Tuesday Clinical Case Conference

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Tuesday Clinical Case Conference
11/2007 Zae Kim, MD
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Days after IVIG infusion
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IVIg-associated acute renal failure
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IVIg-associated acute renal failure

• Overview
• IVIg?
• Epidemiology of IVIg related ARF
• Pathophysiology
• osmotic nephrosis
• vasoconstriction

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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

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• 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

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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
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Product characteristics
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
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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)

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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 35/88 (40)
• Mortality 13/88 (15)
• Oliguria

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Epidemiology FDA report

• Renal biopsy (n15)
• Seven (47) indicated extensive vacuolization of
  prox tubule
• Six received sucrose-containing IGIV prep
• Eight (53) inconclusive biopsy finding

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Epidemiology - Demographic and Clinical Data of
Reported Cases of Renal Failure Following IVIG
Therapy
Intravenous immunoglobulin and the kidneya
two-edged sword_Hedi Orbach_Seminars in Arthritis
and Rheumatism_Volume 34, Issue 3, December 2004,
Pages 593-601
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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
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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

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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
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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
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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. 907918.
• 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. 670690.

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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 196139175-92
• 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

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• 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. 907918.
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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.

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• 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.

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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

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• 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

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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

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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

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