Acute renal failure associated with immunoglobulin therapy

Acute Renal Failure Associated With Immunoglobulin Therapy Thomas G. Cant& PharmD, Edward W. Hoehn-Saric, MD, Kristi M. Burgess, PharmD, Lorraine Racusen, MD, and Paul J. Scheel, MD 0 Four cases of acute renal failure induced by intravenous immunoglobulin are presented, and the literature on the subject is reviewed. The clinical course varies from asymptomatic serum creatinine elevation to anuric renal failure occurring within days of the institution of therapy, followed by the rapid recovery of renal function after termination of therapy. The renal histology demonstrates severe tubular vacuolization with cellular swelling and preservation of the brush border. Glomerular endothelial, mesangial, and epithelial cells also may demonstrate swelling and vacuolization. There is no evidence for inflammatory or immune complex-mediated etiologies. The immunoglobulins or carbohydrate additives in the preparations appear to have a unique and reversible effect on the glomerular and tubular cell function. 0 7995 by the National Kidney Foundation, Inc. INDEX

WORDS:

Acute

renal

failure;

immunoglobulin;

I

MMUNOGLOBULIN therapy, first used to treat immune deficiencies in 19.52, is now being used for a wide variety of disorders. Intravenous immunoglobulins (IVIGs) serve to replace natural deficiencies, such as those accompanying common variable immunodeficiency or chronic lymphocytic leukemia; they modulate the immune system as in the treatment of idiopathic thrombocytopenic purpura, Kawasaki’s syndrome, and Guillain-Barre syndrome, and they aid in the prophylaxis of certain infections, such as cytomegalovirus, in the transplant population.lm4 The seven different preparations of IVIGs that are currently licensed for use in the United States differ in their method of preparation and in their excipients.3 Despite these differences, the IVIG products generally are considered to be equivalent in terms of their clinical effectiveness and their potential for producing side effects. Adverse reactions associated with IVIG therapy usually are allergic in nature and affect 1% to 15% of patients.’ The most common reactions include fever, chills, headache, myalgia, hypertension, and chest pain. Acute renal failure (ARF) also has been attributed to IVIG?r5; however, this reaction occurs infrequently and is not From the Divisions of Clinical Pharmacology, Nephrology, and Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD; and the Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, MD. Received March 24, 1994; accepted in revised form September 7, 1994. Address reprint requests to Paul J. Scheel, MD, Division of Nephrology, Johns Hopkins University School of Medicine, Ross Bldg, 9 South, 720 Rutland Ave, Baltimore, MD 21205 2196. 0 199.5 by the National Kidney Foundation, Inc. 0272.6386/95/2502-0003$3.00/O 228

American

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carbohydrate;

vacuolization.

noted in the Food and Drug Administration labeling of any of the IVIG products.16 As a result, many clinicians are unaware of this potential complication. We report four cases of ARF associated with the use of IVIGs, review the current literature, and discuss possible pathophysiologic mechanisms. PATIENTS Case

No.

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METHODS

1

A Y-year-old man was diagnosed with idiopathic thrombocytopenia. He was treated with corticosteroids and an IVIG (brand administered is not known), which increased his platelet count to 135,000 cells/~L. Subsequently, he was readmitted for repeat IVIG therapy after a routine blood screen identified a platelet count of 8,000 cells/pL. On admission, there was no active bleeding and a review of systems was negative. The physical examination was unremarkable and the initial serum creatinine was 1.2 mg/dL. The patient’s past medical history was significant for a myocardial infarction followed by double vessel coronary artery bypass grafting. His medications on admission included isosorbide dinitrate 20 mg three times a day, digoxin 0.25 mg/d, bumetanide 2 mg hvice a day, and captopril 25 mg three times a day. A 5-day course of IVIG therapy was begun at a dose of 0.670 g/kg/d. The first dose was with 5% Gamimune-N (Cutter Biological, Berkeley, CA), and all subsequent doses were with 6% Sandoglobulin (Sandoz Pharmaceutical, Basel, Switzerland). Each dose was administered over at least 4 hours. On the third day of therapy, serum creatinine was 1.5 mgl dL; by the fifth hospital day, creatinine had increased to 2.9 mg/dL. Renal ultrasonography revealed a right kidney measuring 15 cm and a left kidney measuring 14 cm. There was no evidence of hydronephrosis, and the renal veins and arteries were patent by Doppler ultrasonography. A radioisotopic flow scan showed mildly diminished perfusion to both kidneys with poor function bilaterally. The IVIG therapy was completed on day 5. By the sixth hospital day, the patient was anuric; the serum creatinine reached its maximum of 8.6 mg/dL on day 8. The platelet count did not significantly improve with therapy, and a renal biopsy could not be perof Kidney

Diseases,

Vol 25, No 2 (February),

1995:

pp 228-234

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Fig 1. Photomicrograph depicting a glomerulus and tubules from patient no. 3. There is marked vacuolization and edema of the proximal tubules. Note the relative preservation of the brush border. (Hematoxylineosin stain; magnification x280.)

formed. On day 8, urine output spontaneously ciding with the normalization of the serum

returned, creatinine.

coin-

Case No. 2 A 55year-old man with polymyositis had failed a variety of immunosuppressive therapies but had a history of improvement with IVIG therapy (all with Gamimune-N). Each of these IVIG courses was tolerated without incident, The patient was admitted for another course of IVIG therapy. His past medical history was significant for hypertension, adult-onset diabetes complicated by retinopathy and neuropathy, osteoporosis, and bipolar affective disorder. On admission, the patient’s medications were verapamil sustained-release 160 mg twice a day, ranitidine 150 mg twice a day, carbamazepine 200 mg twice a day, ergocalciferol50 IU each week, prednisone 45 mg/d, glyburide 5 mg/d, furosemide 80 mg/d, calcium carbonate 1,300 mg/d, magnesium oxide 400 mg/d, lithium carbonate 300 mg/d, and calcitonin 50 U/d subcutaneously. The patient’s physical examination was notable for a blood pressure of 160/90 mm Hg and obesity with cushingoid features. There was trace pitting edema of the lower extremities, and he had flaccid, hyporeflexic weakness symmetrically. The initial serum creatinine was 1.1 mg/dL and baseline urinalysis had +I proteinuria. The patient was started on a 3-day course of IVIG therapy at 0.67 g/kg/d (Sandoglobulin, 6%), but developed oliguric renal insufficiency by the second day of treatment. A repeat urinalysis showed + I proteinuria and urinary electrolytes included a sodium of 37 mEq/L, corresponding to a fractional excretion of sodium of 4%. The WIG was stopped after the second dose, and plasmapheresis was initiated with the assumption that the renal failure was induced by an IVIG.

The serum creatinine peaked at 4.6 mg/dL on day 5 and returned to baseline by day 10. This patient has received additional IVIG therapy with Gamimune-N since this episode without a recurrence of ARF.

Case No. 3 A 28-year-old woman who had undergone a combined heart-kidney transplant at the age of 20 years developed severe aplastic anemia due to parvovirus B19 infection 2 months prior to the current hospitalization. Diagnosis was made by polymerase chain reaction, and she was treated with an IVIG (Gamimune-N, 5%) 0.4 g/kg/d for 7 days. The reticulocyte count improved and the polymerase chain reaction for parvovirus B 19 became negative. The serum creatinine remained stable throughout this course of treatment, The aplastic anemia recurred and the polymerase chain reaction results for parvovirus B 19 were again positive. The patient was admitted for blood transfusions and IVIG therapy. On admission the patient’s medication included cyclosporine 75 mg/d (serum level, 238 ng/mL [normal, I50 to 300 ng/ mL]), prednisone 5 mg twice a day, furosemide 80 mg twice a day, spironolactone 50 mg twice a day, and aspirin 80 mg/ d. The initial blood urea nitrogen and serum creatinine were 80 mg/dL and 1.7 mg/dL, respectively. A urinalysis was negative for protein, and the microscopic sediment was benign. Treatment with 0.4 g/kg/d of an IVIG (Sandoglobulin, 6%) was started. Each dose of the IVIG was given over at least 4 hours. On day 3 of therapy, the serum creatinine increased to 2.0 mg/dL and urine output decreased to 70 mUday. The patient remained oliguric and the creatinine continued to increase. A renal ultrasound of the transplanted kidney was unchanged from previous studies. Intravenous immunoglobulin therapy was discontinued on day 5, and the patient re-

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Fig 2. Electron micrograph of a tubule demonstrating the extensive vacuolization throughout the cell wlth preserved apical brush borders. (Magnification ~1,225.)

quired hemodialysis on day 6 for symptomatic uremia and volume overload. The serum creatinine peaked on day 7 at 4.9 mg/dL, and a percutaneous biopsy of the transplanted kidney was performed. Light microscopy showed severe swelling and vacuolization of the proximal tubules with preservation of the brush border (Figs 1 and 2). There also was very focal tubular cell loss and occasional apoptotic cells in vacuolated and nonvacuolated tubules. The outer medulla was not sampled. No acute cellular infiltrates were present in the glomeruli or the interstitium. Immunoglobulin deposition was not detected in the glomeruli or tubular vacuoles by immunofluorescence. Electron microscopy demonstrated vacuolar changes in the tubules and in the glomemlar endothelium, visceral epithelium, and mesangium (Fig 3). Additionally, there were chronic changes consistent with transplant glomemlopathy, including global and segmental sclerosis, wrinkling of capillary loop basement membrane, areas of mesangial interposition, and increased mesangial matrix. No dense deposits or fibrillary or light chain deposits were seen. The patient’s urine output spontaneously improved on day 7, and the creatinine decreased to baseline by day 9.

from a baseline of 1.2 mg/dL to 2.5 mg/dL by day 8. The patient progressed to oligoanuria and required continuous venovenous hemodiafiltration. The patient subsequently became hypotensive, presumably due to sepsis; he died on hospital day 12. A postmortem examination revealed renal histologic changes similar to those noted in patient no. 3. The proximal tubular cells were markedly vacuolated and edematous, but the brush border was preserved (Fig 4). Mild acute tubular

Case No. 4 A 40-year-old human immunodeficiency virus-positive black man was admitted because of complaints of lower extremity weakness; a diagnosis of Guillain-Barre syndrome was made. The patient rapidly progressed to quadriplegia and became ventilator dependent. On hospital day 5, IVIG therapy (Sandoglobulin, 6%) was initiated at a dose of 0.4 gikgld. Again, each IVIG infusion was given over at least 4 hours. Following initiation of IVIG therapy, the creatinine increased

Fig 3. Electron micrograph of a glomerular capillary loop from patient no. 3. Note the glomerular endothelial cell swelling and vacuoles in the epithelial and mesangial cells. (Magnification ~3,000.)

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Fig 4. Photomicrograph of tubules from patient no. 4 demonstrating cellular edema with vacuolar changes in proximal tubules and relative preservation of the brush border. (Periodic acid-Schiff stain; magnification X250.)

injury also was seen, with individual cell loss and accumulation of nucleated cells focally in the vasa recta, reflecting early ischemic injury in the setting of sepsis.

RESULTS

AND

DISCUSSION

Thirty-five cases of ARF associated with IVIG therapy have been reported in the literature.5-‘5 All these reactions involved adults (age range, 20 to 82 years), with 56% of the patients being older than age 65 years. Nineteen patients presented with pre-existing renal disease,5-‘2 six patients had normal renal function prior tc IVIG therapy, 5,7,9~“~13,‘4 and in 10 cases the baseline renal function was not reported.gs15 Increases in serum creatinine were noted after 1 to 6 days of IVIG therapy and creatinine returned to baseline within 2 to 60 days of discontinuing the drug (84% of the cases resolved within 14 days). Oliguria or anuria occurred in 13 patients, with dialysis becoming necessary in nine cases.s-7,9,‘o,L2-‘4 There was no apparent association between the dose of the IVIG and the occurrence of ARF (doses ranged from 0.35 to 1.0 g/kg/d); the concentration of the IVIG solution and the rate of infusion were rarely reported. Acute renal failure occurred during the first exposure to IVIG therapy in all but four cases. In one of these four patients, the first exposure was with Gamimune-

N and the second was with Sandoglobulin.” In another case, the patient received Gammonativ (Kabi Vi&urn, Stockholm, Sweden) for both infusions.13 In the other cases, it is unknown whether the products were identical.‘0,‘5 Biopsy results were reported in only four cases, in which the patients received Immunoglobulines CTS7 and Sandoglobulin.“.” In three biopsies, marked swelling and vacuolization of the proximal tubular epithelial cytoplasm with no antigen-antibody complexes was noted.“~” One biopsy also showed mesangial proliferation with mild interstitial fibrosis and a sparse lymphocytotic infiltrate, which the investigators attributed to a chronic underlying renal process.” The fourth biopsy revealed tubular atrophy and diffuse infiltration of the interstitium by mononuclear cells.7 Intravenous immunoglobulin therapy was successfully reinitiated in one patient after serum creatinine values returned to normal. In this patient, no mention was made whether the IVIG preparation was changed; however, the dose was decreased by 50% and the infusion rate was reduced by half.” Two of the 35 cases described were in an open, prospective trial of six nephrotic patients with glomerulonephritis who were treated with two

232

courses of an IVIG 0.40 g/kg/d for 5 days.5 Each course was separated by 1 to 2 months. Although every patient experienced transient increased in serum creatinine with each course of treatment, the increase was greater than 0.5 mg/dL in only two patients. In one case, the serum creatinine increased from approximately 3.4 mg/dL to 7.4 mg/dL, and the other patient had an increase from approximately 0.8 mg/dL to 1.7 mg/dL. In all cases, the serum creatinine returned to pretreatment values within 10 days. Whether significant changes in blood pressure during the infusion of the IVIG product could have been responsible for some of the alterations in renal function was not discussed by the investigators. The clinical presentation of our patients’ renal failure was consistent with other reported cases. The onset of ARF was noted 2 to 3 days after the initiation of IVIG therapy, and resolution occurred within 4 to 8 days after the drug was discontinued. Unlike most of the cases in the literature, patients no. 1 to 3 in our series tolerated the initial IVIG sessions without complication, but ARF developed when repeat IVIG therapy was instituted several months later. The biopsy findings from cases no. 3 and 4 were similar to previously reported pathologic abnormalities seen with IVIG ARF.‘“~” Specifically, they demonstrated markedly swollen and vacuolated proximal tubular cells with preservation of the brush borders. None of the biopsies demonstrated acute glomerular inflammation or immunoglobulin deposition. The biopsy specimen from case no. 3 also demonstrated edema and vacuolization in glomerular endothelial, mesangial, and visceral epithelial cells, which has not been previously described. The biopsy from case no. 4 also showed focal ischemic injury, reflecting premortem hypotension. The typical side effects of IVIG therapy, including fever, chills, myalgias, vasomotor, cardiovascular, and hypersensitivity reactions2 are thought to be due to an immune-mediated host reaction to the immunoglobulins’7~‘* or secondary to contamination with bioactive substances such as pre-kallikrein activator and kallikrein.” The mechanism(s) for ARF, however, are not known. Endogenous immunoglobulins cause renal injury by several different mechanisms. They can deposit at glomerular basement membranes as part of an immune response, stimulate an in-

CANTlj

ET AL

flammatory response, and produce a proliferative, necrotizing glomerulonephritis, such as that seen with serum sickness or Goodpasture’s syndrome. Alternatively, immune complex deposition in the capillary loop or mesangium may not produce an inflammatory response, resulting instead in membranous or mesangial glomerulonephritis.” Immunoglobulin components may deposit in a lattice structure, resulting in a fibrillary glomerulonephritis, amyloid, or light chain deposition disease. Finally, immunoglobulin components also may obstruct tubules, as found with myeloma cast nephropathy.2’ Exogenously administered immunoglobulins do not appear to cause renal injury by any of these pathophysiologic mechanisms. The biopsy specimens from this series and others do not demonstrate glomerular immunoglobulin deposition in any form, glomerular inflammation, or tubular obstruction by casts. The marked degree of proximal tubular cell swelling and vacuolization with preservation of the brush border seen in these biopsy specimens has been previously described only with severe hypokalemia,22 contrast-induced nephropathy,23 cyclosporine toxicity,24 and following the administration of parenteral carbohydrates, including glucose, mannitol, dextran, and sucrose.25-36Although case no. 3 was receiving cyclosporine, the compound did not clinically appear responsible for the renal failure and was continued without complication. In addition, none of the other cases had hypokalemia or received radiocontrast. However, IVIGs are prepared with carbohydrates as stabilizing agents and, depending on the preparation and method of solubilization, a 5% to 10% concentration of maltose, sucrose, glucose, mannitol, or sorbitol will accompany the immunoglobulins.‘6 Several pathophysiologic models have been proposed to explain the severe vacuolization. It has been theorized that the hyperosmolality common to IVIGs,” parenteral carbohydrates,37 and radiocontrast, causes an osmotic injury to proximal tubule cells. No definitive evidence supports this theory, and several lines of reasoning make it somewhat unlikely. Given intravenously, hypertonic agents are quickly diluted, and when they reach the glomerulus, are in the least concentrated forms. If hypertonicity causes tubular damage, one would expect to see the most severe

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lesions in the distal proximal tubule or beyond, since osmolality increases fivefold to IO-fold as the glomerular filtrate passes through the proximal tubule and water and sodium are resorbed.“’ In contrast, the vacuolization associated with radiocontrast,39 parenteral carbohydrates?’ and immunoglobulins are found in the glomerular epithelium and the proximal segments of the proximal tubule. The lack of reduction in contrast-induced renal insufficiency with non-ionic radiocontrast4’ provides indirect evidence against the theory that hypertonicity directly damages proximal tubular cells. Finally, mannitol’s salutary effect on contrast nephropathy42 also argues against a model based on hypertonicity alone. Renal artery vasoconstriction and ischemic renal damage have been proposed as other mechanisms producing the vacuolization seen with IVIGs,’ I hypertonic agents,43,U and cyclosporine.45 However, with reduced blood flow, distal tubular cells are uniquely sensitive to ischemit damage, and show necrosis and sloughing. Widespread severe vacuolization is not a typical feature of ischemic injury.46 There is some evidence, however, that ischemia may enhance vacuolization.35 Another theory advanced to explain the vacuolization seen with parenteral carbohydrates also could be considered for IVIG preparations. Rat studies using parenteral sucrose, mannitol, glucose, and dextran demonstrated that the vacuoles are of lysosomal origin and contain the infused substances.25340,47348 Extrapolating on the findings, the investigators propose that the carbohydrates enter tubular cells through pinocytosis and are incorporated into lysosomes. Substances that are poorly degraded by these organelles accumulate and cause lysosomes to enlarge, rupture, and fuse together to form vacuoles. In the single case in this series studied by electron microscopy, it was not possible to ascertain the origin of the vacuoles, but the vacuolar contents were not positive on periodic acid-Schiff staining, suggesting that they do not contain carbohydrates. In summary, IVIGs pose a rare but real risk for producing ARF, which can occur on the first or subsequent exposure to IVIG products. Risk factors for this reaction have not been established, although many patients have had underlying renal disease. The clinical course ranges from asymptomatic elevations in serum creatinine to

acute, anuric renal failure that is pathologically characterized by severe tubular vacuolization. When an IVIG is promptly discontinued, renal recovery is rapid. Mechanisms of renal injury in this setting remain speculative. REFERENCES I. Berkman SA, Lee, ML, Gale RP: Clinical uses of intravenous immunoglobulins. Ann Intern Med 112:278-292, 1990 2. NIH Consensus Conference: Intravenous immunoglobulin. Prevention and treatment of disease. JAMA 264:31893193, 1990 3. ASHP Commission on Therapeutics: ASHP therapeutic guidelines for intravenous immune globulin. Clin Pharm 11:117-136, 1992 4. Pennington JE: Newer uses of intravenous immunoglobulins as anti-infective agents. Antimicrob Agents Chemother 34: 1463-1466, 1990 5. Schifferli J, Leski M, Favre H, Imgach P, Nydegger U, Davies K: High dose intravenous IgG treatment and renal function. Lancet 337:457-458, 1991 6. Corvetta A, Della Bitta R, Gabrielli A, Spaeth PJ, Daniel G: Use of high-dose intravenous immunoglobulin in systemic lupus erythematosus: Report of three cases. Clin Exp Rheumatol 7:295-299, 1989 7. Ellie E, Combe C, Ferrer X: High-dose intravenous immunoglobulin and acute renal failure. N Engl J Med 327:1032-1033, 1992 8. Rostoker G, Philippon C, Belghiti D, Ben Maadi A, Remy P, Lang P, Lagrue G, Ozanne P, Bremard-Oury C, Weil B: Intravenous IgG for glomerulonephritis and renal function. Lancet 338:54-55, 1991 9. Donatini B: Transient renal dysfunction in diabetic patients after IVIG therapy. J Intern Med 232:376, 1992 10. Tan E, Hajinazarian M, Bay W, Neff J, Mendell JR Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol 50: 137-l 39, 1993 I1 Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol 36:83-86, 1991 12. Phillips AO: Renal failure after intravenous immunoglobulin. Clin Nephrol 37:217, 1992 13. Kobosko J, Nicol P: Renal toxicity of intravenous immunoglobulin. Clin Nephrol 37:216-217, 1992 14. Barton JC, Herrera GA, Galla JH, Bertoli LF, Work J, Koopman WJ: Acute cryoglobulinemic renal failure after intravenous infusion of gamma globulin. Am J Med 82:624629, 1987 15. Friedman KD, Saddler MC, Tarnower AC, Yang G, Hat-ford AM: Transient renal failure in a patient with idiopathic thrombocytopenic purpura after treatment with concomitant protein-A immunosorption and intravenous immune globulin. Blood 80:483a, 1992 (suppl 1) (abstr) 16. Physician’s Desk Reference, ed 47. Montvale, NJ, Medical Economics Data, 1993 17. Burks AW, Sampson HA, Buckley RH: Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. N Engl J Med 314:560-564, 1986

234 18. Day NK, Good RA, Wahn V: Adverse reactions in selected patients following intravenous infusions of gamma globulin. Am J Med 76:25-32, 1984 19. Alving BM, Tankersley DL, Mason BL, Rossi F, Aronson DL, Finlayson JS: Contact-activated factors: Contaminants of immunoglobulin preparations with coagulant and vasoactive properties. J Lab Clin Med 96:334-346, 1980 20. Glotz D, Druet P: Immune mechanisms of glomerular damage that affect the kidney, in Cameron S, Davison AM, Grunfeld JP, Kerr D, Eberhard R (eds): Oxford Textbook of Clinical Nephrology. New York, NY, Oxford University Press, 1992, pp 240-262 21. Minetti L: Kidney involvement in plasma cell dyscrasias, in Cameron S, Davison AM, Grunfeld JP, Kerr D, Eberhard R (eds): Oxford Textbook of Clinical Nephrology. New York, NY, Oxford University Press, 1992, pp 562-576 22. Relman AS, Schwarz WB: The kidney in potassium depletion. Am J Med 24:764-773, 1958 23. Moreau JF, Droz D, Sabto J, Jungers P, Kleinknecht D, Hinglais N, Michel JR: Osmotic nephrosis induced by water-soluble triiodinated contrast media in man. Radiology 115~329-336, 1975 24. Mihatsch MJ, Thiel G, Ryffel B: Histopathology of cyclosporine nephrotoxicity. Transplant Proc 20:759-77 1, 1988 (suppl 3) 25. Maunsbach AB, Madden SC, Latta H: Light and electron microscopic changes in proximal tubules of rats after administration of glucose, mannitol, sucrose, or dextran. Lab Invest 11:421-432, 1962 26. Helmholz HF: Renal changes in the rabbit resulting from intravenous injections of hypertonic solutions of sucrose. J Pediatr 3:144-157, 1933 27. Stuart FP, Torres E, Fletcher R, Cracker D, Moore FD: Effects of single, repeated and massive mannitol infusion in the dog: Structural and functional changes in kidney and brain. Ann Surg 172:190-204, 1970 28. Schreiner G, Kissane J: The urinary system, in Kissane J (ed): Anderson’s Pathology (ed 9). St Louis, MO, MosbyYear Book, 1990, pp 804-870 29. Cutler HH: Effects of sucrose of the kidney. Proc Staff Meetings Mayo Clin 14:318-320, 1939 30. Anderson WA, Bethea WR: Renal lesions following administration of hypertonic solutions of sucrose. JAMA 114:1983-1987, 1940 31. Rello J, Triginer C, Sanchez JM, Net A: Acute renal failure following massive mannitol infusion. Nephron 53:377-378, 1989 32. Horgan KJ, Ottaviano YL, Watson AJ: Acute renal

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failure due to mannitol intoxication. Am J Nepbrol 9:106109, 1989 33. Dorman HR, Sondheimer JH, Cadnapaphornchai P: Mannitol-induced acute renal failure. Medicine 69: 153-159, 1990 34. Rabetoy GM, Fredericks MR, Hostettler CF: Where the kidney is concerned, how much mannitol is too much? Ann Pharmacother 27:25-28, 1993 35. Olsen S, Solez K: Acute tubular necrosis and toxic renal injury, in Tisher CC, Brenner BM (eds): Renal Pathology With Clinical and Functional Correlations (ed 2). Philadelphia, PA, Lippincott, 1994, pp 796-809 36. Morgan TO, Little JM, Evans WA: Renal failure associated with low-molecular weight dextran infusion. BMJ 2~737-739, 1966 37. Allen AC: Diseases of the tubules, in The Kidney. New York, NY, Grune & Stratton, 1951, pp 207-298 38. Berkseth RO, Kjellstrand CM: Radiologic contrastinduced nephropathy Med Clin North Am 68:35 l-37 1, 1984 39. Berns AS: Nephrotoxicity of contrast media. Kidney Int 36:730-740, 1989 40. Janigan DT, Santamaria A: A histochemical study of swelling and vacuolation of proximal tubular cells in sucrose nephrosis in the rat. Am J Path01 39:175-193, 1961 41. Schwab SJ, Hlatky MA, Pieper KS, Davidson CJ, Morris KG, Skelton TN, Bashore TM: Contrast nephrotoxicity: A randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 20:149-153, 1989 42. Anto HR, Chou SY, Porush JG, Shapiro WB: Infusion intravenous pyelography and renal function: Effects of hypertonic mannitol in patients with chronic renal insufficiency. Arch Intern Med 141:1652-1656, 1981 43. Lilien OM: The paradoxical reaction of renal vasculature to mannitol. Invest Urol 10:346-353, 1973 44. Caldicott W, Hollenberg NK, Abrams HL: Characteristics of response of renal vasculature bed to contrast media. Invest Radio1 5:539-547, 1970 45. Kahan BD: Cyclosporine nephrotoxicity: Pathogenesis, prophylaxis, therapy, and prognosis. Am J Kidney Dis 8:323-331, 1986 46. Venkatachalam MA, Bernard DB, Donohoe JF, Levinsky NG: Ischemic damage and repair in the rat proximal tubule: Differences among the Sl, S2, S3 segments. Kidney Int 14:31-49, 1978 47. Schwartz SL, Johnson CB: Pinocytosis as the cause of sucrose nephrosis. Nephron 8:246-254, 1971 48. Trump BF, Janigan DT: The pathogenesis of cytologic vacuolization in sucrose nephrosis: An electron microscopic and histochemical study. Lab Invest 11:395-411, 1962