Tuesday Clinical Case Conference
11/2007
Zae Kim, MD
Days after IVIG infusion
u/o
600cc 800cc
3L
3L
IVIg-associated acute renal failure
IVIg-associated acute renal failure
• Overview
– IVIg?
– Epidemiology of IVIg related ARF
– Pathophysiology
• “osmotic nephrosis”
• vasoconstriction
Introduction - IVIG
– Collected from pooled human plasma, consisting
mainly of immunoglobulin G subclass
– Initially developed in 1952 to treat primary immune
deficiency syndrome
– First licensed by FDA in 1981 to treat six conditions:
–
–
–
–
primary immunodeficiencies
immune-mediated thrombocytopenia
Kawasaki syndrome
recent bone marrow transplantation in patients aged greater than or
equal to 20 years
– chronic B-cell lymphocytic leukemia
– pediatric human immunodeficiency virus type 1 (HIV-1) infection
– Used to treat 50-60 unapproved conditions
– IVIG infusion related adverse reactions (fever, HA,
myalgia, chills, nausea, and vomiting)
• thought to be 2/2 formation of immunoglobulin aggregates
during manufacture or storage
– carbohydrates added to reduce aggregate formation
• Stabilized with
– Glucose, maltose, gycine, sucrose, sorbitol, or albumin
– In 1981, Gamimune became the first IGIV licensed in
the United States.
• It was formulated with 10% maltose as a stabilizer to
eliminate the severe adverse events
Acute Renal Failure After Large Doses of Intravenous Immune Globulin, Janet A Haskin, David J Warner, and Douglas U Blank, The Annals of Pharmacotherapy,
1999 July/August, Volume 33
Product characteristics
Gamunex
Talecris
258 mOsm/kg
0
Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation A Single-Center Experience_Ashley A. Vo_ Clin J
Am Soc Nephrol 1 844-852, 2006
trace
Epidemiology – IVIg related ARF
• Incidence is unknown
– According to FDA report, approximately 120 reports
worldwide (88 in the US) from 1985 -1998
– Risk factors, based on available data from 54/88 pts
• Age > 65,
35 (65%)
• DM,
30 (56%)
• Prior renal insuff
32 (59%)
• Sucrose-containing IVIg (Sandoglobulin)
79/88 (90%)
Epidemiology - FDA report
• Time course, based on 33 patients
• onset occurred less than 7 days following IGIV
administration
• Peak sCR were reached on the fifth day (range: 3-8)
• Mean recovery (80%) was 10 days (range of 3-42 d)
• Outcome
• Dialysis
• Mortality
• Oliguria
35/88 (40%)
13/88 (15%)
Epidemiology – FDA report
• Renal biopsy (n=15)
– Seven (47%) indicated extensive vacuolization of
prox tubule
• Six received sucrose-containing IGIV prep
– Eight (53%) inconclusive biopsy finding
Epidemiology - Demographic and Clinical Data of
Reported Cases of Renal Failure Following IVIG
Therapy
Intravenous immunoglobulin and the kidney—a two-edged sword_Hedi Orbach_Seminars in Arthritis and Rheumatism_Volume 34, Issue 3,
December 2004, Pages 593-601
Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation A Single-Center Experience_Ashley A. Vo_ Clin J Am Soc Nephrol 1 844852, 2006
Pathophysiology
• The mechanism of renal injury following IVIG
has not been clearly established
• Exogenously administered immunoglobulins
cause renal injury by a completely different
mechanism unrelated to the Igs
• The histologic changes lends us a clue
– vacuolization and swelling of proximal tubules
leading to narrowing of tubular lamina
– c/w “Osmotic nephrosis” often seen with mannitol
infusion
proximal tubular cells, which are
enlarged and filled with numerous
small to medium sized
cytoplasmic vacuoles
Trichrome stain showing
extensive tubular cytoplasmic
isometric vacuolization.
Impairment of renal function after intravenous immunoglobulin_Sandra Soares_Neph Dial Transp_21_816_2006
Electron microscopy
proximal tubular cells enlarged with numerous small to medium
sized cytoplasmic vacuoles consistent with an osmotic injury
Impairment of renal function after intravenous immunoglobulin_Sandra Soares_Neph Dial Transp_21_816_2006
Experimental studies - Osmotic nephrosis
– Experimental studies in animals revealed that
proximal tubular cell swelling could be reproducibly
induced by intravenous infusion of sucrose
– This lesion was also observed with parenteral
infusion of other filtered macromolecules such as
mannitol, dextran and radiocontrast
– Alterations in renal function in these animals
correlated with the severity of cell swelling and
tubular obstruction
» H. Lindberg and M. Wald, Renal changes following the administration of
hypertonic solutions, Arch. Intern. Med. 63 (1939), pp. 907–918.
» R.H. Rigdon and E.S. Cardwell, Renal lesions following the intravenous
injection of hypertonic solution of sucrose: a clinical and experimental
study, Arch. Intern. Med. 69 (1942), pp. 670–690.
Mechanism underlying
formation of vacuoles –
“osmotic nephrosis”
– Postulated that the proximal
tubular cells take up filtered
macromolecule via pinocytosis
• based on animal model
»
Janigan DT, Santamaria A. A histochemical study of swelling and vacuolization of
proximal tubular cells in sucrose nephrosis in the rat. Am J Pathol 1961;39:175-92
– Intra cellular accumulation
• Pinocytosis -> formation of vacuoles containing
macromolecule
• followed by the accumulation of cellular water due to the
oncotic gradient generated across the cell membrane
• Induction of cell swelling (causing disruption of cellular
integrity) as well as tubular luminal occlusion from swollen
tubular cells
• In animal models
– Swelling and vacuolization of tubular cells develop as
early as 1 h after sucrose infusion
– Reach maximum severity at approximately 48 to 72h
– By the 7th day, resolution of these lesions
commences
– Complete resolution by approximately 2 weeks
H. Lindberg and M. Wald, Renal changes following the administration of hypertonic solutions, Arch. Intern. Med. 63 (1939), pp. 907–918.
Conclusion
• It is likely that the “osmotic nephrosis” from
sucrose is the mechanism of renal damage
caused by IVIG
• This hypothesis is supported by several facts:
– The clinical time course of acute renal failure is
similar to the clearance rate of sucrose molecules in
animal models.
– The majority of reported cases used IVIG with
sucrose as a stabilizer.
– The histopathological findings in patients who
underwent renal biopsy are identical to those seen in
animals with sucrose nephropathy.
– Patients who have tolerated maltose-containing
preparations subsequently developed renal
insufficiency following use of sucrose containing IVIG
preparations.
Why Sucrose?
• IVIG products with different stabilizing agent
–
–
–
–
–
Disaccharides: sucrose and maltose
Monosaccharide: glucose
Polyphilic sugar alcohol: D-sorbitol
Non-essential aa: Glycine
Albumin
• all stabilizing sugars is metabolized in liver or at
the brush border of the prox tubule
– except for sucrose
• Sucrose  glucose and fructose (in small
intestine) by sucrase
• When given intravenously, no hydrolyzation
occurs -> all of the sucrose is filtered at the
glmoerulus and eliminated unchanged in the
urine
– Decreased renal function prolongs exposure of the
tubule to the sucrose load
• High osmolar sucrose load, intracellular
accumulation, and lack of degradation ->
osmotic nephrosis
Preglomerular vasoconstriction may
contribute to the fall in glomerular
filtration rate
• Increase in tubular osmolality, in conjuction with
increased choloride delivery to the macula
densa, could activate the tubuloglomerular
feedback system and decrease single-nephron
GFR
Conclusion
• Incidence of IGIV-associated ARF cannot be
determined
– but reported cases suggest low incidence
• Keep in mind the at-risk population
– Pre-existing renal disease, DM, hypovolemia, sepsis,
concomitant tx w nephrotoxic agents, or aged greater
than or equal to 65 yo
• Mechanism of insult still unclear
• Epidemiologic evidence suggestive
• Animal/experimental models provide additional insight