Tuesday Clinical Case Conference

1. Tuesday Clinical Case Conference 11/2007 Zae Kim, MD

2. Days after IVIG infusion

3. IVIg-associated acute renal failure

4. IVIg-associated acute renal failure • Overview • IVIg? • Epidemiology of IVIg related ARF • Pathophysiology • “osmotic nephrosis” • vasoconstriction

5. 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

6. 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

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. 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

9. 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%)

10. 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

11. 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

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. 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. 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

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. 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. 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.

18. 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

19. 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.

20. 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.

21. 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.

22. 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

23. 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

24. 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

25. 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