Renal Insufficiency After Intravenous Immune Globulin Therapy: a Report of Two Cases and an Analysis of the Literature

AMERICAN RENAL TRAINING CENTERS SERIES

Renal Insufficiency after Intravenous Immune Globulin Therapy: A Report of Two Cases and an Analysis of the Literature

ANTONIO V. CAYCO,*t MARK A. PERAZELLA,*t and JOHN P. HAYSLETTt *Sectjon of Nephrology, tDepart,nent of Medicine, Yale University School of Medicine, New Haven,

Connecticut.

Abstract. Over the past decade, intravenous immune globulin in some cases recovery may be delayed and require renal therapy (IVIG) has gained widespread use for a variety of replacement therapy. In such patients, recurrence of ARF may clinical disorders. IVIG treatment is associated with a number be avoided by selection of a preparation with a different of complications, including acute renal failure (ARF). Al- stabilizing agent. Two cases of IVIG-induced ARF are de- though the cause of IVIG-associated ARF is unknown, it may scribed, and all reported cases are analyzed to assess the be rebated to the stabilizing agent used in the IVIG preparation. probable mechanism of renal injury. (J Am Soc Nephrol 8: The development and resolution of ARF is typically rapid, but 1788-1794, 1997)

Therapy with intravenous immune globulin (IVIG) was intro- We present two cases of ARF associated with IVIG therapy, duced in 1952 to replace natural deficiencies of immunoglobu- analyze reported cases for potential risk factors that may pre- bins for prophylaxis during infection (1). IVIG treatment has dispose to ARF, and discuss possible mechanism(s) involved also been demonstrated to be useful in patients with chronic in the development of IVIG-induced ARF. lymphocytic leukemia (CLL), primary immunodeficiency disorders, and steroid-resistant idiopathic thrombocytopenic pur- Case Reports pura (I). Recently, the indications for such treatment have Case 1 broadened to include a wide number of clinical disorders, A 5 1-yr-old white man with a 10-yr history of hypertension including Kawasaki ‘ s disease, autoimmune disorders, bums, was hospitalized with acute idiopathic thrombocytopenic pur- cytomegabovirus infections in transplant patients, gbomerulo- pura (ITP) associated with ecchymoses and epistaxis. He was nephritis, and immune-mediated neuromuscular disorders such treated with prednisone, 60 mg/d for 18 d, without improve- as myasthenia gravis, Guillain-Barr#{233} syndrome, and demyeli- ment in the platelet count (12,000/ml). He subsequently un- nating neuropathies (1). Currently, seven commercial prepara- derwent therapy with IV immune globulin (Sandoglobulin; tions of immunogbobubin are approved for intravenous admin- Sandoz, East Hanover, NJ) in a dosage of 0.4 gfkg per d for a istration. total of 5 consecutive days. The only other medication admin- Despite its widespread utilization, side effects associated istered was amlodipine, 10 mg/d. He was a nonsmoker and with IVIG therapy remain relatively uncommon (1 to 15%) and only occasionally drank alcohol. include two types of complications: (1) fever, chills, headache, Physical examination performed on the day of nephrologic myalgia, hypertension, and chest pain due to complement consultation revealed a well-developed male subject (86 kg). activation by IgG aggregates, and (2) anaphylactic reactions in His BP was 135/90 mmHg and his pulse rate was 80 beats per patients with underlying IgA deficiency ( 1 ,2). Acute renal mm without othostasis. Head and neck examination was unre- failure (ARF) was not noted as a complication of IVIG treat- markable. His lungs were clear while his heart exam revealed ment in the initial drug trials but over time has been recognized an 54 heart sound; neither a murmur nor rub was observed. The as a side effect of IVIG administration (2). On the basis of abdominal examination was benign and there was no edema. published reports, the development of ARF after IVIG therapy Ecchymoses were present on the trunk, arms, and legs. The appears to occur only rarely. neurologic examination was physiologic. The hospital course is summarized in Table 1 . A rise in serum creatinine level was noted on the third day of IVIG Received October 9, 1996. Accepted December 18, 1996. treatment and reached a peak of 4.2 mg/dl on day 8. Oliguria Correspondence to Dr. Mark A. Perazella, Yale University School of Medi- occurred on the fifth day of treatment. Urinalyses performed on eine, Section of Nephrology, LMP 2071, 333 Cedar Street. New Haven, CT 06520-8029. days 1 and 5 were negative for protein and blood and were notable only for the presence of tubular epithelial cells with 1046-6673/0801 1- 1788$03.00/0 Journal of the American Society of Nephrology abundant vacuoles. An ultrasound of the kidneys revealed Copyright © 1997 by the American Society of Nephrology normal-sized kidneys with normal echogenicity and absence of Renal Insufficiency and IVIG 1789

Table 1. Summary of clinical courses was given for 3 d (days 2 through 4). A rise in serum creatinine level was noted on the third day of treatment and reached a BP Input/Output BUN/Creatinine Hospital Day (mmHg) (L/24 h) (mg/dl) peak of 2.5 mg/dl before returning to baseline 7 d after IVIG was terminated. Urine volume decreased on the third day of Case 1 treatment and oliguria occurred several days after treatment. 1 125/80 2.5/2.8 18/1.4 Urinalysis revealed 2+ proteinuria on dipstick and micro- 2i 130/88 3.1/2.7 17/1.4 scopic examination of the urine sediment revealed the presence 3a 135/90 3.5/2.1 20/1.5 of renal tubular epithebial cells with cytoplasmic vacuobes and 4a 140/89 3.4/1.5 24/1.7 a few granular casts; no other abnormalities were found. Dur- 5a 144/92 3.5/1.0 35/2.2 ing hospitalization, nephrotoxic agents-including radiocon- 6’ 150/95 2.5/0.4 44/3.1 trast material-were not administered. BP remained normal 7 160/95 1.5/0.8 55/3.9 and the patient was asymptomatic. 8 155/92 1.0/1.8 62/4.2 9 149/92 1.1/3.5 63/3.7 10 145/90 1.2/4.1 64/3.0 Discussion 11 144/88 2.0/3.8 55/2.1 IVIG-associated ARF was first reported in 1987 (3). All 12 135/85 2.5/3.6 50/1.7 cases reported since the first report are summarized in Table 2. 13 140/88 2.8/3.3 41/1.5 Including the two cases reported here, a total of 50 cases of

Case 2 IVIG-induced ARF have been published. The indications for 1 145/90 2.8/2.6 32/1.5 IVIG therapy were varied, but the majority consist of ITP, neurobogic disorders, and other hematologic diseases. In gen- 2b 135/86 2.1/2.0 30/1.4 3b 130/82 2.5/2.0 35/1.5 eral, a clinical diagnosis of IVIG-associated ARF has been 4b 136/83 2.3/1.3 38/1.7 made through the exclusion of other causes of ARF and by the 5 145/84 2.1/1.0 48/2.0 temporal association of ARF with IVIG infusion. 6 136/80 2.0/0.7 61/2.3 In the reported cases of IVIG-associated ARF, 2 1 patients 7 131/78 1.5/0.3 78/2.5 (45%) had a baseline serum creatinine level either documented 8 140/81 1.2/0.9 65/2.4 as less than 1 .5 mg/dl or stated to be normal (3-1 3), whereas 9 145/85 1.5/2.2 60/2.0 25 cases (55%) had underlying renal insufficiency defined as a 10 140/88 2.0/3.6 43/1.6 baseline serum creatinine level greater than or equal to 1.5 11 138/78 2.5/3.7 35/1.5 mg/dl or stated as abnormal (4-6,9, 1 1 , 14-2 1 ). Twenty-three patients (58%) were 65 yr of age or older (4 -10,13,18-21), a Received intravenous immunogbobubin whereas 17 patients (42%) were less than 65 yr of age (3- (Sandoglobulin, 0.4 g/kg per d). b Received intravenous immunogbobulin 5,9,11,12,14,16,17,19,22). Other reports did not mention age. (Sandoglobulin, 1.0 glkg per d). Nine patients (1 8%) were treated with IVIG for renal disease, six of whom carried a diagnosis of nephrotic syndrome (mem- branous, 4; mesangiocapillary, 1 ; minimal change, I) and three hydronephrosis. Throughout the hospital course, the patient did of whom had glomerubonephritis (4,15). not receive any known nephrotoxic agent including radiocon- The clinical course of IVIG-associated ARF generally fob- trast material. Urine output exceeded 2 L per day and the serum bowed a similar pattern. Acute renal insufficiency developed creatinine level returned to baseline by 3 and 7 d, respectively. approximately 3 d (range, 1 to 10 d) after the initiation of IVIG treatment. Oliguric renal failure appeared to occur more com- Case 2 monly than nonoliguric renal failure, and the duration of renal A 61-yr-old white woman with a history of hypertension, insufficiency was approximately 13 d (range, 3 to 42 d). Of the non-insulin--dependent diabetes melbitus, chronic renal insuf- 18 cases (including our two cases) that documented urine ficiency with a baseline creatinine level of 1 .5 mg/dl, and output, 16 patients developed oliguric renal failure (3,5-7,9- hyperlipidemia was treated with IVIG (Sandogbobulin) in a 11,14,19,21). At times, renal replacement therapy was re- dose of 1 g/kg per d for three consecutive days after failing quired. In this series, 15 patients (30%) treated with IVIG steroid therapy for chronic inflammatory demyelinating poly- underwent dialytic intervention (6-9,11,17-22). In the major- neuropathy. Other medications included enalapril, 10 mg twice ity of cases (84%), ARF was reversible and renal function daily; amlodipine, 20 mg each day; fluvastatin, 10 mg/d; and returned to baseline after discontinuation of IVIG therapy. Of furosemide, 40 mg/d. those patients who did not recover renal function to baseline, At the time of the nephrology consultation, examination five died (sepsis, 2; cardiac death, 2; stroke, I), two had stable revealed an obese woman (88 kg) with a BP of 142/78 mmHg chronic renal failure, and one required chronic hemodialysis. In and a pulse of 78 beats per minute without orthostasis. Exam- the one patient who required chronic renal replacement ther- ination of the lungs, heart, and abdomen was normal, except apy, underlying gbomerulonephritis may have contributed to for lower-extremity weakness. the development of irreversible renal failure (16). Plasma- A summary of the hospital course is shown in Table 1 . IVIG pheresis was also performed in two patients with IVIG-asso- 1790 Journal of the American Society of Nephrology

Table 2. Reported and current cases of intravenous immunoglobulin (IVIG)-induced renal failur&’

Onset of ARF Duration of ARF Reference No. of Cases Age IVIG Preparation BaselinefPeak Cr (mg/dl) (d) (d)

(3) 1b Sandoglobulin 1.0/6.0 1 40 (14) IC 40 Sandogbobulin 1.8/5.2 3 8 (4) 6 NM Sandoglobulin 1.1/1.5 2 10 to 12 1 20 NM 1.6/2.1 4 14 I 78 NM 3.5/6.1 5 7 (15) 3 NM Biotransfusion 2.0/2.4 2 5 to 30 (5) 1h Sandoglobulin 2.3/7.9 2 14 1 73 Sandoglobulin 1.0/1.8 1 3 I 69 Sandogbobulin 1 .7/6.0 2 7 (16) 1 21 Gammonativ 2.1/4.2 5 ESRD 1d (17) 48 Sandoglobulin 2.5/10.0 1 42 9d (1 8) >70 Sandogbobulin NS 2 to 5 5 to 12 1b.d (6) 76 Immunogbobulin 1.6/9.7 5 56 CTS 1d 83 NM 0.8/3.1 4 Died 1d (22) NM NS/12 10 NS (19) 1b.d Sandoglobulin 1.6/8.7 3 NS l 69 NM 1.6/5.5 5 9 (7) 1d 65 NM NS 2 NS 1d 66 NM N.S. 2 Died 1 65 NM 1.2/2.8 2 7 1d (8) 69 NM NS/12 4 7 (9) 1 72 Gamimmune 1.4/7.1 5 8 1 65 Sandogbobulin 1.2/4.0 5 10 1d 52 Sandoglobulin 1.6/7.7 3 10 to 14 (10) 1b Sandoglobulin 1.4/7.4 5 7 (11) 1 55 Sandoglobulin 1.2/8.6 5 NS l’ 55 Sandoglobulin 1.1/4.6 2 10

1)d 28 Sandoglobulin 1.7/4.9 3 9 1 b.d 40 Sandoglobulin I .2/2.5 3 Died (12) IC 53 Endobulinl 1.2/6.9 1 5 Biotransfusion 1d (20) 3 Sandoglobulin 2.0/7.5 2 Died (13) 1 72 NM 1.4/8.4 3 NS 1b.d (21) 41 Sandoglobulin 3.7/9.5 2 12 Present 1 51 Sandoglobulin 1.4/4.2 3 7 1 61 Sandoglobulin 1.5/2.5 3 7

a Total number of cases, 50. Cr, creatinine; ARF, acute renal failure; NM, not mentioned; ESRD, end-stage renal disease; NS, values not specified. I) Renal biopsy performed. C Plasmapheresis performed. d Patient required dialytic intervention.

ciated ARF (10, 1 1). These patients recovered renal function renal insufficiency were treated with Biotransfusion (Biotrans- after plasmapheresis. fusion, France). The immunoglobulin preparation was not Of the seven immunogbobubin preparations available for use, specified in 10 cases. Table 3 summarizes the IVIG products Sandoglobulin was used in the majority of cases (82.5%) in and their respective stabilizing agents. which renal failure developed. Single case reports of ARF were The dose of IVIG administered ranged from a daily dose of also noted in association with Gammimmune (Cutter, Emo- 0.35 to 1 .0 g/kg, whereas the total dose ranged from 70 to ryvible, CA), Gammonativ (Kabi Vitrum AB, Stockholm, Swe- 279 g (Table 4). These doses correspond to the dosage typi- den), Immunoglobulin CTS (France), or Endobulin (Immuno, cally used for routine therapy with IVIG. Although a few Vienna, Austria) therapy. Four patients who developed acute patients appeared to benefit from a lower dose of IVIG or a Renal Insufficiency and IVIG 1791

Table 3. Intravenous immunoglobulin preparations available dothelial deposits. Indirect immune staining of the kidney in the United States tissue using anti-idiotypic antibodies directed against the rheumatoid factor, however, revealed a staining pattern identical to Product Name Stabilizing Agent the pattern obtained with direct immunofluorescence. This Sandoglobulin (Sandoz) 5% to 10% sucrose finding suggested that immune complex deposits consisted of Iveegam (hiiniuno) 5% glucose, 0.3% NaCI IgG from the IVIG infusion and the endogenously produced Gammagard (Hyband) 2% glucose, glycine 1gM kappa paraprotein. Another biopsy revealed mononuclear 0.3% albumin cell infiltrates in the interstitium and tubular atrophy, consis- Gamimune N (Cutter) 10% maltose tent with an immunological reaction (6). The features of the Gammar IV (Armour) 5% to 10% sucrose remaining seven biopsy specimens, however, exhibited the Venoglobulin-I (Alpha Therapeutic) 2% mannitol following common features (5,10,11,19): marked swelling, 0.5% NaC1 cytoplasmic vacuolization and degeneration of proximal tubu- 1% albumin lar epithebium, and bumina that were narrowed or completely Polygam S/D (American Red Cross) 2% glucose, glycine occluded by the swollen cells. Glomei-uli were spared, although 0.3% albumin one biopsy specimen demonstrated mesangial proliferation (1 1). Immune deposits were consistently absent by both elec- tron microscopy and immunofluorescence studies, except in one patient who had underlying IgA nephropathy (21). Table 4. Total IgG doses in selected reported cases and the No clear risk factors for the development of IVIG-associated corresponding amount of sucrose in each IVIG ARF are apparent upon analysis of the cases reported. How- dose ever, patients with underlying renal insufficiency (55% in this Amount of series) may be predisposed to acute renal injury with IVIG I C Ts, Total Dose Sucrose per therapy (4-6,9,1 1,13-20). Older age may also represent a risk Reference g se No. of Doses of IgG Dose of (g/dose) (g) IgG’ factor for IVIG-associated ARF (8. 13, 1 8). In this series, 23 (g/IgG dose) patients (58%) with ARF were over 65 yr of age. It is possible that unrecognized renal impairment in elderly patients may (5) 93 3 279 155 provide a predisposition for nephrotoxicity (Table 5). 35 2 70 58 The clinical course of our cases are similar to that of previ- 55 3 165 91 ously reported patients with IVIG-associated ARF. Both pa- (17) 27 3 81 45 tients had mild renal insufficiency before IVIG therapy and (9) 19 5 95 32 were over 50 yr of age. Onset of renal insufficiency occurred 65 4 260 108 several days after the start of treatment in the absence of other (10) 36 5 180 60 known causes of renal injury. Subsequently, renal function (20) 70 2 140 117 recovered within a week after discontinuation of therapy. Al- (21) 70 2 140 117 though renal biopsies were not performed, the presence of Present 34 5 170 56 vacuolated tubular epithelial cells in the urine may reflect 88 3 264 147 tubular injury. Similar urinary findings were reported in six

a Each gram of immunogbobubin in a Sandogbobulin preparation patients after the infusion of mannitol (23). is stabilized with 1 .67 g of sucrose. The amount of sucrose given The mechanism of renal injury induced by IVIG has not per dose is derived by multiplying the amount of IgG per dose by been established (Table 6). It is well known that renal disease 1.67. leading to renal insufficiency may occur in gammopathies associated with the production of either mono- or polycbonal immunogbobulins. In these disorders, the deposition of kappa longer interval between immunoglobulin dosing when IVIG or lambda fragments, or immune complexes, in glomerular therapy was reintroduced, there was no correlation between capillaries may cause glomerubonephritis that characteristically dose and the development of ARF (9, 18,19). The data con- does not rapidly resolve without treatment. As noted above, a ceming infusion rate and the concentration of the IVIG sobu- similar reaction or interstitial nephritis may rarely occur in tion are incomplete, and no conclusions can be reached con- patients during IVIG treatment. It seems likely, however, on cerning their relationship to renal injury. the basis of renal histopathological studies, that renal injury in Renal biopsy was obtained in nine cases. The first reported case of IVIG-associated ARF occurred in a patient with a monoclonal 1gM kappa paraprotein with rheumatoid factor Table 5. Proposed risk factors for IVIG-associated acute activity (3). In this case, renal histologic features were consis- renal insufficiency tent with acute cryogbobulinemic glomerulonephritis and ex- Preexisting renal insufficiency (creatinine level 1.5 mg/db) hibited lobular accentuation with proliferation and polymor- Older age (age >65 years) phonuclear cell infiltration, occlusion of capillary loops with Underlying paraproteinemia with rheumatoid factor activity hyaline “thrombi,” and mesangial cell interposition of suben- 1792 Journal of the American Society of Nephrology

Table 6. Potential mechanisms of acute renal insufficiency ischemic renal damage (5). It has been theorized that IVIG, like induced by IVIG radiocontrast and mannitol infusion in animals, may induce renal artery vasoconstriction and subsequent ischemic renal Tubular obstruction from proximal renal tubular cell injury (5). However, the site of tubular injury typically de- swelling secondary to sucrose nephropathy scribed with reduced renal blood flow is most often the distal . majority of cases of IVIG-associated renal insufficiency nephron (1 1). This is in contrast to the proximal location of the involves preparations containing sucrose. lesion seen with immunogbobulin therapy and suggests that . IVIG preparations containing maltose are better ischemic injury is not the major etiology of acute renal failure tolerated. associated with IVIG. . the histopathobogical lesions seen on most renal biopsy Finally, Poulbin and colleagues have speculated that IVIG specimens from patients with IVIG-associated renal causes acute renal failure, in a manner similar to dextran, insufficency are identical to those of sucrose through the hyperosmotic effect of immunoglobulin in the nephropathy. glomerulus (12). Although immediate recovery of renal func- . the clinical course of IVIG-associated renal insufficiency tion occurred after plasmapheresis in two patients with IVIG- corresponds to the course of sucrose nephrosis associated ARF, the lack of a true “hyperoncotic syndrome” in demonstrated in animal studies. these patients makes this theory unlikely (12). Ischemia secondary to renal artery vasoconstriction The model of sucrose nephropathy has been postulated by Abnormal gbomerular hemodynamics due to an elevated some authors to represent the mechanism by which IVIG plasma oncotic pressure causes ARF (10, 1 1,19,20). The hypothesis that renal insuffi- Deposition of immune complexes in the glomerulus or ciency secondary to IVIG is primarily related to proximal interstitium tubular swelling is supported by the following: First, 82% of reported cases are due to Sandoglobulin, which contains sucrose (Table 3). IVIG preparations that contain maltose have the majority of patients is caused by the rapid uptake of a not been associated with ARF, except in one case in which filtered macromolecule into proximal tubular epithelial cells other nephrotoxins were administered (9). This is likely related and the subsequent swelling of these cells, which occlude the to the fact that maltose is digested and metabolized to CO2 by tubular lumina. The finding of massive swelling of proximal kidney cells, whereas sucrose is not (20). Additionally, reports epithelial cells was initially reported in patients who died of exist in which patients have tolerated maltose-containing IVIG renal failure after the administration of sucrose and led to the but have developed ARF when treated with sucrose-containing term sucrose nephropathy (24). Studies in experimental ani- IVIG (5,1 1). Second, the clinical course of IVIG-associated mals also showed that proximal cell swelling could be repro- ARF corresponds to the rate of clearance of sucrose molecules ducibly induced by infusion of this disaccharide (25,26). Al- from proximal cells in animal studies (25,29). Third, the renal terations in renal function apparently depended on the severity lesions found on the majority of biopsy specimens of patients of tubular obstruction (25,26). This lesion was also subse- treated with IVIG are identical to those described with sucrose quently observed with parenteral infusion of mannitol, dextran, nephropathy. Fourth, a subgroup of patients with acute renal and radiocontrast preparation and suggested that the mecha- insufficiency, apparently due to cellular swelling, exhibited nism causing this unique lesion involved the uptake of non- intact renal parenchymal function as reflected by low urine metabolizable molecules by pinocytosis into proximal cells, sodium levels (5,20). Although measures of urinary electro- followed by the accumulation of cellular water due to the lytes have not been routinely obtained, urine sodium was low oncotic gradient generated across the cell membrane (27,28). in two patients with IVIG-associated ARF when measurements The evolution of structural changes that follow an intrave- were made (5,20). Morphological studies in experimental an- nous infusion of sucrose has been described in experimental imals demonstrated intact proximal tubular cells with a normal animals (25,29). In dogs, swelling and vacuolization of tubular brush border (24). Finally, preexisting renal insufficiency ap- cells develop as early as 1 h after sucrose infusion and reach pears to be a risk factor for IVIG-associated ARF. It is possible maximum severity at 48 to 72 h (25). Resolution commences that renal insufficiency may prolong exposure of proximal by the seventh day after infusion and approaches completion tubular cells to the macromolecule and facilitate pinocytotic by 2 wk. The mechanism by which sucrose precipitates tubular uptake and greater intracellular accumulation of this undigest- swelling and vacuolization has been studied histochemically ible carbohydrate (20). (29). Sucrose enters proximal tubular cells via pinocytosis rather than through an apical membrane transporter. Pinocy- Conclusion totic vesicles containing sucrose coalesce to form vacuoles that Acute renal failure is a relatively rare complication of IVIG over time fuse to cytoplasmic lysosomes and form phagolyso- therapy. Including our two cases, a total of 50 cases have been somes. Because renal cells do not possess the enzymes neces- reported in the literature. Acute renal insufficiency usually sary to digest sucrose, this disaccharide accumulates in the occurs within several days after the initiation of IVIG infusion cytoplasm and leads to the accumulation of cellular water and and may persist for 1 to 2 wk. Although risk factors have not subsequent cell swelling (29). been definitely established, preexisting renal impairment and It is also possible that IVIG-associated ARF develops from older age may predispose to IVIG-associated ARF. The renal Renal Insufficiency and IVIG 1793 lesion is found mainly in the proximal tubule and is charac- 14. Corvetta A, Della Bitta R, Gabriella A, Spaeth PJ, Danielbi G: tenzed by marked cytoplasmic vacuolization and cellular Use of high dose intravenous immunoglobulin in systemic lupus swelling with tubular lumen occlusion. Immune deposits are erythematosus: Report of three cases. C/in Exp Rheumato/ 7: usually absent. Renal insufficiency is typically reversible, and 295-299, 1989 management consists of discontinuation of IVIG and support- 15. Rostoker G, Philippon C, Belghitti D, Ben Maadi A, Remy P. ive measures. In less than one-third of the cases, dialysis is Lang P. Lagrue G, Ozanne F, Bremard-Oury C, Weil B: Intra- required. The pathogenesis of IVIG-associated ARF is cur- venous IgG for gbomerulonephritis and renal function. Lancet rently unknown; however, it is likely to be multifactorial. In 338: 544-555, 1991 most cases, it appears that sucrose is the probable cause of the 16. Kobosko J, Nicob P: Renal toxicity of intravenous immunoglob- characteristic renal tubular lesion and acute renal failure. ulin. Clin Nephrol 37: 216-217, 1992 17. Phillips AO: Renal failure and intravenous immunogbobulin. References C/in Nephro/ 37: 217, 1992 1. ASHP Commission on Therapeutics: ASHP therapeutic guide- 18. Donatini B: Transient renal dysfunction in diabetic patients after lines for intravenous immune globulin. Clin Pharmacol. 1 1: IVIG therapy. J Intern Med 232: 376, 1992 117-36, 1992 19. Tan E, Hajinazarian M, Bay W, Neff J, Mendell J: Acute renal 2. Duhem C, Dicato M, Ries F: Side effects of intravenous immune failure resulting from intravenous immunogbobulin therapy. Arch globulins. Clin Exp Immunol 97[Suppl 1]: 79-83, 1994 Neuro/ 50: 137-139, 1993 3. Barton J, Herrera G, Galla J, Bertoli L, Work J, Koopman W: 20. Winward DB, Brophy MT: Acute renal failure after administra- Acute cryogbobulinemic renal failure after intravenous infusion tion of intravenous immunoglobulin: review of the literature and of gamma globulin. Am J Med 82: 624-629, 1987 case report. Pharmacotherapy 15: 765-772, 1995 4. Schifferli J, Leske M, Favre H, Imbach P. Nydegger U, Davies 21. Hansen-Schmidt S. Sibomon J, Keller F: Osmotic nephrosis due K: High dose intravenous IgG treatment and renal function. to high dose immunogbobulin therapy containing sucrose (but not Lancet 337: 457-458, 1991 with glycine) in a patient with immunogbobulin A nephritis. Am J 5. Rault R, Piraino B, Johnston J, Oral A: Pulmonary and renal toxicity Kidney Dis 28: 451-453, 1996 of intravenous immunoglobulin. Clin Nephrol 36: 83-86, 1991 22. Friedman KD, Saddler MC, Tarnover AC, Yang G, Harford AM: 6. Ellie E, Combe C, Ferrer X: High-dose intravenous immune globulin and acute renal failure. N Engi J Med 327: 1032-1033, 1992 Transient renal failure in a patient with idiopathic thrombocyto- 7. Stewart R, Winney R, Cash J: Renal toxicity of intravenous penic purpura after treatment with concomitant protein-A immu- immunoglobulin. Vox Sang 65: 244, 1993 nosorption and intravenous immune globulin [Abstract]. Blood 8. Ruggeri M, Castaman G, de Narde 0, Rodeghiero F: Acute renal 80[Suppb 1]: 483, 1992 failure after high-dose intravenous immune globulin in a patient 23. Dorman HR. Sondheimer JH, Cadapaphornchai P: Mannitiob- with idiopathic thrombocytopenic purpura. Haematologica 78: induced acute renal failure. Medicine 69: 153-1 59, 1990 338-339, 1993 24. Anderson W, Bethea W: Renal lesions following administration 9. Pasatiempo A, Kroser J, Ruducek M, Hoffman B: Acute renal of hypertonic solutions of sucrose. JAMA 1 14: 1983-1987, 1940 failure after intravenous immunoglobulin therapy. J Rheumatol 25. Lindberg H, Wald M: Renal changes following the administra- 21: 347-349, 1994 tion of hypertonic solutions. Arch I,itern Med 63: 907-91 8, 1939 10. Ahsan N, Palmer B, Wheeler D, Greenlee R, Toto R: Intravenous 26. Rigdon RH, Cardwell ES: Renal lesions following the intrave- immunogbobulin-induced osmotic nephrosis. Arch Intern Med nous injection of hypertonic solution of sucrose: a clinical and 154: 1985-1987, 1994 experimental study. Arch Intern Med 69: 670-690, 1942 1 1. Cantu 1, Hoehn-Saric E, Burgess K, Racusen L, Scheel P: Acute 27. DiScala V, Mautner W, Cohen J, Levitt M, Churg J, Yunis S: renal failure associated with immunoglobulin therapy. Am J Tubular alterations produced by osmotic diuresis with mannitol. Kidney Dis 25: 228-234, 1995 Ann intern Med 63: 767-775, 1965 12. Poullin P. Moulen B, Ollier J, Benarcha M, Olmer M, Gabriel B: 28. Morgan T, Little J, Evans W: Acute renal failure associated with Hyperoncotic renal failure after intravenous immunoglobulin therapy. Presse Med 24: 44 1-444, 1995 low-molecular weight dextran infusion. Br Med J 2: 737-739. 13. Arunabh S, Kuman G, Aviba V: Acute renal failure induced by 1966 intravenous immune globulin. Am Fam Physician 53: 862-863, 29. Schwartz SL, Johnson CB: Pinocytosis as cause of sucrose 1996 nephrosis. Nephron 8: 246-254, 1971 1794 Journal of the American Society of Nephrology

The Training Program in Nephrology at the Yale University School of Medicine

Postdoctoral training in nephrobogy at Yale University originated in the 1940s within the Section of Metabolism created by Dr. John Peters. Since 1972, a distinct nephrology program has existed, which is currently directed by Dr. Peter Aronson. The goal of our program is the training of academic nephrobogists. Presently, 70% of our graduates hold full-time faculty appointments. Our traditional fellowship is 3 (or more) years in duration and includes I year of full-time clinical training and 2 (or more) years devoted to investigative training. Clinical-only and research-only fellowships are also available. Clinical training is based at the Yale-New Haven Hospital, the West Haven VA Medical Center, and the Yale- Gambro Dialysis Center. Our fellows gain expertise in the diagnosis and management of patients with a broad array of disorders, including electrolyte disturbances, gbomerubonephritis, hypertension, acute and chronic renal failure, and intoxications. Fellows receive intensive training in the application of continuous venovenous hemodiafiltration (CVVH and CVVHD), participate meaningfully in the care of patients with renal albografts, and perform all of our renal biopsies. Training in the outpatient practice of nephrobogy includes longitudinal participation in the care of patients requiring maintenance hemodiabysis or home peritoneal dialysis, and emphasizes the continuity of care. The Section of Nephrobogy has 19 full-time faculty. Basic research interests include mechanisms and regulation of epithelial transport, the molecular basis of hereditary renal disease, mechanisms of gene regulation, T cell immunobiobogy, and mechanisms of acute renal failure. Clinical research interests include selection for and complications of renal transplantation, disorders of potassium homeostasis, natural history and treatment of glomerular disease. renal complication of therapeutic agents, outcomes in dialysis management, nutritional inadequacy in renal failure, and anemia of renal insufficiency. Clinical investigation is enhanced by the GAMBRO Dialysis Patient Database, the Connecticut Kidney Biopsy Database, and a close working relationship with the Robert Wood Johnson Clinical Scholars Program. Research training is supported by a training grant from the National Institutes of Health. Yale University School of Medicine is unique in having a large group of distinguished faculty outside the Section of Nephrobogy whose interests include the study of the kidney and who also serve as research mentors for nephrology trainees. This provides fellows with access to a broad range of research projects within the fields of biostatistics, genetics, transplantation biology, physiology, and cell biology.