use of albumin in clinical practice

1. Albumin & Nephrology
Dr. Lalit AgarwalMD Medicine DM DNB nephrology
Consultant Nephrologist
Woodland Hospital, Kolkata, INDIA

2. Introduction -1
• Albumin is the most abundant multifunctional water soluble
circulating protein found in plasma at a con. of 3.5-5g/dl.
• Albumins are Non-glycosylated polypeptide sequence formed
by 585 amino acids. Encoded in chromosome no 4.
• Synthesized by liver hepatocytes & rapidly excreted in blood
stream at a rate of 10g-15g/day.
• Once Albumin enters the circulation 30-40% stays in blood
stream & remaining 60% enters the interstitial space (normal
transcapillary leakage rate of albumin is 5% per hour) which
again returns to circulation via Lymphatic system. Its half life is
27 days.

3. Introduction - 2
• The 3D structure of Albumin by X-Ray Crystallography to a
resolution of 2.5 angstroms.
• Albumin is a negatively charged 67 K Da protein.
• It comprises 3 homologous alpha-helix domains. Each domain is a
product of 2 subdomains that posses common structural motifs.
• It has 3 essential functional domains – a metal binding domain,
domains that bind to other substance and a domain that confers
stability.

4. Physiologic functions of Albumin
• Albumin as a modulator of plasma oncotic pressure
(maintaining fluid balance between IC-EC space).
• Transporter of Endogenous & Exogenous (i.e. drugs) Ligands.
• Albumin has anti oxidant and anti inflammatory properties.it
binds to highly toxic reactive metal species and its thiol group
from cysteine 34 residue act as a potent scavengers of ROS.

5. Albumin as a modulator of Plasma oncotic
pressure
• Albumin makes up to 50% of human plasma protein. it contributes
80% normal colloid osmotic pressure. Osmotic effect is attributed to
its large M.WT & rest from negative charge. This -ve charge allows
Albumin to attract +vely charged molecules & ultimately water in
intravascular compartment.
• By influencing oncotic pressure, Albumin has a major influence on
Capillary Membrane Pressure (CP) which is represented by the
equation:
CP = (cHP- iHP)-R(cOP- iOP)
r = reflection co-efficient

6. Albumin as a transporter
• Endogenous Ligands: Bilirubin, Cations, Fatty acids, Hormones.
• Exogenous Ligands: Drugs:-methadone propranolol, thiopental,
furosemide, warfarin, methotrexate, alfentanil, & many others.
• Hypoalbuminemia leads to larger amounts of unbound
exogenous drugs, which lead to increased drug sensitivity
(specially if serum Albumin lower than 2.5g/dl).

7. Albumin Homeostasis
• Plasma albumin concentration is the result of the balance
between albumin synthesis , exchange between intravascular
and interstitial compartments, albumin degradation by
catabolism occurring in all tissues ( 40 to 60% is degraded in
muscles, liver and kidney) and renal or intestinal loss.
• The albumin levels are affected by poor supply of raw
material/nutrition, the supply is there but poor absorption in
the gut (protein losing enteropathy), production (synthesis)
defects in CLD and excessive loss from kidney (GN/NS), Skin in
burns and Sepsis/inflammation.

8. Nephroprotective Potential of Human Albumin Infusion
Unique Pharmacodynamic properties of
human albumin with nephroprotective
potential
 Important for the maintenance of kidney function; has positive effects
on vessel wall integrity.
 Facilitates the achievement of negative fluid balance in
hypoproteinemia and in diseases or conditions promoted by edema.
 Helps in maintaining glomerular filtration via hemodynamic and oncotic
mechanisms.
 Not nephrotoxic in contrast to artificial colloids.
 Biological plausibility, freedom from nephrotoxicity (safety), and
reduction of renal morbidity in liver cirrhosis (effectiveness) speak for
the nephroprotective efficacy of human albumin.
Mechanism
• Mitigation of the nephrotoxicity of
medications
• Restoration of balanced net fluid balance
• Protection against the loss of glycocalyx
• Maintenance of glomerular filtration
Nephroprotective potential of human albumin infusion
Hypoalbuminemia is associated with risk of AKI
Wiedermann CJ, et al. Gastroenterol Res Pract. 2015;2015:912839.

9. MALNUTRITION
• Albumin is utilized to evaluate the nutritional status of pts.
Other lab measurements include pre-albumin, transferrin &
retinol binding protein. These Lab parameters must be
combined with physical exam of pts, dietary recalls of food
intake and measurements of acute phase reactants (albumin is
negative acute phase reactants).
• Malnourished pts have low serum Albumin level. Low levels are
strong predictor of mortality and hospitalizations.
• Fasting can decrease serum Albumin by 1/3 within 24 to 48
hours fasting onset. However this reverses quickly with
replenishment of nutrition.

10. Liver disease and Albumin( medication and/or
as volume replacement)
• CIRRHOSIS is associated with a decrease in Albumin due to impaired
hepatocellular functions and reduced Albumin synthesis which can reach
60-80% reduction in advanced Cirrhosis.
• Albumin is a significant predictor of death in over hundred studies in
patients with cirrhosis.
• Albumin is widely used in prognostic score in cirrhosis, the Child -Pugh -
Turcotte score which predict mortality.
• In cirrhosis Albumin quality also changes. Albumin undergoes several
reversible and irreversible posttranscriptional (PTM) changes that changes
its properties such as oxidation, Glycosylation, truncation at C and N
terminus, dimerization and carboxylation. These PTM results in structural
and functional heterogeneity of circulating albumin.

11. Treatment with Albumin in Cirrhosis
(increase ECFV)
Approved indications for albumin solutions
• After large volume paracentesis to prevent paracentesis induced
circulatory dysfunction.
( LVP 6-8g albumin for each lit of ascitic fluid drained)
• Spontaneous bacterial peritonitis
• Hepatorenal syndrome (functional renal failure) Type 1/HRS-AKI and
Type2/HRS-AKD, HRS-CKD for prevention use vasopressor/Terlipressin
and albumin
Controversial proposed indications such as non - SBP infections, ascites
and encephalopathy

12. Terlipressin and Albumin Combination vs. Dopamine, Furosemide, and Albumin
in Hepatorenal Syndrome
Srivastava S, et al. J Clin Exp Hepatol. 2015;5(4):276-285.
Comparison of Pre-Treatment to Post-Treatment Changes in Outcome Parameters Between the Two Treatment
Groups in Both Types of HRS
Triple therapy is as effective as terlipressin treatment, between both the types of HRS.
HRS: Hepatorenal syndrome.

13. Role of Albumin Infusion in Patients With Acute Decompensation of Cirrhosis and
Acute Kidney Injury
Garcia-Martinez R, et al. Liver Int. 2015;35(2):335-343.
Changes in cardiac, hepatic, and renal hemodynamics after albumin infusion
Albumin infusion improved renal function in acutely decompensated cirrhotic patients with acute
kidney injury by impacting on renal blood flow autoregulation.
Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both
groups were treated with intravenous albumin infusion, 40–60 g/days over 3–4 days.

14. MARS (Liver dialysis)
• ALF, ACLF or decompensated ESLF waiting for liver transplant.
• Accumulation of toxic metabolites that results in End organ
dysfunction, multiorgan dysfunction and death.
• MARS has 3 different circuits- a blood circuit, an albumin circuit
with anionic exchange column and an activated charcoal absorber
and dialysate circuit. The closed loop albumin circuit interconnects
blood and dialysate circuits. Dialysis done against albumin solution
across an albumin permeate membrane. 600 ml of 10-20% albumin
dialysate is used to fill the circuit. The protein bound and free toxins
in blood diffuses in albumin dialysate.
• The protein bound toxins are removed by anionic exchanger and
activated charcoal absorber. The water soluble toxins are removed
in a diaflux dialyser. Now the purified albumin recirculates again.

15. Albumin in Hypovolemic shock
• Advocated as it remains intravascular for longer than crystalloids however benefit
has not been proven in trials. Clinician must consider higher cost c/w crystalloids
• Cochrane systemic review of 30 RCT and meta analysis in 1998 showed a higher
mortality rate with the use of albumin c/t saline in critically ill patients with
hypovolemia from injury or surgery, burns & hypoalbuminemia, although the
difference in mortality was not significant (p=0.06)
• Meta analysis by Wilkes et al in 2001 failed to show association between albumin
and increased mortality
• IV albumin is suggested as a second line therapy when hemodynamic stability
cannot be achieved with crystalloids alone.

16. Albumin replacement controversy
• HSA has prognostic significance.1g/dl decrease in albumin, the OR of
mortality increased by 137%,the risk of morbidity increased by 89%,
and the length of hospital stay increased by 71% (Vincent)
• Albumin replacement therefore seems reasonable in critically ill
patients with hypoalbuminemia.
• RCT showing benefit for albumin in critical care are still lacking
• For that reason routine albumin replacement in this patient cohort is
not recommended in surviving sepsis campaign.

17. Critically ill sepsis patients
• TYPE OF FLUIDS -Colloids ( ALBUMIN, HES) vs crystalloids (SALINE,
BALANCED SOLUTIONS) AND
• DOSE OF FLUIDS IS ALSO IMPORTANT (EGDT,SURVIVING SEPSIS
GUIDELINES) Give fluid when necessary, but not too much ( check -
fluid overload and interstitial edema, worsening of AKI/RRT by Clinical
factors, Paraclinical, Static and Dynamic tests) and only enough.

18. Choice of Fluids: Crystalloids vs. Colloids
Colloids
Crystalloids
 Normal (0.9%) saline, Ringer’s lactate, and plasmalyte
are commonly used crystalloids
 In animal sepsis models, infusions of 0.9% saline have
shown to increase inflammatory cytokines, worsen
hypotension and hyperlactatemia, and more likely
cause renal failure.
 Infusion of large quantities of 0.9% saline has shown to
result in hyperchloremic acidosis.
 In a randomized double-blind study, comparison of
lactated Ringer’s solution and 0.9% saline during renal
transplantation showed that lactated Ringer’s solution
was associated with less hyperkalemia and acidosis
compared to saline.
Madhusudan P, et al. Biomed Res Int. 2014;2014:984082. HES: Hydroxyethyl starch.
 Albumin and HES are commonly used colloids.
 The use of gelatins and dextrans has been
associated with anaphylactoid reactions.

19. SAFE(comparison of albumin and saline in icu) TRIAL
• No difference in pts survival at 28 days between 4% Albumin and
0.9% normal saline in critically ill patients..
• During the initial 4 days the volume of albumin to volume of saline
was 1:1.4. after that there was no difference in volume of fluids
administered between the groups.
• Subgroup analysis : 1. post hoc analysis - trauma pts (traumatic brain
injury) has worse outcome with 4% albumin so avoid.
2. septic pts had a trend toward improved survival with albumin
though non significant

20. ALBIOS trial (ALBUMIN Italian outcome sepsis)
• infusion of 60g of albumin daily in order to keep serum albumin
above 3g/dl in pts with severe sepsis or septic shock.
• Both groups received crystalloids infusion as clinically indicated
• Albumin group has higher MABP, lower net fluid balance BUT no
difference in mortality at 28 and 90 days, total volume of fluid
administered , incidence of AKI or need for dialysis
• Those treated with albumin had better SOFA sub scores and received
fewer vasopressors or inotropes.
• SURVIVING SEPSIS CAMPAIGN (international guidelines for the
management of sepsis and septic shock): Recommended use of
albumin for initial resuscitation and subsequent volume replacement
only in patients requiring high volumes of crystalloid solutions. ( weak
recommendations due to low quality evidence)

21. Hyperoncotic albumin (20-25%)
• In an observational study of colloids , hyperoncotic albumin was associated with
more kidney events (doubling of serum creatinine or need for dialysis) and
increased ICU mortality in a propensity matched sample when c/w crystalloids.
• Albumin with lower osmolality ( as used in SAFE trial ) did not show this trend
• KDIGO AKI GUIDELINES: Recommends against using synthetic colloids for volume
resuscitation. So it is better to use crystalloids as volume resuscitation
WITHIN CRYSTALLOIDS ARE BALANCED SOLUTIONS BETTER THAN ISOTONIC
SALINE?
• N Saline greatly differs from the electrolyte composition of plasma. NS delivers
50 mm more chloride than a liter of plasma. This high chloride is the main
culprit.
• TG feedback system activated – decrease RBF and GFR.
• Loss of bicarbonate and rise in Cl concentration (normal AG acidosis)

22. Isotonic Sodium Chloride (0.9% Saline) Associated With AKI
Collins MG, et al.Trials. 2020 May 25;21(1):428.
Physicochemical characteristics of selected electrolyte solutions and human plasma
0.9% saline may be harmful due to its high chloride concentration relative to plasma, which
causes hyperchloremic metabolic acidosis.
AKI: Acute Kidney Injury.

23. ALBUMINURIA in CKD
• More severe proteinuria (Dipstick, ACR, PCR, 24UTP) was
independently associated with an increased risk of kidney failure
regardless of baseline eGFR
• Recent clinical guidelines for ckd management accepts ALBUMINURIA
as an independent predictor of kidney, cardiovascular and mortality
outcomes resulting in previous eGFR based CKD staging system (NKF-
kdoqi) to KDIGO that considers both severity of eGFR decline and
albuminuria.
• Guidelines refer specifically to use albuminuria rather then
proteinuria.

24. Prognosis of CKD by GFR and Albuminuria: KDIGO 2012
Murton M, et al. Adv Ther. 2021;38(1):180 – 200. CKD: Chronic kidney disease; GFR: Glomerular filtration rate;
KDIGO: The Kidney Disease: Improving Global Outcomes.

25. NEPHROTIC SYNDROME
• Proteinuria(>3.5g/24 in adults and > 40mg/sq m/hr in children),
hypoalbuminemia and hyperlipidemia
• If pt has severe edema (ascites, pl effusion scotal and labial edema)
and resistant to diuretics then IV albumin infusion can be tried to
mobilise fluids.

26. Diabetic nephropathy

27. ALBUMIN AND RRT
• Studies support the use of albumin administration
during hemodialysis because of improved
hemodynamic stability (fewer episodes of
hypotension), improved fluid withdrawal and
increased overall safety.

28. Serum Albumin Is a Strong Predictor of Death in Chronic Dialysis Patients
Jellinge ME, et al. PLoS One. 2014;9(8):e105983.
Discrimination plot of albumin as a predictor of 30-day
all-cause mortality
 Crude 30-day mortality in patients with low albumin
was 16.3% compared to 4.3% among patients with
normal albumin (p< 0.0001).
 Patients with low albumin were older and admitted for
a longer period of time than patients with a normal
albumin, while patients with high albumin had a lower
30-day mortality, were younger, and were admitted for
a shorter period.
 Hypoalbuminemia was found to be associated with
30-day all-cause mortality in acutely admitted medical
patients.

29. Is Albumin Infusion Before Hemodialysis More Effective For Water Removal Than
Other Infusion in Chronic Renal Failure Patients On Maintenance Hemodialysis?
Hsu WC, Ho CC, Guo SE, et al. JBI Evidence Implementation. 2012;10(3):257.
Efficacy of isotonic saline 0.9%, albumin 20%, and HES
10%, concluded that HES is a promising fluid in preserving
blood volume, comparable to albumin, but superior to
saline.
Analysis on effects of 20% albumin and 4% gelatin in
dialysis hypotension-prone patients unresponsive to
prevention measures showed more effect of albumin than
gelatin to increase blood pressure.
Predialytic albumin infusion in patient with maintenance
hemodialysis can be applied to refractory intradialytic
hypotension.
HES: Hydroxyethylstarch.

30. ALBUMIN AND PERITONEAL DIALYSIS
• Albumin is the strongest predictor of patients survival on peritoneal
dialysis
• Serum albumin is much more than a nutritional marker as it is
influenced by peritoneal transport status and presence of systemic
illness or inflammation. So dietary protein intake has only a minor
effect on serum albumin.

31. TPE/PLASMAPHERESIS
• Large quantities of plasma are removed from a patient and replaced
with FFP or Albumin solutions in normal saline
• In plasmapheresis replacement by colloidal agents is essential to
maintain hemodynamic stability. In practice this is limited to Albumin
or FFP.
• 5% albumin per liter can be replaced in a volume equal to that of the
removed plasma

32. Indications for the Use of Albumin: Italian Society of Transfusion Medicine and
Immunohematology (SIMTI)
Liumbruno GM, et al. Blood Transfus. 2009;7(3):216-234.

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