Post-transplant hemolytic-uremic syndrome

Kidney International, Vol. 62 (2002), pp. 1093–1104

NEPHROLOGY FORUM

Post-transplant hemolytic-uremic syndrome Principal discussant: Piero Ruggenenti Mario Negri Institute for Pharmacological Research, Negri Bergamo Laboratories, Clinical Research for Rare Diseases: “Aldo e Cele Dacco´,” and Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy

CASE PRESENTATIONS A 26-year-old white man with IgA nephropathy and endstage renal failure received a renal transplant from a cadaveric donor 15 months ago. The surgery and the post-surgical course were uneventful. He was immunosuppressed by steroids, cyclosporine, and azathioprine. Four days later he was well. His blood pressure was 150/90 mm Hg; serum creatinine was 1.4 mg/dL, and he was discharged. One week later, he experienced macrohematuria. The blood pressure was 125/85 mm Hg and his serum creatinine had increased to 2.4 mg/dL. The hemoglobin concentration was 10.2 mg/dL; platelets, 120 ⫻ 103/␮L; and trough cyclosporine, 310 ng/mL. An ultrasound evaluation showed an enlarged, hyperechogenic graft with an increased resistive index (0.83) and no evidence of hypoperfusion or urinary tract obstruction. Three daily pulses of intravenous methylprednisolone (500 mg each) were planned. Two days later, however, the daily urinary output had decreased to 500 mL; serum creatinine was 7.3 mg/dL; hemoglobin concentration, 9.1 g/dL; platelet count, 88 ⫻ 103/␮l; and serum LDH, 985 IU/L (normal range, 230460 IU/L). He was admitted to the Nephrology Unit of the Bergamo Hospital, where two units of packed red cells were transfused during a hemodialysis session and a percutaneous renal biopsy was performed. The tissue sample contained 10 The Nephrology Forum is funded in part by grants from Amgen, Incorporated; Merck & Co., Incorporated; Dialysis Clinic, Incorporated; and Bristol-Myers Squibb Company. Key words: Shiga toxin, thrombocytopenia, cyclosporine, tacrolimus, total-body irradiation, graft-versus-host disease, thrombotic microangiopathy.

 2002 by the International Society of Nephrology

retracted, ischemic glomeruli, with capillary lumina narrowed by a swollen endothelium or occluded by packed erythrocytes and thrombi (Fig. 1). The capillary walls were markedly thickened with many double contours. The tubular cells were diffusely necrotic and detached from the basement membrane with occasional vacuolar degeneration (Fig. 2). The interstitium was mildly edematous and the arterioles were normal. A thrombotic microangiography with glomerular involvement and an acute tubular necrosis were diagnosed. Cyclosporine was withdrawn and a course of daily exchanges with two liters of fresh frozen plasma was started. Intravenous methylprednisolone was rapidly tapered and withdrawn, azathioprine was replaced by mycophenolate mofetil, and two 20 mg doses of Basiliximab were injected four days apart. In the following days, several transfusions of packed red blood cells were needed to treat his symptomatic anemia. However, a diuresis promptly ensued and renal function progressively improved. Persistent (for two consecutive days) normalization in serum LDH and platelet count was achieved after six plasma exchanges. Three weeks after admission, his hemoglobin concentration was 10.8 g/dL and serum creatinine 2.4 mg/dL, and he was discharged. He was maintained on prednisone, 16 mg/day, and mycophenolate mofetil, 500 mg twice daily. His subsequent course was uneventful, the only exception being a cytomegalovirus reactivation treated by intravenous ganciclovir. One year later he is well, and his serum creatinine is 1.2 mg/dL.

DISCUSSION Dr. Piero Ruggenenti (Assistant Professor, Negri Bergamo Laboratories, Clincal Research Center for Rare Diseases, “Aldo e Cele Dacco´,” Villa Camozzi, Ranica; and Unit of Nephrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy): Hemolytic-uremic syndrome (HUS) is a disease of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure that affects approximately 2 in 100,000 children worldwide every year. Peak incidence rates reach approximately 20 of 100,000 children in Argentina annually [1]. In western countries only 2% to 4% of affected children progress to end-stage renal disease (ESRD). The outcome is remarkably poorer in Latin America, where as many as 20% of children require chronic renal replacement therapy. In adults, HUS is much less frequent, affecting no more than one in every 100,000 people per year [2], but the disease is much more severe than in

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Nephrology Forum: Post-transplant HUS Table 1. Forms of thrombotic microangiopathy

STX-associated HUS E. coli S. dysenteriae Non-STX associated HUS/TTP Neuraminidase-associated Sporadic, idiopathic Familial/relapsing Genetically determined Secondary Pregnancy TTP Severe pre-eclampsia/HELLP Syndrome Post partum HUS HIV infection Systemic disease Antiphospholipid syndrome Malignant hypertension Systemic lupus erythematosus, Scleroderma Cancer Transplant Drugs

children, leading to ESRD in approximately 50% of patients [3]. This difference is largely because Shiga toxin (STX)-associated HUS accounts for at least 80% of childhood, but no more than 5% of adult, cases. STXassociated HUS is a relatively benign form of HUS precipitated by infections with specific strains of E. coli or S. dysenteriae [4]. The exotoxins (Shiga toxin or STX-1 or -2) produced are toxic to the endothelial cell. On the other hand, non-STX-associated forms, which are associated with a 50% to 100% progression rate to ESRD (Table 1), cluster in older subjects and account for the high morbidity and mortality rate frequently reported in adult series. Non-STX forms (Table 1) can be precipitated by certain drugs or can be associated with concomitant diseases, but most often, as in familial or recurrent forms, the non-STX forms lack a well-characterized inciting agent [1]. Regardless of the underlying cause, activation of microvascular endothelium plays a central role in the pathogenesis of both STX- and non-STX–associated HUS [1]. This activation eventually leads to endothelium-blood cell interaction and platelet thrombosis, with occlusion of small vessels and capillaries (thrombotic microangiopathy) of target organs and secondary organ failure [5]. Platelet consumption in the microvascular thrombi and red blood cell fragmentation in the damaged microvasculature account for the thrombocytopenia and the microangiopathic hemolytic anemia that characterize the disease. Definitions and classification of post-transplant HUS Among secondary forms of HUS, post-transplant HUS is being reported with increasing frequency and appears to affect a progressively increasing number of patients worldwide. The incidence of the disease appears

Table 2. Post-transplant HUS De novo HUS Drugs CsA, tacrolimus OKT3, ATG Cyclophosphamide, methotrexate Viruses Influenza A Parvovirus Cytomegalovirus TBI GVHD Recurrent HUS STX HUS Non-STX Genetically determined Non-genetically determined

to be remarkably higher in transplant patients than in the general population, most likely because of the clustering of several risk factors in this particular group of patients. In the setting of renal transplantation, HUS can ensue for the first time (de novo post-transplant HUS) or it can affect patients whose primary cause of ESRD was HUS (recurrent post-transplant HUS; Table 2). De novo post-transplant HUS occurring in renal and non-renal transplant recipients is usually triggered by immunosuppressive drugs such as calcineurin inhibitors [6] or, less frequently, by viral infections [7] and, specifically in renal transplant recipients, by acute vascular rejection [8]. A peculiar form of de novo post-transplant HUS affects recipients of bone marrow transplants (BMT), usually in the setting of graft-versus-host disease (GVHD) or of intensive GVHD prophylaxis, including total-body irradiation (TBI; Table 2). Recurrent post-transplant HUS is reported most frequently in patients who progressed to ESRD because of non-STX HUS, in particular in those with recurrent/ familial forms and with an underlying genetic abnormality predisposing to the disease. Whether the precipitating factors associated with de novo HUS also contribute to disease recurrence in the renal graft is still a debated question. In this Forum, I will discuss de novo HUS separately from recurrent post-transplant HUS, and I will look at recurrences following STX-HUS separately from those following non-STX forms. De novo post-transplant HUS Multiple factors have been implicated in the development of post-transplant HUS. These factors include the use of calcineurin inhibitors, such as cyclosporine A (CsA) or tacrolimus [6], or other immunosuppressive drugs such as OKT3 [9], and systemic viral infections, particularly cytomegalovirus [7]. More recently, the association between anticardiolipin antibody and post-transplant HUS was described in a subset of hepatitis C virus–positive renal allograft recipients [10].

Nephrology Forum: Post-transplant HUS

The association between CsA and HUS was suggested in 1981 by Shulman et al, who described three cases of a rapidly fatal syndrome in BMT recipients receiving CsA immunosuppression [11]. The patients developed thrombocytopenia, hemolytic anemia, hypertension, and renal failure. Postmortem examination of the kidneys showed arteriolar and glomerular capillary thrombosis, mesangial sclerosis, and severe tubulointerstitial disease. A similar syndrome was later recognized by Atkinson et al in 1983, who described multiorgan failure with clinical and histologic findings reminiscent of thrombotic thrombocytopenic purpura (TTP) in two BMT recipients taking CsA [12]. Clinically, the patients presented with grand mal seizures, hemorrhagic pulmonary edema, and anuric renal failure. Plasma from one patient caused aggregation of normal platelets. At autopsy, the kidneys showed arteriolar and capillary thromboses, congested glomeruli, and tubular injury. With the more widespread use of CsA, CsA-induced HUS also occurred in solid organ transplantation, first reported in liver allograft recipients [13], then in renal [14] and cardiac transplant recipients [15]. These findings suggested a causal relationship between this drug and the microangiopathic process, a hypothesis corroborated by evidence that HUS also occurs in patients receiving CsA for conditions not related to transplantation, such as uveitis, rheumatoid arthritis, and psoriasis [16]. After the first reports, Zarifian and coworkers in 1999 carefully described the course of 26 CsA-associated cases of HUS in 188 consecutive renal transplant patients over a 3-year follow-up [17]. Only 2 of the 26 patients had systemic evidence of microangiopathic hemolytic anemia with increased lactate dehydrogenase (LDH), fragmented erythrocytes in the peripheral smear, and decreased platelet count. The finding that the other 24 patients manifested no systemic clues to the diagnosis of HUS, except for an acute rise of serum creatinine of 0.5 mg/dL above baseline, underscored the importance both of considering HUS in the differential diagnosis of patients with renal graft dysfunction, even in the absence of systemic symptoms, and of performing a renal biopsy to confirm the diagnosis. The heightened clinical suspicion and the liberal use of renal biopsy likely accounted for the relatively high frequency of the disease in this retrospective analysis (15%). Indeed, in less rigorously investigated series, the incidence of CsA-induced post-transplant HUS ranged between 3% and 5% [6]. Of note, disease frequency was even higher in patients treated with the microemulsion form of CsA, Neoral, which conceivably reflected the increased CsA bioavailability and serum peak levels achieved by Neoral as compared to an older preparation (Sandimmune).

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The introduction of tacrolimus into clinical practice in 1989 has been accompanied by reports of its successful use in transplant recipients with CsA-associated HUS [18]. As tacrolimus has become more widely used, however, cases of tacrolimus-induced HUS also have been recognized [19]. Since 1991, 24 patients have been identified, with a reported incidence of approximately 1% in recipients of renal transplants, although the actual incidence is probably higher [6]. Both CsA- and tacrolimus-associated HUS can present with a spectrum of clinical signs ranging from variable degrees of hematologic or renal abnormalities to the fullblown pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic signs, fever, and renal failure [6]. The hematologic changes can precede or follow the signs of target organ dysfunction that occasionally can be the only sign of the disease. The disease affects about 6% of recipients of either allogenic or autologous BMT; more than 60% of these are younger than 18 years. After an insidious onset, with only mild hemolysis and renal dysfunction, the disease usually progresses to oligoanuric renal failure and secondary fluid retention with edema, pulmonary congestion, and severe hypertension, occasionally accompanied by hypertensive encephalopathy and generalized seizures. The most common glomerular abnormalities are ballooning of the glomerular lobules and disintegration of the mesangial matrix (mesangiolysis) combined with diffuse arteriolar necrosis and glomerular and arteriolar thrombosis [20]. In renal transplant recipients, the diagnosis occasionally can be established on the basis of graft biopsies performed to determine the cause of delayed graft function or to rule out acute rejection, even in patients with normal platelet count and no laboratory evidence of hemolysis. No organ system is spared by the vascular lesions caused by CsA or tacrolimus. Pulmonary, dermatologic, musculoskeletal, hepatic, and gastrointestinal involvement (presenting as hemorrhagic colitis) have been described in CsA-associated HUS [21]. Although the pathogenesis of CsA-associated HUS is poorly understood, multiple CsA thrombotic effects have been implicated. These effects include a direct endothelial injury, demonstrated by increased LDH and 51chromium (51Cr) release from bovine aortic endothelial cells exposed in vitro to CsA [22], and a reduction of both prostacyclin synthesis and the prostacyclin-to-thromboxane A2 ratio; these changes lead to vasoconstriction, platelet aggregation, and thrombus formation [23]. Decreased generation of activated protein C from endothelial cells, and increased production of thromboplastin from mononuclear cells and of high-molecular-weight von Willebrand factor (vWF) multimers from endothelial cells, can further sustain the thrombotic process [23–25]. Although less systemically studied, similar mechanisms have been

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Nephrology Forum: Post-transplant HUS

involved in the pathogenesis of tacrolimus-induced HUS [26]. Moreover, both CsA and tacrolimus have direct and indirect preglomerular constricting properties, the latter through a stimulatory effect on endothelin secretion [27], which in turn can result in increased vascular shear stress, abnormal vWF fragmentation, and platelet activation, with further amplification of the microangiopathic process [1]. Administration of OKT3 has been associated with de novo post-transplant HUS but only rarely. Among the suggested mechanisms that might explain the thrombotic properties of the drug are a four- to sixfold increased prothombin activity, complement activation, and increased TNF-␣ release [9, 28]. Conditioning regimens including cyclophosphamide and methotrexate have been specifically associated with post-BMT HUS. A direct endothelial toxic effect of these drugs has been claimed as the inciting event of the disease [29]. Several viruses, including influenza A virus [30], parvoviruses [31], and cytomegalovirus [7, 32] have been implicated in the pathogenesis of de novo HUS following bone marrow and solid organ transplantation. A parvovirus B19 infection was recently reported as triggering four cases of biopsy-proven HUS occurring 12 to 50 days after renal transplantation [31]. Patients presented with fever, fatigue, arthralgias, aplastic anemia, and thrombocytopenia followed by deterioration of renal function that required hemodialysis in three cases. Of note, the viral genome was isolated in all the renal biopsy specimens. Actually, parvoviruses can infect the endothelial cell through a specific binding to the P-antigen on the cell surface. The consequent endothelial injury can then sustain the microangiopathic process. Similar mechanisms have been involved in the setting of infection with cytomegalovirus, which, in addition to directly damaging the endothelial cell, can sustain platelet adhesion to the microvascular wall by inducing the expression of adhesion molecules and the release of vWF [7, 32]. Both TBI and GVHD play peculiar and independent roles in the pathogenesis of BMT-associated HUS. When the renal tolerance dose (2000 cGy) is exceeded or the endothelial sensitivity to radiation becomes more pronounced because of chemotherapy, the mitotic apparatus of the endothelial cell is damaged, and cellular mitosis is invariably followed by cell death, with a consequent disruption of the normal endothelial barrier and intravascular thrombosis [33]. When a critical number of cells is affected, usually 2 to 6 months after TBI, widespread glomerular and arteriolar thrombosis and necrosis occur, with consequent acute and usually irreversible renal failure (acute radiation nephritis). Hemolytic-uremic syndrome also has been associated with GVHD. Actually, some clinicians consider GVHD and HUS two clinical manifestations of the same systemic inflammatory response syndrome (SIRS) that can

follow BMT and is sustained by excessive production of inflammatory cytokines and secondary widespread vascular endothelial damage and organ dysfunction [33]. A suggested mechanism is that during GVHD, increased production of interferon gamma by activated lymphocytes stimulates monocytes to secrete interleukin-1 and tissue necrosis factor alpha, which, in turn, can cause endothelial damage and microangiopathy. This result is consistent with the finding that BMT-associated HUS is reported more frequently in patients with GVHD and with evidence that the severity of the two syndromes is very often correlated. Recurrent post-transplant HUS The first reported case of recurrent HUS was a 51year-old man who received a living-related renal allograft from his son 5 months following the onset of postHUS ESRD (abstract; Howard et al, Kidney Int 10:544, 1976). Primary allograft function was good until the third postoperative day, when the patient developed hemolytic anemia, thrombocytopenia, and oligoanuria. A renal transplant biopsy revealed extensive glomerular and arteriolar thrombus formation with no evidence of interstitial or perivascular cellular infiltrate. Following several isolated reports, in 1991 Hebert et al reviewed a series of 17 patients including 12 children younger than 9 years old who had received a total of 27 renal transplants over a 20-year period [34]. Eleven grafts (9 from living related donors) transplanted into 7 patients were lost because of biopsy-proven recurrences of HUS. In 3 additional grafts, the disease remitted without sequelae. With the exception of 3 adult cases reported by Grino et al [35], these poor outcomes were not confirmed in other series (abstract; Pirson et al, Nephrol Dial Transplant 1:134, 1986; Repetto et al, Pediatr Nephrol 3:C185, 1989) [36]. In fact, an extremely variable rate of recurrence, ranging from 9% to 54%, has been reported in different series [reviewed in 37]. Differentiating recurrent HUS from other conditions (for example, renal vascular rejection, acute CsA or tacrolimus nephrotoxicity, and malignant hypertension) largely accounted for these contrasting findings. More reliable information on this controversial issue is derived by a recent meta-analysis of 10 selected studies in 159 grafts in 127 patients with a well-documented history of HUS in native kidneys and biopsyproven thrombotic microangiopathy in the transplanted kidney; this analysis found an overall 27% recurrence rate [37]. Older age at onset of HUS, shorter mean interval between HUS and transplantation or ESRD, living related transplant, and treatment with calcineurin inhibitors were associated with an increased risk of recurrence. Conceivably, older age at onset and faster progression to ESRD both reflected non-STX-associated HUS, whereas

Nephrology Forum: Post-transplant HUS

the increased risk associated with living related transplantation most likely disclosed a genetic (familial) predisposition to the disease. In 1994, Miller et al pointed out that the risk of recurrence is not simply a function of the patient’s age per se, but rather is associated with the type of HUS that caused progression to ESRD [38]. In a series of 24 patients who received 36 transplants, HUS recurred 16 times in 14 grafts in 11 patients. Of these 11 patients, 9 had non-diarrhea- (conceivably non-STX-) associated HUS and only one diarrhea- (conceivably STX-) associated HUS. In one patient, the nature of the prodrome could not be determined. Combining their series with previous reports, the authors found that in 25 of 26 patients with post-transplant recurrent HUS, a diarrheal illness did not precede the original episode of HUS [38]. Thus, the high prevalence of STX-associated HUS in children explains why recurrence is seldom or never reported in pediatric series. The opposite is true for adult series, in which non-STX HUS accounts for at least 95% of HUS cases and is associated with a very high risk of post-transplant recurrence. Retrospective analyses of European (abstract; Pirson) [36], Argentinean (abstract; Repetto) [39], and North American [40] series reported no recurrences in children with post STX-HUS ESRD who received a renal transplant. This finding is probably because in this setting, reexposure to the causative agent would be required to trigger disease recurrence. Evidence that anti-STX-neutralizing antibodies persist over the long term in the circulation of these patients renders this possibility extremely unlikely, even in areas where the disease is endemic [41]. The few available reports suggest that even adult patients with STX-HUS are virtually without risk of post-transplant recurrence. For instance, in our department, we have seen 3 adult patients with STX-HUS who received renal allografts, and all of them experienced prompt graft function without recurrence as long as 5 years after follow-up. Non-STX forms of HUS, in addition to having a poor outcome with a 50% to 100% incidence of ESRD, also retain a substantial risk of recurrence and graft loss after renal transplant both in children and adults. Disease recurrence and graft loss have been invariably observed in the few patients who received one or more additional transplants after the first one failed because of recurrent HUS [42]. A genetic predisposition has been advocated to account for such a dramatic outcome. Overall, children have a post-transplant recurrence rate ranging from 50% to 90% [34, 38, 43]. Of 61 children reported to the North American Pediatric Renal Transplant Registry, 5 developed recurrence of HUS within the allograft [40]. Of these, 4 patients had progressed to ESRD because of non-STX HUS. In the remaining one, the differential diagnosis between STX and non-STX

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HUS could not be ascertained. In all series, recurrences usually occurred within one or two months post transplantation, with extremes of onset ranging from as short as one day to as long as 13 years. Graft outcome is invariably poor, with graft loss reported in 80% to 90% of cases, usually within two or three weeks after HUS recurrence [34, 38, 43]. Only a few studies, including individual case reports without biopsy confirmation of disease recurrence, have described the outcome of recurrent HUS in adults [42–44]. A recent retrospective study of the Ile-de-France Transplantation Cooperative Group [43] contributed substantially to clarifying this controversial issue. From 1975 to 1995, 16 patients with biopsy-proven HUS who received a total of 25 allografts were identified. Of these, 9 patients (56%) developed definite clinical and pathologic evidence of recurrence in at least one graft, and 4 additional patients showed clinical or pathologic evidence of recurrence that, however, could not be definitely distinguished from acute vascular rejection. Of note, all the recurrences were reported in patients with previous non-STX HUS, whereas the only 3 disease-free patients had a previous diagnosis of diarrhea- (conceivably STX-) associated HUS. As previously observed in children, recurrences were frequent and early, occurring within one month after transplant in one-half the cases. An interesting finding, however, was that the risk of recurrence was remarkably lower in patients with pre-transplant bilateral nephrectomy (50%) than in non-nephrectomized patients (92%). These findings were confirmed and extended by an overview of 21 papers reporting an overall 52% recurrence rate in 71 patients receiving a total of 90 grafts [45]. Again, the recurrences primarily occurred in non-STX and familial forms, with an incidence that was 50% lower in pre-transplant nephrectomized (35%) than in non-nephrectomized (77%) patients. Graft loss was a constant sequela and accounted for the poor overall one-year (43%) and 5-year (32%) kidney survival observed in the whole series of patients. The outcome is even poorer in familial forms. Actually, an overview [46] of three series [46–48], including 11 patients with autosomal recessive inheritance of HUS receiving 14 transplants, found 9 recurrences that, regardless of treatment, led to graft loss. Of note, the risk of recurrence was high regardless of treatment (with or without calcineurin inhibitors) or kidney source (cadaver or living related donors). However, the finding that 5 of the recurrences occurred in living related transplants should discourage the use of living related donors in this setting. A genetic background predisposing to microvascular thrombosis has been demonstrated in rare forms of HUS. Often occurring in families, these forms are characterized by frequent recurrences, both on native and transplanted kidneys, and associated with a high risk of death

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Nephrology Forum: Post-transplant HUS

or severe neurologic or renal sequelae [49–52]. Both autosomal-recessive and autosomal-dominant modes of inheritance have been recognized, with precipitating events such as pregnancy, virus-like disease, or sepsis being identified in some, but not all series [49–52]. Evidence that some of these patients recovered, at least transiently, with plasma infusion or exchange, suggested that the one or more underlying genetic defects were the cause of one or more abnormalities in plasma components essential to the integrity of the microvascular circulation and/or to the defense mechanism of the host endothelium against injurious agents. Finding reduced serum levels of the third component of complement (C3) in a number of HUS cases and in some family members, but not in healthy controls and their relatives, led Noris et al to suggest that the disease could be sustained by overactivity of the alternative complement pathway that resulted in increased C3 consumption in the microcirculation [49]. Since low C3 and decreased factor H bioavailability or activity are almost invariably associated with recurrent/familial HUS, increased C3 consumption might be the result of impaired function of factor H [49, 53]. Indeed, interaction of factor H with sialic acid and other polyanions on human cells and tissues increases the affinity of factor H for C3b and increases its inhibitory effect on the alternative pathway of complement activation. This control step protects host cells from autolytic attack of the alternative complement pathway, because complement activation induces the deposition of C3b indiscriminately onto host and foreign particles. This phenomenon applies particularly to endothelial cells, with their high surface density of heparanlike glycosaminoglycans [54]. Thus, when an environmental trigger activates the alternative complement pathway, modification of the heparan-binding capacity of mutated factor H might facilitate the occurrence of microvascular thrombosis. More specifically, when the bioavailability or the activity of factor H is congenitally defective, intercurrent exposure to agents that damage the vascular endothelium, such as certain viruses, bacteria, toxins, immunocomplexes, and drugs, results in uncontrolled C3bBb convertase formation and complement activation [55], which causes microangiopathic damage and disease manifestation. Immunologic and toxic endothelial injury associated with vascular rejection or treatment with calcineurin inhibitors might explain why all renal transplant patients with factor H abnormalities so far reported experienced an early disease recurrence invariably followed by graft failure [49–53]. A similar outcome was reported by Loirat and coworkers in children with non-STX HUS and decreased vWF cleaving protease activity (Loirat et al, data presented at the 12th Cong Int Pediatr Nephrol Assoc, Seattle, WA, 2001). When genetically determined, this abnormality predisposes to repeated microangiopathic episodes that are usually associated with severe renal and neurologic

involvement both in adults [56] and children (Loirat C, unpublished data) [1, 57]. Patients can transiently recover while the protease activity is restored by plasma infusion or exchange, but generally they relapse after treatment withdrawal. When affecting the kidney, repeated relapses lead to progressive and irreversible renal dysfunction (Loirat C, unpublished data). Disease recurrence has been reported even in a kidney graft and has been associated with premature graft loss (Loirat C, unpublished data). The clinical features of post-transplant HUS are few. Anemia is usually mild, and thrombocytopenia is reported in no more than 50% of patients. Renal dysfunction can be the only non-specific sign of a post-transplant disease recurrence. However, since concomitant diseases such as acute rejection, CsA or tacrolimus nephrotoxicity, or cytomegalovirus infection can confound the clinical picture, the definite diagnosis almost invariably rests on the biopsy findings [58]. Typical changes include glomerular and arteriolar thrombosis, endothelial cell swelling and detachment from the basement membrane, glomerular ischemia and, in the healing phase, onion-skin hypertrophy of the arteriolar walls. These changes, however, also can reflect an acute vascular rejection that should always be considered in the differential diagnosis with recurrent HUS, in particular when tubulitis and interstitial infiltration are accompanied by severe endovasculitic lesions affecting the entire vascular tree of the graft (Fig. 3). Treatment Treatment of post-transplant HUS rests on removal of the inciting factor(s), relief of symptoms, and plasma infusion or exchange. No other approach has proven effective. Drug withdrawal or dose reduction is firstline therapy for de novo CsA- or tacrolimus-associated forms, but it is effective in fewer than 50% of patients. A remarkably higher success rate (84%) has been reported with adjunctive plasma infusion or exchange [6, 17]. A similar response rate, but in a much smaller series, was reported with intravenous IgG infusion, which was given with the rationale of neutralizing hypothetical circulating cytotoxic or platelet-agglutinating factors [59]. After remission is achieved, patients who are rechallenged with decreased doses of CsA or tacrolimus [60, 61], switched from one drug to the other [62], or, finally, treated with mycophenolate mofetil [63] have been sporadically reported to maintain adequate immunosuppression without inducing disease recurrence. Recently, “compassionate treatment” with rapamicin was associated with a remarkably good outcome in 15 patients with CsA- or tacrolimus-associated post-transplant HUS, with no patient requiring rapamicin withdrawal because of disease recurrence [abstract; Leichtman et al, Am J Transplant 1(Suppl 1):141, 2001]. Monoclonal anti-IL-2 receptor

Fig. 1. Glomerulus from a patient with de novo, CsA-associated, posttransplant HUS. Some glomerular capillaries are occluded by thrombi containing packed erythrocytes. Other capillaries are surrounded by double contours.

Fig. 3. Autopsy kidney section from a patient with recurrent posttransplant HUS or vascular rejection. The arterioles and all the glomerular capillaries are occluded by thrombi and erythrocytes. The interstitium is diffusely infiltrated by erythrocytes. A diagnosis of vascular rejection rather than of recurrent HUS is suggested by the severe and diffuse vascular involvement.

antagonists also can be a valid option for maintaining adequate immunosuppression and avoiding the toxic effects of calcineurin inhibitors. The outcome of de novo forms occurring in the setting of viral infection parallels the response to treatment of the underlying disease [30–32]. Despite intensive plasma therapy or rescue treatment with plasma cryosupernatant or protein A immunoadsorption exchanges [64], the outcome of de novo forms complicating BMT is still dramatically poor, with a mortality rate close to 90%. In addition to the severity of the microangiopathic process—quantified on the basis of serum LDH levels and percentage of circulating fragmented erythrocytes—infection, progressive GVHD, or relapse of the underlying disease might account for these discouraging figures [19]. Equally poor is the outcome of recurrent forms of post-transplant HUS that usually do not respond to any

Fig. 2. Glomerulus from a patient with de novo, CsA-associated, posttransplant HUS. The vascular pole and a capillary of the tuft are occluded by thrombi containing packed erythrocytes. The tubular cells are diffusely necrotic and detached from the basement membrane with occasional vacuolar degeneration. The interstitium is mildly edematous.

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Nephrology Forum: Post-transplant HUS

type of therapy and are associated with graft loss close to 100%. On the basis of these data, renal transplantation should be considered an effective and safe treatment of ESRD for patients with STX-associated HUS, but considered with extreme caution in patients with non-STX-forms. In particular, until new strategies that can effectively limit or prevent the risk of recurrence in the graft become available, renal transplantation is contraindicated in familial/relapsing forms and in all cases with a well-characterized genetic abnormality predisposing to the disease. QUESTIONS AND ANSWERS Dr. Marina Noris (Negri Bergamo Laboratories, Bergamo, Italy): Piero, you have shown that patients with factor H mutations have a 100% post-transplant recurrence rate. However, other cases of familial HUS that are genetically determined do not recur [46]. How do you explain such a different outcome? Dr. Ruggenenti: The different post-transplant recurrence rates depend on the different biochemical changes sustained by the genetic mutation. When these changes affect a circulating factor (such as factor H) that interferes with the thromboresistance of normal endothelium, the same conditions that promoted the disease in native kidneys also might affect the transplanted kidney. The converse might be true when the biochemical change affects fixed molecules within the endothelium itself. In this case, since the transplanted kidney does not have the abnormality, the disease might not recur. However, a more precise answer will be possible only when the mutations involved in familial forms that do not recur are identified. Dr. Jordan J. Cohen (President, Association of American Medical Colleges, Washington, DC): We know that only a small proportion of patients exposed to Shiga toxin develop HUS. This might suggest a genetic predisposition in these patients. Might this genetic trait predispose to disease recurrence even after renal transplantation? Dr. Ruggenenti: Several factors affect the risk of developing HUS after exposure to STX. Some of these might be environmental factors such as the amount of the toxin or treatments with antimotility agents or antibiotics that, when used to treat STX-induced hemorrhagic colitis, might subsequently favor the onset of full-blown HUS [65]. Other factors, however, are likely genetically determined and might predispose to the disease even when exposure to STX occurs after the transplant. Since patients who received a renal transplant because of ESRD secondary to STX-associated HUS are few, the data in available series are too small to definitely establish the role of genetic predisposition in post-transplant recurrence.

Dr. Adalberto Sessa (Head, Division of Nephrology, Ospedale Vimercate, Vimercate, Italy): How frequent is neurologic involvement in post-transplant HUS, either in de novo or recurrent forms? Dr. Ruggenenti: Neurologic and other extrarenal manifestations of the disease are relatively uncommon in post-transplant HUS. However, central nervous system involvement has been described in adults and children and has presented with spontaneous cerebral hemorrhage (abstract; Mochon et al, J Am Soc Nephrol 1:765, 1990) [66]. Dr. Arrigo Schieppati (Unit of Nephrology and Dialysis, Ospedali Riuniti di Bergamo and Clinical Research Center for Rare Diseases “Aldo e Cele Dacco´,” Ranica, Italy): In the case you presented, I believe that withdrawal of cyclosporine was likely the major step in achieving disease remission. Whether plasma exchange had a specific, additional role seems questionable. Do we have any evidence that plasma infusion or exchange is useful in post-transplant HUS, and is there any other potentially effective therapy? Dr. Ruggenenti: You are right. As the first treatment step, one does have to eliminate any precipitating factor. We have no definite evidence that plasma exchange was effective in our patient or that it improves the outcome of post-transplant HUS. Plasma infusion or exchange is used in this setting because of the results achieved in the treatment of forms affecting native kidneys. Adding plasma infusion/exchange might limit the microangiopathic process in cases sustained by plasma abnormalities (such as defective factor H activity) that can be corrected by normal plasma infusion. Whether this approach is effective in other familial/recurrent forms is a reasonable hypothesis, but not a proven one. Other treatments, such as immunoperfusion—perfusion of autologous plasma over filters containing staphylococcal protein A [64]— have been attempted. There is no reason, however, to believe that this procedure offers any advantage as compared to plasma exchange. Finally, as I mentioned, highdose intravenous immunoglobulin infusion has been reported effective in some cases associated with CMV infection [32]. Dr. Cohen: You showed us quite convincingly that patients with HUS associated with factor H abnormalities should not receive renal transplants because HUS is highly likely to recur. However, you also suggested that patients with other non-STX-associated forms should not receive transplants either. Do you mean that in these cases there also is a strong genetic predisposition to recurrence? Dr. Ruggenenti: I am convinced that most non-STXassociated forms have a strong genetic predisposition even if the genetic abnormalities predisposing to the disease have not yet been recognized. I believe that a transplant in these patients is unsafe and should not be performed. An exception to this rule might be secondary forms of HUS precipitated by some drugs, which can be

Nephrology Forum: Post-transplant HUS

avoided after transplantation. For sure, a renal transplant is contraindicated in familial and recurrent forms. Dr. Giuseppe Remuzzi (Director, Negri Bergamo Laboratories and Unit of Nephrology and Dialysis, Ospedali Riuniti di Bergamo): Piero, I’d like to offer another argument in support of your concept of avoiding living-related donor transplants. Living-related donors might have the same genetic abnormality that contributes to local complement activation. Locally formed complement can be important in determining acute rejection, glomerulonephritis, and progression of renal disease [67]. The possibility that the donor might have a factor H abnormality predisposing to such local complement activation thus is an additional reason to avoid livingrelated transplantation. Dr. Cohen: Piero, you discussed the difficulty in differentiating post-transplant HUS from acute vascular rejection. How is differentiation possible, and what are the clinical issues you can rely on? Dr. Ruggenenti: Distinguishing between HUS and vascular rejection is important because treatment is different and an incorrect diagnosis might result in loss of the graft. Unfortunately, differential diagnosis is extremely hard on clinical grounds, as both cases can be associated with acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Fever and graft tenderness are more frequent with vascular rejection but are not specific. In addition, even the histologic diagnosis is problematic because in both cases typical signs of thrombotic microangiopathy can be observed. Vascular changes might be more prominent with vascular rejection, but this is not a definite criterion for vascular rejection. Cellular infiltration and tubulitis might suggest a diagnosis of vascular rejection, but these changes, albeit less prominent, also can be observed in HUS. Dr. Cohen: Beppe, putting aside the difficulty in differentiating these conditions, in your Nephrology Forum of 15 years ago, you discussed the relationship between HUS and TTP [68]. What is your opinion now? Are these two diseases related or not? Dr. Remuzzi: Two papers published in the New England Journal of Medicine showed that patients with TTP have a decreased vWF-cleaving protease activity associated with abnormally large vWF multimers that predispose to intravascular thrombosis [69, 70]. In contrast, vWF-cleaving protease activity was reported to be normal in patients with HUS. Thus, it has been claimed that a decreased vWF-cleaving protease activity differentiates patients with TTP from those with HUS [71]. However, I believe that this is an oversimplification. Miriam Galbusera from our group studied several cases (abstract; Mannucci et al, J Am Soc Nephrol 12:115A, 2001) and Dr. Loirat (unpublished data) six cases (one STXassociated and five non-STX-associated) of HUS associated with undetectable vWF-cleaving protease activity

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that in non STX-cases persisted even after remission of the acute episode. They were children with recurrent HUS who had their first episode at birth and who had exactly the same genetic abnormality described by Furlan et al in adult TTP [72]. These findings lead me to believe that I should maintain the stance I took at the Forum I delivered in 1987: that HUS and TTP are, in fact, a single entity [68]. That HUS and TTP are just two different expressions of the same disease is consistent with the reports of familial cases that, despite the same genetic abnormality, were classified as HUS or TTP in different members of the same family [73]. Even more convincing are the reports of different episodes of recurrent disease in the same patient that were on some occasions defined as HUS and in others as TTP, even if they were obviously associated with the same genetic defect [74]. In all reported cases, the term HUS tended to be preferred in children with renal insufficiency and the term TTP in adults with predominantly neurologic involvement. Thus, with the only exception being STX-associated HUS, all the other forms cannot be classified as HUS or TTP just on the basis of a specific genetic abnormality. Dr. Norberto Perico (Clinical Research Center for Rare Diseases “Aldo e Cele Dacco´”): Piero, you have shown that cyclosporine might have a direct toxic effect on the endothelial cell and that, by up-regulating the expression of adhesion molecules, CsA might favor leukocyte adhesion to the endothelial surface and cause consequent vascular damage and thrombosis. The in vitro effect, however, is observed at concentrations that largely exceed those usually found in the circulation of transplant patients. Thus, in this clinical setting, a direct toxic effect should seldom play a major role unless it is accompanied by concomitant ischemic or immune damage. However, at pharmacologic doses, cyclosporine has a potent vasoconstrictive effect that can result in renal hypoperfusion and ischemia [75]. Increased release of endothelin and other mediators might then amplify endothelial damage and sustain the microangiopathic process. Dr. Ruggenenti: This is an important point. As you pointed out, at usual blood levels, cyclosporine induces a potent pre-glomerular vasoconstriction. Extreme vascular lumina narrowing results in accelerated blood flow and increased shear stress. Shear stress might favor platelet activation and vWF proteolysis to fragments that more effectively bind activated platelets [76]. This sequence of events favors the microangiopathic process, especially when the physiologic thromboresistance of vascular endothelium is decreased by concomitant ischemic, immune, or toxic damage. Dr. Carla Zoja (Negri Bergamo Laboratories): Some years ago we found in our laboratories that cyclosporine increases the adhesion of leukocytes to endothelial cells

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in culture under physiologic flow conditions, up-regulating the endothelial expression of adhesion molecules [77]. Do you think that this sequence of events might have a role in the pathogenesis of cyclosporine-associated post-transplant HUS? Dr. Ruggenenti: Yes, I think that up-regulation of adhesion molecule expression on endothelial cell surface and secondary leukocyte adhesion to endothelial surface might play a major role in the sequence of events leading to microangiopathic thrombosis. These changes have been clearly demonstrated in STX-associated HUS. Neutrophils from children in the acute phase of STX-associated HUS adhere to endothelial cells more tightly than do normal neutrophils and induce endothelial injury by degrading endothelial cell fibronectin, possibly by the release of neutrophil-specific proteases [78]. In vitro, STX promotes massive leukocyte adhesion and transmigration to endothelium under flow conditions by upregulating endothelial expression of adhesive proteins and chemokines (abstract; Zoja et al, J Am Soc Nephrol 10:595A, 1999). Conceivably, the same sequence of events could be precipitated by CsA-induced up-regulation of adhesive molecules. This might enhance the prothrombotic effects discussed before that are sustained by CsAinduced vasoconstriction and increased shear stress. Dr. Gina Gregorini (Division of Nephrology, Spedali Civili, Brescia, Italy): I have a practical question. We often see sporadic cases that are difficult to classify. In particular, the diagnosis of STX-associated HUS cannot be definitely confirmed or excluded because the history is not clear and the toxin was not looked for or was looked for only after resolution of the acute episode or after the patient already had received antibiotics. What do you suggest for these patients who develop end-stage renal disease? Should a renal transplant be discouraged? Dr. Ruggenenti: Finding a high titer of circulating anti-STX antibodies might suggest a diagnosis of STX HUS even if the history is uncertain. On the other hand, if there is another case in the family or the patient denies a history of diarrhea, the possibility of a non-STX-associated form is extremely high and the transplant is at increased risk. In all these cases, as well as in cases in which a diagnosis of STX HUS is not definitely established, patients should be studied to look for recognized factor H or vWF-cleaving protease abnormalities. These studies are expensive and time consuming, but they are largely cost-effective considering the tremendous medical, psychologic, and economic drawbacks of an unsuccessful transplant. Dr. Cohen: Beppe, this still leaves a large group of patients without clear-cut evidence of STX HUS who do not have factor H or vWF-cleaving protease abnormalities. What do we do with these patients if their kidneys fail? Dr. Remuzzi: Our recommendation is to not give

these patients transplants. However, I have to say that, unlike the several HUS cases with factor H mutations reported to recur, to the best of my knowledge, only one child with recurrent HUS associated with defective vWFcleaving protease activity has received a renal transplant (Loirat C, unpublished data). This child lost the kidney because of a post-transplant recurrence of HUS. This is only one case, but this is enough in my opinion to prohibit transplantation in this setting as well. Dr. Miriam Galbusera (Negri Bergamo Laboratories): In regard to the issue of decreased vWF-cleaving protease activity, I wish to emphasize that this abnormality is frequent in other diseases such as liver cirrhosis or end-stage renal failure, and even in physiologic conditions such as old age and pregnancy. Thus, decreased vWF protease activity is a nonspecific finding that might have a poor diagnostic value but that, however, might help identify patients who might benefit from plasma infusion or exchange. Dr. Ruggenenti: I suggest a note of caution before one decides to infuse or exchange plasma on the basis of decreased vWF-cleaving protease activity. Indeed, regardless of the activity of the protease, plasma therapy is invariably recommended in adult forms and in children with non-STX-associated HUS. On the other hand, whether decreased vWF-cleaving protease activity is a cause or just a sign of recurrent HUS or TTP is not definitely established. Finding that plasma therapy restores protease activity and that this restoration occurs in parallel with disease remission does not necessarily imply that normalization of protease activity is the determinant of response to plasma. Indeed, evidence that plasma is effective even in forms with normal protease activity implies that other mechanisms might be involved and that these mechanisms might play a major role even in recurrent forms. As for the nonspecificity of decreased vWF-cleaving protease activity, I wish to point out that this abnormality has been reported during the acute phase of STX-associated HUS (Loirat C, unpublished data). Indeed, persistence of the abnormality after disease remission is the finding that distinguishes familial/recurrent forms with a genetically determined defect from sporadic forms with acquired and transient protease abnormalities. Reprint requests to Dr. P. Ruggenenti, Negri Bergamo Laboratories, Via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: [email protected]

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