Case Report: Thrombotic Microangiopathy Post-intravenous Immunoglobulin in the Context of BK Nephropathy and Renal Transplantation F.F. Pan, L. Hidayati, P. Hughes, A. Murugasu, and R. Masterson ABSTRACT Intravenous immunoglobulin (IVIg) is a blood product with immunomodulating properties that have been widely applied in the management of renal transplant recipients. In general, IVIg has been considered a relatively safe therapy, with most adverse events being mild and transient. Although rare, a serious and well-recognized complication of IVIg is large-vessel thrombotic events, which are thought to be related to hyperviscosity. We describe here two cases in which there was a temporal relationships between the administration of IVIg, an acute decline in allograft function, and the histologic finding of de novo thrombotic microangiopathy (TMA). In both cases, IVIg had been administered to facilitate immunosuppressive dose reduction in the context of BK nephropathy. We believe this is the first report of TMA associated with IVIg administration in renal allograft recipients.

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NTRAVENOUS immunoglobulin (IVIg) is a blood product that has been widely used in the management of renal transplant recipients. In general, it has been considered a relatively safe therapy with few side effects. A welldescribed complication of IVIg therapy is large-vessel thrombosis, particularly in those patients who have a previous history of venous thromboembolism and vascular disease. To date there have been no cases described in the literature of microvascular thrombosis associated with the administration of IVIg. We describe here the course of two renal allograft recipients who developed thrombotic microangiopathy (TMA) immediately post-IVIg administration. Both patients had been administered IVIg to facilitate reduction in overall immunosuppression in the context of known BK nephropathy. CASE 1 A 54-year-old man who had end-stage kidney disease secondary to IgA nephropathy received a deceased donor renal transplant (5-antigen mismatch) in November 2011. Baseline immunosuppression (IS) consisted of basiliximab, prednisolone, mycophenolate mofetil (MMF) and tacrolimus. A biopsy performed for delayed graft function (serum creatinine level was 160 mmol/L) 4 weeks post-engraftment showed minimal abnormality. Three months posttransplantation, the serum creatinine level was 180 mmol/L and serum BK virus was detected by urine polymerase chain reaction (PCR) on routine screening (viral load:15,539 copies/mL). At this time, IS consisted of prednisolone (5 mg), MMF (1500 mg), and tacrolimus (trough levels of 5 to 8 ng/mL). A 3-month protocol 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.10.038 278

biopsy specimen showed mild interstitial inflammation but no features of active rejection. Positive BK viral nuclear staining of a single tubular epithelial cell was also detected. In response to the BK nephropathy, overall IS was reduced (MMF to 750 mg total daily dose and tacrolimus to achieve levels of 3 to 5 ng/mL). Despite this IS dose modification, the BK viral load increased to 2.1 million copies/mL over the next 10 days. To facilitate further aggressive IS dose reduction, IVIg (Kiovig, Baxter AG, Vienna, Austria) 0.75g/ kg was administered with saline pre-hydration and prophylactic enoxaparin. The patient became systemically unwell and oliguric post infusion. The serum creatinine level increased from 229 mmol/ L immediately pre-IVIg to 544 mmol/L within 36 hours of the infusion. Acute renal vascular thrombosis was excluded by Doppler ultrasound. In association with the acute decline in allograft function, there was a decrease in platelet count from 170 to 112  109/L and an increase in lactate dehydrogenase (LDH) (706 IU/L), although no fragments were noted on the blood film. A transplant biopsy, performed only 19 days after the previous biopsy, now revealed de novo TMA involving 50% of the glomerular loops on a background of acute tubular injury and interstitial inflammation thought to be secondary to BK nephropathy. Peritubular capillaritis was absent and C4d staining was negative. ADAMTS13 activity was

From the Departments of Nephrology (F.F.P., L.H., P.H., R.M.) and Anatomical Pathology (A.M.), Royal Melbourne Hospital; and the Department of Medicine, University of Melbourne (P.H., R.M.), Melbourne, Vic, Australia. Address reprint requests to Dr Rosemary Masterson, Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail: [email protected]

Crown Copyright ª 2014 Published by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 278e280 (2014)

THROMBOTIC MICROANGIOPATHY normal (98%) and testing for lupus inhibitor, anti-cardiolipin antibodies, and anti-b2 glycoprotein antibodies were negative. Hemodialysis and intensive plasma exchange (PEx) over a period of 5 weeks were initiated with further IS dose reduction (MMF to 500 mg/d and tacrolimus to achieve levels of 1 to 2 ng/mL). Three weeks after cessation of PEx, renal allograft function slowly improved (serum creatinine level of 409 mmol/L from peak of 946 mmol/L), with normalization of hemoglobin, platelet count, serum LDH, and a decrease in BK viral load to 32,000 copies/mL. A follow-up transplant biopsy performed 2 months later showed resolving TMA and mild interstitial fibrosis and tubular atrophy. No BK virus was identified. One year after transplantation, his serum creatinine level is 260 mmol/L with a urine protein:creatinine ratio of 26 mg/mmol. His BK viral PCR is negative.

CASE 2 A 52-year-old man who had end-stage kidney disease secondary to autosomal dominant polycystic kidney disease received a living unrelated donor renal transplant from his wife (6 Ag mismatch). Baseline immunosuppression consisted of basiliximab, prednisolone, MMF, and tacrolimus. Post-transplantation, immediate graft function ensued and the serum creatinine level decreased to a nadir of 160 mmol/L. BK was detected in serum by PCR on routine screening 1 month post-transplantation (viral load: 3775 copies/mL). In response to the positive serum BK PCR, overall IS was reduced (MMF:1000 mg total daily dose and tacrolimus to achieve a level of 4 ng/mL). Despite the overall reduction in IS, the serum BK viral load continued to increase reaching 526,500 copies/mL by 8 weeks post-transplantation. A regimen of IVIg (KIOVIG) 1 g/kg infused according to local guidelines with saline pre-hydration and prophylactic enoxaparin was initiated to facilitate further IS dose reduction. During the first IVIg infusion, the patient became febrile and the infusion was ceased and recommenced 24 hours later with pre-infusion hydrocortisone and cetirizine, which was well tolerated. Day 5 post-infusion, an acute decline in renal allograft function was noted with the serum creatinine level increasing from 160 mmol/L pre-IVIg to 562 mmol/L. Coincident with the decline in renal allograft function, the Hb level decreased from 114 g/L to 88 g/L, the platelet count decreased from 592 to 360  109/L, and the LDH level was mildly increased (560 IU/L). No fragments were observed on blood film. A renal transplant biopsy specimen showed acute endothelial cell injury and features suggestive of early TMA. There was no evidence of BK nephropathy, acute tubular necrosis, or antibody-mediated rejection. In response to the histopathologic diagnosis of early TMA, PEx was initiated, with 4 exchanges being performed over a 10-day period. One week after cessation of PEx, the serum creatinine level had decreased to 160 mmol/L, and by 4 weeks it had decreased further to 140 mmol/L. Cidofovir infusion was commenced for ongoing management of an increasing serum BK PCR with good response. His creatinine level 3 months after development of TMA was 145 mmol/L with undetectable serum BK as measured by PCR.

DISCUSSION

IVIg is a blood product prepared from the serum of between 1000 and 15,000 donors per batch. It is an immunomodulating agent that has been widely used in the management of renal transplant recipients. Its proposed mechanisms of action are pleiotropic including effects on autoantibodies, complement activation, cytokines,

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saturation of macrophage Fc receptors, and the activation of inhibitory Fc receptors [1,2]. The most common indication for its use after renal transplantation is in the management of antibody-mediated rejection and less commonly to facilitate immunosuppressive dose reduction in the context of viral infection [3e5]. In general, IVIg has been considered a relatively safe therapy, with most adverse events being mild and transient. Although rare, a serious and well-recognized complication of IVIg is large vessel thrombotic events, with cases of deep vein thrombosis, pulmonary emboli, cerebral sinus thrombosis, stroke, and myocardial infarction all described in the literature [6,7]. The mechanisms of thromboembolic complications are thought to be related to hyperviscosity, especially in high-risk patients including those with a history of thromboembolism, vascular disease, diabetes, and hypertension. Acute renal failure (ARF) in native kidneys post-IVIg has also been reported, especially with sucrose-based solutions [8]. For cases in which biopsies have been performed in the setting of ARF, histopathologic findings typically reveal proximal tubular epithelial injury with cytoplasmic vacuolization, cellular swelling, and tubular luminal occlusion, similar to that found in sucrose nephropathy. TMA is a rare condition characterized by microangiopathy hemolytic anemia, thrombocytopenia, and microvascular occlusion causing ischemic damage to organs including the kidneys, brain, heart, and gastrointestinal system [9,10]. It most commonly occurs in the setting of abnormal von Willebrand factor processing due to ADAMTS13 deficiency (in thrombotic thrombocytopenia purpura), endothelial injury, and complement activation due to shiga toxin or inherited abnormalities of complement regulation (in atypical hemolytic uremic syndrome) [9,10]. TMA can also occur in association with pregnancy, certain drugs, malignancy, organ and hematopoietic transplantation, and with some infections. In the two cases outlined above, the temporal relationship between the administration of IVIg, the acute decline in allograft function, and the finding of de novo TMA suggest IVIg as the cause for the pathology. Although calcineurin inhibitors are recognized as precipitating TMA after renal transplantation, both patients had had stable allograft function despite relatively high serum tacrolimus levels in the months before IVIg administration. Indeed, the patient outlined in the first case had had a renal biopsy just 3 weeks before the administration of IVIg which had shown no features of endothelial injury or fibrin microthrombi within glomerular loops. The mechanism by which the IVIg triggered the development of TMA remains unclear. ADAMTS13 activity measured in patient 1 before the commencement of PEx was normal. Studies of complement regulatory genes, which can be abnormal in atypical hemolytic uremic syndrome, have not been undertaken in these patients; however, neither had a history of TMA before treatment with IVIg and neither have had a recurrence. As this is an extremely rare complication of IVIg therapy, it is possible that either the particular IVIg product

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or BK viremia predisposed the patient to the development of TMA. The mechanisms through which IVIg could cause microvascular thrombosis are unclear but could potentially include direct endothelial cell activation and damage or complement activation. As thrombotic microangiopathy has not previously been reported as a complication of IVIg administration, it is also possible that there was an interaction between the IVIg and the high levels of BK virus detectable in the blood of these patients at the time of the infusion; although we have not observed similar reactions in previous patients with BK viremia receiving IVIg. Although BK viral proteins are typically found in epithelial cells, a case of disseminated endothelial cell infection by BK virus was reported in a renal transplant recipient who ultimately died from complications of widespread necrotizing endothelial infection [11]. The authors noted that this infection represented an extension of the usual tissue tropism of BK virus and proposed that the altered target cell specificity could have been related to viral coding region mutations. There is one further report in the literature of biopsyproven BK viral encephalitis in a hemopoietic stem cell transplant patient who subsequently developed a hematological and biochemical picture consistent with TMA [12]. The authors did not specifically look for BK viral endothelial cell infection and had no histopathologic evidence of TMA. Given the paucity of reports in the literature of an association between BK viral infection and TMA, it is unlikely that the primary cause of our patients’ TMA was due to the BK infection. One further potentially important contributing factor may have been the use of KIOVIG in both of these patients which represented a departure from our usual practice of prescribing Octagam (Octapharm, NSW, Australia), a situation which arose in the context of a temporary nationwide shortage of Octagam. Both cases responded well to PEx, although the first patient described has been left with significant chronic

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allograft dysfunction. To our knowledge, these are the first cases of renal TMA described in association with either of these IVIg preparations.

REFERENCES [1] Eible MM. History of immunoglobulin replacement. Immunol Allergy Clin North Am 2008;28(4):237e64. [2] Baerenwaldt A, Biburger M, Nimmerjahn F. Mechanisms of action of intravenous immunoglobulins. Expert Rev Clin Immunol 2010;6(3):425e34. [3] Fehr T, Gaspert A. Antibody-mediated kidney allograft rejection: therapeutic options and their experimental rationale. Transplant Int 2012;25(6):623e32. [4] Kuypers DR. Management of polyomavirus-associated nephropathy in renal transplant recipients. Nat Rev Nephrol 2012;8(7):390e402. [5] Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant 2011;11(2):196e202. [6] Rajabally YA, Kearney DA. Thromboembolic complications of intravenous immunoglobulin therapy in patients with neuropathy: a two-year study. J Neurol Sci 2011;308(1-2):124e7. [7] Caress JB, Hobson-Webb L, Passmore LV, et al. Casecontrol study of thromboembolic events associated with IV immunoglobulin. J Neurol 2009;256(3):339e42. [8] Itkin YM, Trujillo TC. Intravenous immunoglobulinassociated acute renal failure: case series and literature review. Pharmacotherapy 2005;25(6):886e92. [9] Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant 2012;27(7):2673e85. [10] Zipfel PF, Heinen S, Skerka C. Thrombotic microangiopathies: new insights and new challenges. Curr Opin Nephrol Hypertens 2010;19(4):372e8. [11] Petrogiannis-Haliotis T, Sakoulas G, Kirby J, et al. BKrelated polyomavirus vasculopathy in a renal transplant recipient. N Engl J Med 2001;345(17):1250e5. [12] Lopez da Silva R, Ferreira I, Teixeira G, et al. BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient. Transpl Infect Dis 2011;13(2):161e167.

Case report: thrombotic microangiopathy post-intravenous immunoglobulin in the context of BK nephropathy and renal transplantation.

Intravenous immunoglobulin (IVIg) is a blood product with immunomodulating properties that have been widely applied in the management of renal transpl...
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