Research Committee, Urmia University of Medical Sciences, Urmia, Iran
6 National Institute of Health Research, Tehran University of Medical Sciences, Tehran, Iran

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Date of Web Publication7-May-2011
 

   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.

How to cite this article:
Ghafari A, Mehdizadeh A, Alavi-Darazam I, Rahimi E, Kargar C, Sepehrvand N. Co-administration of albumin-furosemide in patients with the nephrotic syndrome. Saudi J Kidney Dis Transpl 2011;22:471-5

How to cite this URL:
Ghafari A, Mehdizadeh A, Alavi-Darazam I, Rahimi E, Kargar C, Sepehrvand N. Co-administration of albumin-furosemide in patients with the nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Nov 17];22:471-5. Available from: http://www.sjkdt.org/text.asp?2011/22/3/471/80482

   Introduction Top


The nephrotic syndrome is a condition characterized by edema, proteinuria, hypo-albuminemia, and hyper-triglyceridemia. It is caused by glomerular diseases which cause urinary loss of more than 3.5 g of albumin per day. Some of the secondary diseases include infectious diseases, collagen vascular diseases, malignancies and drugs. Sometimes, no primary disease is found, and the condition is called idiopathic nephrotic syndrome. Generalized edema is one of the most important complications in these patients which could sometimes cause critical conditions like pulmonary edema, heart failure and hypertension. Etiology of the edema includes possible decrease in glomerular filtration rate (GFR), inadequate excretion of sodium in distal tubules and hypo-albuminemia. [1]

Hypo-albuminemia, through decreasing the oncotic pressure, causes the intravascular fluids to enter the extracellular spaces and this results in a decrease in tidal volume and increase in the reabsorption of sodium from the distal tubules. The decrease in tidal volume causes a reduction in renal blood circulation and GFR, which results in a decrease in sodium excretion. [2] One of the treatments for edema is using diuretics, especially loop diuretics, and furosemide is the drug of choice. [2] Furosemide reduces the re-absorption of sodium, chloride and potassium from the loop of Henle. However, the drug has to cross the tubular space to reach to loop of Henle. Furosemide, after administration, usually binds to albumin and is carried to the peri-tubular capillaries in the proximal tubules and secreted to the intra-tubular space and reaches its target site, the loops of Henle. [2],[3],[4],[5]

In patients with hypo-albuminemia, furosemide diffuses into the extracellular spaces and a lesser proportion reaches the target site, which causes a reduction in the drug's efficacy. [4] Co-administration of albumin with furosemide increases the efficacy of this drug in patients with nephrotic syndrome; additionally, albumin increases the oncotic pressure. [6],[7],[8],[9] There are reports suggesting that the efficacy of albumin/furosemide co-administration must be reconsidered. Firstly, the albumin received through infusion would be filtrated from the kidneys in a short while; [10],[11] secondly, albumin administration would increase GFR through an increase in tidal volume and this results in an increase in sodium excretion which has no connection with furosemide's diuretic effect; [10],[12],[13],[14] and thirdly, albumin reaching the loops of Henle binds with the secreted furosemide and inhibits its binding to the receptors. [3],[4],[5],[14]

These observations and the high cost of albumin, along with the side effects, made us feel the need to compare the 24-hour urine volume and sodium levels after using furosemide alone and with albumin in patients with nephrotic syndrome.


   Materials and Methods Top


In this randomized clinical trial, we enrolled ten patients with nephrotic syndrome (with standard sodium intake), the diagnosis of which was made using the following criteria: proteinuria more than 3.5 g in 24 hours, hypo-albuminemia (plasma albumin level less than 3.5 g/dL), edema and hyperlipidemia. Informed consent was obtained from all the participants. The patients were randomly selected from among those admitted to the Imam Khomeini Hospital in Urmia, Iran, over a period of one year. The patients were randomly divided into four categories. Three therapeutic protocols were randomly administrated to each group. Each group received all the three protocols in a random sequence. Protocols were as follows:

  1. Furosemide (FU) 2 mg/kg/TDS + sham solution (100 mL normal saline 0.9%)
  2. Human albumin (HA) 0.5 g/kg/TDS + sham solution (normal saline 0.9% or ringer lactate)
  3. FU 2 mg/kg/TDS + HA 0.5 g/kg/TDS mixed previously.
The sequences of receiving protocols were as follows:



These sequences were selected in a random manner for each group. The period between two protocols was 48 hours. Before each drug infusion and after 12, 24 and 48 hours, serum creatinine, urine volume, urine creatinine and urine sodium were measured.

The inclusion criteria for the study were the following:

  1. Nephrotic syndrome criteria including proteinuria more than 3.5 g/24 hours, hypo-albuminemia (serum albumin level less than 3.5 g/dL), edema, hyperlipidemia.
  2. Patients who had been diagnosed with nephrotic syndrome for the first time and had edema.


The exclusion criteria were the following:

  1. Patients who were anuric at the beginning of the study.
  2. Patients whose edema had resolved before the completion of all three protocols.
  3. Patients who were unable to execute the orders, who had less than 85% co-operation or needed more than 100 units of insulin per day.
  4. Patients whose nephrotic syndrome was diagnosed recently and were receiving steroids, cytotoxic drugs or cyclosporine.
  5. Patients for whom the interventions could not be performed.
  6. Patients who had used diuretics before the beginning of our study.


Finally, after all the therapeutic protocols were fulfilled, the data gathered from the laboratory tests (the variables of study) were analyzed using non-parametric tests in SPSS software version 11.5.


   Results Top


In this study, the average urine volume after receiving albumin only, furosemide only, and albumin plus furosemide protocols were 742 ± 528 mL, 1707 ± 745 mL, and 2175 ± 97 mL, respectively, and these differences were statistically significant (P = 0.015) [Table 1]. The fractional excretion of sodium (FENa) was 1.96 ± 0.251%, 3.18 ± 0.25%, and 4.77 ± 0.25%, respectively, in the three therapy groups. There was significant difference in this parameter between patients receiving different protocols (P = 0.000) [Table 2]. The 24-hour urinary sodium levels after receiving these protocols were 118.3 ± 6.68, 208.4 ± 5.27, and 260 ± 8.45, respectively [Table 3], while the GFR levels were 104.5, 96.6 and 106.6 after administrating these protocols respectively (P = 0.021) [Table 4].
Table 1: The 24-hour urine volume in the three different therapy groups.

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Table 2: The fractional excretion of sodium in the three therapy groups.

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Table 3: The 24-hour urine sodium levels in the three therapy groups.

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Table 4: The glomerular filtration rates in the three therapy groups.

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   Discussion Top


This study shows that furosemide administration alone and with albumin in patients with nephrotic syndrome who had normal kidney function caused different urinary volumes and sodium levels. Since the sodium intake was constant in the three different protocols, the increase in sodium excretion could be due to albumin administration which causes an increase in effective circulating volume or potentiates the diuretic effect of furosemide. As the GFR in the three different groups had significant differences, the increase in urine volume and sodium excretion could partially be due to the increase in GFR in groups receiving albumin. Significant difference was noted in the FENa in the different study groups; the difference between groups receiving furosemide alone and furosemide with albumin could not be explained solely by the increase in GFR in the group receiving albumin, and could suggest an improvement in furosemide's diuretic effects in addition.

Fliser et al studied nine patients with nephrotic syndrome. Their study included dietary equilibration, and they measured the amount of furosemide that reached the site of action. Albumin increased the response to furosemide by 20%. The mechanism seemed to involve an increase in renal blood flow. Those authors concluded that the effects were statistically significant but likely, not clinically, relevant. [10]

Davison et al reported, in their study on six nephrotic patients that infusion of human salt-poor albumin produced prompt diuresis, loss of weight and correction of the abnormal biochemical findings. [13] Gentilini et al demonstrated that albumin infusion produced a 26% increase in sodium excretion caused by furosemide in hospitalized cirrhotic patients with ascites. [15] Akicek et al studied the effects of albumin alone, furosemide alone, and the combination in eight hypo-albuminemic patients with nephrotic syndrome. Each patient received each treatment in a random order, but there was no re-equilibration between phases of the study. Albumin alone had negligible natriuretic effects and had no effect on the response to furosemide. [9]

Our study suggests that co-administration of albumin and furosemide in patients with nephrotic syndrome can lead to an increase in sodium excretion and urine volume, when compared to the administration of furosemide alone, which is due to an increase in GFR as well as furosemide's diuretic effect. In view of the controversy which still exists about this issue in different studies, further studies should be conducted.

 
   References Top

1.Barter DC. Resistance to diuresis: Emphasis on a pharmacological perspective. Drugs 1981;22: 477-94.  Back to cited text no. 1
    
2.Inoune M, Okajima K, Iton K, et al. Mechanism of Furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int 1987;32:198-203.  Back to cited text no. 2
    
3.Sjostrom PA, Odlind BG. Beermann BA, Karlberg BE. Pharmacokinetics and effects of Frusemide in patients with nephrotic syndrome. Eur J Clin Pharmacol 1989;37:173-80.  Back to cited text no. 3
    
4.Kirchner KA, Voelker JR, Brater DC. Intratubular albumin blunts the response to Furosemide- a mechanism for diuretic resistance in the nephrotic syndrome. J Pharmacol Exp Ther 1990;252:1097-101.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Burg MB. Tubule Chloride transport and the mode of action of some diuretics. Kidney Int 1976;9:189-97.  Back to cited text no. 5
[PUBMED]    
6.Seely JF, Dirks JH. Diuretic site of action. Kidney Int 1977;11:1-8.  Back to cited text no. 6
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7.Green TP, Mir Kin BL. Furosemide disposition in normal and protein uric rats: urinary drug-protein binding as a determinant of drug excretion. J Pharmacol Exp Ther 1981;218:122-7.  Back to cited text no. 7
    
8.Ellison DH. The physiologic basis of diuretic synergism: it's role in treating diuretic resistance. Ann Intern Med 1991;144:886-94.  Back to cited text no. 8
    
9.Akicek F, Yalniz T, Basci A, Ok E, Mees EJ. Diuretic effect of furosemide in patients with nephrotic syndrome: Is it potentiated by intravenous albumin? Br Med J 1995;310:162-3.  Back to cited text no. 9
    
10.Fliser D, Zurbruggen I, Mutschler E, et al. Co administration of Albumin and Furosemide in patients with the nephrotic syndrome. Kidney Int 1999;55:629-34.  Back to cited text no. 10
    
11.Kim DH, Earm JH, Han JS, et al. Does albumin infusion enhance the diuretic action of Furosemide in nephrotic syndrome? Korean J Nephrol 1998;17:567-73.  Back to cited text no. 11
    
12.Farthing D, Karnes T, Gehr TW, March C, Fakhry I, Sica DA. External standard high performance liquid chromatographic method for quantitative determination of Furosemide in plasma by using solid phase extraction and online elution. J Pharm Sci 1992;81:569-71.  Back to cited text no. 12
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13.Davison AM, Lambie AT, Verth AH, Cash JD. Salt-poor human Albumin in management of nephrotic syndrome. Br Med J 1974;16:481-4.  Back to cited text no. 13
    
14.Okusa MD, Ellison DH. Physiology and pathophysiology of diuretic action. In: Seldin DW, Giebisch G, (Eds). The kidney. Philadelphia: Lippincott Williams and Wilkins; 2000;2878-922.  Back to cited text no. 14
    
15.Gentilini P, Casini-Raggi V, Di Fiore G, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: Results of a randomized, controlled trial. J Hepatol 1999; 30:639-45.  Back to cited text no. 15
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Correspondence Address:
Nariman Sepehrvand
Imam Khomeini Hospital, UMSU, Ershad St, Urmia
Iran
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PMID: 21566302

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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