IVIg-associated acute renal failure
Tuesday Clinical Case Conference 11/2007 Zae Kim, MD
Days after IVIG infusion u/o 600cc 800cc 3L 3L
IVIg-associated acute renal failure <ul><li>Overview </li></ul><ul><ul><li>IVIg? </li></ul></ul><ul><ul><li>Epidemiology o...
Introduction - IVIG <ul><ul><li>Collected from pooled human plasma, consisting mainly of immunoglobulin G subclass </li></...
<ul><ul><li>IVIG infusion related adverse reactions (fever, HA, myalgia, chills, nausea, and vomiting) </li></ul></ul><ul>...
Acute Renal Failure After Large Doses of Intravenous Immune Globulin, Janet A Haskin, David J Warner, and Douglas U Blank,...
Product characteristics Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation...
Epidemiology – IVIg related ARF <ul><li>Incidence is unknown </li></ul><ul><ul><li>According to FDA report, approximately ...
Epidemiology - FDA report <ul><li>Time course, based on 33 patients </li></ul><ul><ul><ul><li>onset occurred less than 7 d...
Epidemiology – FDA report <ul><li>Renal biopsy (n=15) </li></ul><ul><ul><li>Seven (47%) indicated extensive vacuolization ...
Epidemiology - Demographic and Clinical Data of Reported Cases of Renal Failure Following IVIG Therapy Intravenous immunog...
Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation A Single-Center Experie...
Pathophysiology <ul><li>The mechanism of renal injury following IVIG has not been clearly established </li></ul><ul><li>Ex...
proximal tubular cells, which are enlarged and filled with numerous small to medium sized cytoplasmic vacuoles Trichrome s...
Electron microscopy  proximal tubular cells enlarged with numerous small to medium sized cytoplasmic vacuoles consistent w...
Experimental studies -  Osmotic nephrosis <ul><ul><li>Experimental studies in animals revealed that proximal tubular cell ...
Mechanism underlying formation of vacuoles – “osmotic nephrosis” <ul><ul><li>Postulated that the proximal  </li></ul></ul>...
<ul><li>In animal models </li></ul><ul><ul><li>Swelling and vacuolization of tubular cells develop as early as 1 h after s...
Conclusion <ul><li>It is likely that the “osmotic nephrosis” from sucrose is the mechanism of renal damage caused by IVIG ...
<ul><ul><li>The histopathological findings in patients who underwent renal biopsy are identical to those seen in animals w...
Why Sucrose? <ul><li>IVIG products with different stabilizing agent </li></ul><ul><ul><li>Disaccharides: sucrose and malto...
<ul><li>Sucrose    glucose and fructose (in small intestine) by sucrase </li></ul><ul><li>When given intravenously, no hy...
Preglomerular vasoconstriction may contribute to the fall in glomerular filtration rate <ul><li>Increase in tubular osmola...
Conclusion <ul><li>Incidence of IGIV-associated ARF cannot be determined </li></ul><ul><ul><li>but reported cases suggest ...
 
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37 ivig related acute kidney injury

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  • identifies the some commonly used IVIg products Gamimune-N-10% excipient (Glycine) had the least amount of sodium chloride, had no sucrose, and is isosmolar (274 mOsm/L at 10%). Carimune is a lyophilized powder that can be reconstituted in sterile water or normal saline. It contains 1.67 g sucrose/g IVIg and at 12% in saline has an osmolality of 1074 mOsm/L and when reconstituted in sterile water has an osmolality of 768 mOsm/L. Polygam 10% also is lyophilized and can be reconstituted in sterile water or normal saline. If reconstituted in NS, Polygam 10% has an osmolality of 1250 mOsm/L. In fact, at 10%, the osmolality is identical to a 2% saline infusion In 2003, Bayer introduced Gamunex, stablizied with glycine, to date has not been associated with any reports of acute renal failure. At Tisch, Gamunex is used, while at BH Carimune (Sandoglobulin) is used
  • A literature search of articles published on the efficacy of IVIG in the treatment of nephritis between 1985 and 2003 Thirty-two reports entailing 78 patients with IVIG-induced nephrotoxicity their data were compared with 88 patients reported to the FDA. -Overall, no specific differences were noted between the 2 groups of patients, as their age and indications for using IVIG were similar. -Preexisting renal disease, defined as a baseline serum creatinine of 1.4 mg/dL, was noted in 45% of case reports, while the data from the FDA reports were incomplete; in 54 cases, 26% had prior renal insufficiency ( P 0.05). -Most of the patients in both groups who developed renal toxicity received sucrose-containing IVIG products. (72% in the literature and 90% in the FDA group) The time of acute renal failure onset occurred between 1 and 10 days following IVIG administration. Peak serum creatinine levels were reached in all patients between 3 and 8 days (median, 5 days). In most cases renal failure was oliguric. -A high percentage of patients required hemodialysis, 31% in published cases and 40% in the FDA report. -The duration of the renal failure ranged from 3 to 45 days and in about 85% of cases it was reversible, with return of sCr level to baseline. -Death occurred in 10 to 15% of all patients in both groups despite treatment. All deaths were in patients with severe underlying medical conditions (pneumonia, cardiac disease, and SLE) and the extent to which renal failure contributed to their deaths was undetermined. -Renal histology done in a minority of the cases (n=9) demonstrated vacuolization and swelling of the proximal tubules c/w osmotic injury. -In the other 9 published patients -7 had tubular injury and vacuolization consistent with osmotic nephrosis; -1 patient had tubulo-interstitial infiltrates, and one had cryoglobulin deposits. -In 8 of these 9 cases the stabilizing agent used in the IVIG preparation was sucrose.
  • described one institution’s experience with IVIg-related complications This study is a retrospective analysis of infusion-related AE that are associated with various IVIg products Eight (8.2%) patients (P &lt; 0.0001) in the Carimune group developed ARF, while none of the other groups developed ARF. This finding coincides with previously report that 90% of ARF occurred with sucrose-based products. One of the patients who underwent biopsy showed “vacuolization” of proximal tubule.
  • identical to those described in humans and experimental animals following infusion of hypertonic sucrose or mannitol solutions, known as “osmotic nephrosis”
  • renal histology extensive vacuolization of the proximal tubules, with swelling and narrowing of the tubular lumina consistent with osmotic injury No acute glomerular inflammation or immunoglobulin deposition in the glomeruli or obstruction of the urinary tubules by immunoglobulins observed
  • Anderson WA, Bethea WR. Renal lesions following administra tion of hypertonic solutions of sucrose. JAMA 1940; 114: 1983–1987 Maunsbach AB, Madden SC, Latta H. Light and electron microscopic changes in proximal tubules of rats after administra tion of glucose, mannitol, sucrose or dextran. Lab Invest 1962; 11: 421–432 Schwartz SL, Johnson CB. Pinocytosis as the cause of sucrose nephrosis. Nephron 1971; 8: 246–254
  • reconstituted Sandoglobulin with sterile water instead of the NaCl 0.9% provided with the product. This reduced the osmolality of the 10% solution from approximately 1550 to 640 mOsm/kg.20 However, this was still much higher than the osmolality of the plasma (300 mOsm/kg). (ARF after large IVIg, haskin)
  • 37 ivig related acute kidney injury

    1. 1. IVIg-associated acute renal failure
    2. 2. Tuesday Clinical Case Conference 11/2007 Zae Kim, MD
    3. 3. Days after IVIG infusion u/o 600cc 800cc 3L 3L
    4. 4. IVIg-associated acute renal failure <ul><li>Overview </li></ul><ul><ul><li>IVIg? </li></ul></ul><ul><ul><li>Epidemiology of IVIg related ARF </li></ul></ul><ul><ul><li>Pathophysiology </li></ul></ul><ul><ul><ul><li>“ osmotic nephrosis” </li></ul></ul></ul><ul><ul><ul><li>vasoconstriction </li></ul></ul></ul>
    5. 5. Introduction - IVIG <ul><ul><li>Collected from pooled human plasma, consisting mainly of immunoglobulin G subclass </li></ul></ul><ul><ul><li>Initially developed in 1952 to treat primary immune deficiency syndrome </li></ul></ul><ul><ul><li>First licensed by FDA in 1981 to treat six conditions: </li></ul></ul><ul><ul><ul><ul><li>primary immunodeficiencies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>immune-mediated thrombocytopenia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Kawasaki syndrome </li></ul></ul></ul></ul><ul><ul><ul><ul><li>recent bone marrow transplantation in patients aged greater than or equal to 20 years </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chronic B-cell lymphocytic leukemia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>pediatric human immunodeficiency virus type 1 (HIV-1) infection </li></ul></ul></ul></ul><ul><ul><li>Used to treat 50-60 unapproved conditions </li></ul></ul>
    6. 6. <ul><ul><li>IVIG infusion related adverse reactions (fever, HA, myalgia, chills, nausea, and vomiting) </li></ul></ul><ul><ul><ul><li>thought to be 2/2 formation of immunoglobulin aggregates during manufacture or storage </li></ul></ul></ul><ul><ul><li>carbohydrates added to reduce aggregate formation </li></ul></ul><ul><ul><ul><li>Stabilized with </li></ul></ul></ul><ul><ul><ul><ul><li>Glucose, maltose, gycine, sucrose, sorbitol, or albumin </li></ul></ul></ul></ul><ul><ul><li>In 1981, Gamimune became the first IGIV licensed in the United States. </li></ul></ul><ul><ul><ul><li>It was formulated with 10% maltose as a stabilizer to eliminate the severe adverse events </li></ul></ul></ul>
    7. 7. 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
    8. 8. 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 Gamunex Talecris 258 mOsm/kg 0 trace
    9. 9. Epidemiology – IVIg related ARF <ul><li>Incidence is unknown </li></ul><ul><ul><li>According to FDA report, approximately 120 reports worldwide (88 in the US) from 1985 -1998 </li></ul></ul><ul><ul><li>Risk factors, based on available data from 54/88 pts </li></ul></ul><ul><ul><ul><li>Age > 65, 35 (65%) </li></ul></ul></ul><ul><ul><ul><li>DM, 30 (56%) </li></ul></ul></ul><ul><ul><ul><li>Prior renal insuff 32 (59%) </li></ul></ul></ul><ul><ul><ul><li>Sucrose-containing IVIg (Sandoglobulin) </li></ul></ul></ul><ul><ul><ul><li>79/88 (90%) </li></ul></ul></ul>
    10. 10. Epidemiology - FDA report <ul><li>Time course, based on 33 patients </li></ul><ul><ul><ul><li>onset occurred less than 7 days following IGIV administration </li></ul></ul></ul><ul><ul><ul><li>Peak sCR were reached on the fifth day (range: 3-8) </li></ul></ul></ul><ul><ul><ul><li>Mean recovery (80%) was 10 days (range of 3-42 d) </li></ul></ul></ul><ul><li>Outcome </li></ul><ul><ul><ul><li>Dialysis 35/88 (40%) </li></ul></ul></ul><ul><ul><ul><li>Mortality 13/88 (15%) </li></ul></ul></ul><ul><ul><ul><li>Oliguria </li></ul></ul></ul>
    11. 11. Epidemiology – FDA report <ul><li>Renal biopsy (n=15) </li></ul><ul><ul><li>Seven (47%) indicated extensive vacuolization of prox tubule </li></ul></ul><ul><ul><ul><li>Six received sucrose-containing IGIV prep </li></ul></ul></ul><ul><ul><li>Eight (53%) inconclusive biopsy finding </li></ul></ul>
    12. 12. 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
    13. 13. 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
    14. 14. Pathophysiology <ul><li>The mechanism of renal injury following IVIG has not been clearly established </li></ul><ul><li>Exogenously administered immunoglobulins cause renal injury by a completely different mechanism unrelated to the Igs </li></ul><ul><li>The histologic changes lends us a clue </li></ul><ul><ul><li>vacuolization and swelling of proximal tubules leading to narrowing of tubular lamina </li></ul></ul><ul><ul><li>c/w “Osmotic nephrosis” often seen with mannitol infusion </li></ul></ul>
    15. 15. 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
    16. 16. 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
    17. 17. Experimental studies - Osmotic nephrosis <ul><ul><li>Experimental studies in animals revealed that proximal tubular cell swelling could be reproducibly induced by intravenous infusion of sucrose </li></ul></ul><ul><ul><li>This lesion was also observed with parenteral infusion of other filtered macromolecules such as mannitol, dextran and radiocontrast </li></ul></ul><ul><ul><li>Alterations in renal function in these animals correlated with the severity of cell swelling and tubular obstruction </li></ul></ul><ul><ul><ul><ul><ul><li>H. Lindberg and M. Wald, Renal changes following the administration of hypertonic solutions, Arch. Intern. Med. 63 (1939), pp. 907–918. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>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. </li></ul></ul></ul></ul></ul>
    18. 18. Mechanism underlying formation of vacuoles – “osmotic nephrosis” <ul><ul><li>Postulated that the proximal </li></ul></ul><ul><ul><li>tubular cells take up filtered </li></ul></ul><ul><ul><li>macromolecule via pinocytosis </li></ul></ul><ul><ul><ul><li>based on animal model </li></ul></ul></ul><ul><ul><ul><ul><ul><li>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 </li></ul></ul></ul></ul></ul><ul><ul><li>Intra cellular accumulation </li></ul></ul><ul><ul><ul><li>Pinocytosis -> formation of vacuoles containing macromolecule </li></ul></ul></ul><ul><ul><ul><li>followed by the accumulation of cellular water due to the oncotic gradient generated across the cell membrane </li></ul></ul></ul><ul><ul><ul><li>Induction of cell swelling (causing disruption of cellular integrity) as well as tubular luminal occlusion from swollen tubular cells </li></ul></ul></ul>
    19. 19. <ul><li>In animal models </li></ul><ul><ul><li>Swelling and vacuolization of tubular cells develop as early as 1 h after sucrose infusion </li></ul></ul><ul><ul><li>Reach maximum severity at approximately 48 to 72h </li></ul></ul><ul><ul><li>By the 7 th day, resolution of these lesions commences </li></ul></ul><ul><ul><li>Complete resolution by approximately 2 weeks </li></ul></ul>H. Lindberg and M. Wald, Renal changes following the administration of hypertonic solutions, Arch. Intern. Med. 63 (1939), pp. 907–918.
    20. 20. Conclusion <ul><li>It is likely that the “osmotic nephrosis” from sucrose is the mechanism of renal damage caused by IVIG </li></ul><ul><li>This hypothesis is supported by several facts: </li></ul><ul><ul><li>The clinical time course of acute renal failure is similar to the clearance rate of sucrose molecules in animal models. </li></ul></ul><ul><ul><li>The majority of reported cases used IVIG with sucrose as a stabilizer. </li></ul></ul>
    21. 21. <ul><ul><li>The histopathological findings in patients who underwent renal biopsy are identical to those seen in animals with sucrose nephropathy. </li></ul></ul><ul><ul><li>Patients who have tolerated maltose-containing preparations subsequently developed renal insufficiency following use of sucrose containing IVIG preparations. </li></ul></ul>
    22. 22. Why Sucrose? <ul><li>IVIG products with different stabilizing agent </li></ul><ul><ul><li>Disaccharides: sucrose and maltose </li></ul></ul><ul><ul><li>Monosaccharide: glucose </li></ul></ul><ul><ul><li>Polyphilic sugar alcohol: D-sorbitol </li></ul></ul><ul><ul><li>Non-essential aa: Glycine </li></ul></ul><ul><ul><li>Albumin </li></ul></ul><ul><li>all stabilizing sugars is metabolized in liver or at the brush border of the prox tubule </li></ul><ul><ul><li>except for sucrose </li></ul></ul>
    23. 23. <ul><li>Sucrose  glucose and fructose (in small intestine) by sucrase </li></ul><ul><li>When given intravenously, no hydrolyzation occurs -> all of the sucrose is filtered at the glmoerulus and eliminated unchanged in the urine </li></ul><ul><ul><li>Decreased renal function prolongs exposure of the tubule to the sucrose load </li></ul></ul><ul><li>High osmolar sucrose load, intracellular accumulation, and lack of degradation -> osmotic nephrosis </li></ul>
    24. 24. Preglomerular vasoconstriction may contribute to the fall in glomerular filtration rate <ul><li>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 </li></ul>
    25. 25. Conclusion <ul><li>Incidence of IGIV-associated ARF cannot be determined </li></ul><ul><ul><li>but reported cases suggest low incidence </li></ul></ul><ul><li>Keep in mind the at-risk population </li></ul><ul><ul><li>Pre-existing renal disease, DM, hypovolemia, sepsis, concomitant tx w nephrotoxic agents, or aged greater than or equal to 65 yo </li></ul></ul><ul><li>Mechanism of insult still unclear </li></ul><ul><ul><ul><li>Epidemiologic evidence suggestive </li></ul></ul></ul><ul><ul><ul><li>Animal/experimental models provide additional insight </li></ul></ul></ul>
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