Post-transplant hemolytic-uremic syndrome
2002; Elsevier BV; Volume: 62; Issue: 3 Linguagem: Inglês
10.1046/j.1523-1755.2002.00543.x
ISSN1523-1755
Autores Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoA 26-year-old white man with IgA nephropathy and end-stage 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/μL; 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/μl; and serum LDH, 985 IU/L (normal range, 230-460 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 retracted, ischemic glomeruli, with capillary lumina narrowed by a swollen endothelium or occluded by packed erythrocytes and thrombi Figure 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 Figure 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 Cyclosporine was withdrawn and a course of daily exchanges with two liters of fresh frozen plasma was started. Intravenous methylprednisolone was rapidly tapered and withdrawn, azathioprine was replaced by mycophenolate mofetil, and two 20 mg doses of Basiliximab were injected four days apart.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.Figure 2Glomerulus from a patient with de novo, CsA-associated, post-transplant 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.View Large Image Figure ViewerDownload (PPT) DR. PIERO RUGGENENTI (Assistant Professor, Negri Bergamo Laboratories, Clincal Research Center for Rare Diseases, "Aldo e Cele Daccó," 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 annually1Ruggenenti P. Noris M. Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.Kidney Int. 2001; 60 (10.1046/j.1523-1755.2001.060003831.x): 831-846Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar. 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 year2Petitt R.M. Thrombotic thrombocytopenic purpura; a thirty year review.Semin Thromb Hemost. 1980; 6: 350-355Crossref PubMed Scopus (61) Google Scholar, but the disease is much more severe than in children, leading to ESRD in approximately 50% of patients3Schieppati A. Ruggenenti P. Plata Cornejo R. For the Italian Registry of hemolytic uremic syndrome: Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome.J Am Soc Nephrol. 1992; 2: 1640-1644PubMed Google Scholar. 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. STX-associated HUS is a relatively benign form of HUS precipitated by infections with specific strains of E. coli or S. dysenteriae4Remuzzi G. Ruggenenti P. The hemolytic uremic syndrome.Kidney Int. 1995; 47: 2-19Abstract Full Text PDF Scopus (220) Google Scholar. 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 agent1Ruggenenti P. Noris M. Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.Kidney Int. 2001; 60 (10.1046/j.1523-1755.2001.060003831.x): 831-846Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar.Table 1Forms of thrombotic microangiopathySTX-associated HUS E. coli S. dysenteriaeNon-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 Open table in a new tab Regardless of the underlying cause, activation of microvascular endothelium plays a central role in the pathogenesis of both STX- and non-STX–associated HUS1Ruggenenti P. Noris M. Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.Kidney Int. 2001; 60 (10.1046/j.1523-1755.2001.060003831.x): 831-846Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar. 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 failure5Remuzzi G. Ruggenenti P. Bertani T. Thrombotic microangiopathy,.Renal Pathology with Clinical and Functional Correlations. edited by Tisher CC, Brenner BM. Philadelphia, Lippincott1994: 1154-1184Google Scholar. 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. 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 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).Table 2Post-transplant HUSDe novo HUS Drugs CsA, tacrolimus OKT3, ATG Cyclophosphamide, methotrexate Viruses Influenza A Parvovirus Cytomegalovirus TBI GVHDRecurrent HUS STX HUS Non-STX Genetically determined Non-genetically determined Open table in a new tab De novo post-transplant HUS occurring in renal and non-renal transplant recipients is usually triggered by immunosuppressive drugs such as calcineurin inhibitors6Pham P.T.T. Peng A. Wilkinson A.H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy.Am J Kidney Dis. 1999; 36: 556-560Google Scholar or, less frequently, by viral infections7Waiser J. Budde K. Rudolph B. De novo hemolytic uremic syndrome post renal transplant after Cytomegalovirus infection.Am J Kidney Dis. 1999; 34: 556-560Abstract Full Text Full Text PDF PubMed Google Scholar and, specifically in renal transplant recipients, by acute vascular rejection8Mor E. Lustig S. Tovar A. Thrombotic microangiopathy early after kidney transplantation: Hemolytic uremic syndrome or vascular rejection?.Transplant Proc. 2000; 32: 686-687Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar. 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. 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 tacrolimus6Pham P.T.T. Peng A. Wilkinson A.H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy.Am J Kidney Dis. 1999; 36: 556-560Google Scholar, or other immunosuppressive drugs such as OKT39Abramowicz D. Pradier O. Marchant A. Induction of thromboses within renal grafts by high-dose prophylactic OKT3.Lancet. 1992; 339: 777-778Abstract PubMed Scopus (88) Google Scholar, and systemic viral infections, particularly cytomegalovirus7Waiser J. Budde K. Rudolph B. De novo hemolytic uremic syndrome post renal transplant after Cytomegalovirus infection.Am J Kidney Dis. 1999; 34: 556-560Abstract Full Text Full Text PDF PubMed Google Scholar. More recently, the association between anticardiolipin antibody and post-transplant HUS was described in a subset of hepatitis C virus–positive renal allograft recipients10Baid S. Pawqual M. Williams Jr, W.W. Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients.J Am Soc Nephrol. 1999; 10: 146-153PubMed Google Scholar. 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 immunosuppression11Shulman H. Striker G. Deeg H.J. Nephrotoxicity of cyclosporine A after allogeneic marrow transplantation.N Engl J Med. 1981; 305: 1393-1395Crossref Scopus (311) Google Scholar. 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 CsA12Atkinson K. Biggs J.C. Hayes J. Cyclosporine A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: Three distinct syndromes.Br J Haematol. 1983; 54: 59-67Crossref PubMed Scopus (135) Google Scholar. 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 recipients13Bonser R.S. Adu D. Franklin I. McMaster P. Cyclosporin-induced haemolytic uraemic syndrome in liver allograft recipient.Lancet. 1984; 2: 1337Abstract PubMed Scopus (91) Google Scholar, then in renal14Van Buren D. Van Buren C.T. Flechner S.M. De novo hemolytic uremic syndrome in renal transplant recipients immunosuppressed with cyclosporine.Surgery. 1985; 98: 54-62PubMed Google Scholar and cardiac transplant recipients15Galli F.C. Damon L.E. Tamlanovich S.J. Cyclosporine-induced hemolytic uremic syndrome in a heart transplant recipient.J Heart Lung Transplant. 1983; 12: 440-444Google Scholar. 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 psoriasis16Mihatsch M.J. Gudat F. Ryffel B. Thiel G. Cyclosporine nephropathy,.Renal Pathology with Clinical and Functional Correlations. edited by Tisher CC, Brenner BM. Philadelphia, Lippincott1994: 1641-1681Google Scholar. 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-up17Zarifian A. Meleg-Smith S. O'Donovan R. Cyclosporine-associated thrombotic microangiopathy in renal allografts.Kidney Int. 1999; 55 (10.1046/j.1523-1755.1999.00492.x): 2457-2466Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar. 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%6Pham P.T.T. Peng A. Wilkinson A.H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy.Am J Kidney Dis. 1999; 36: 556-560Google Scholar. 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). The introduction of tacrolimus into clinical practice in 1989 has been accompanied by reports of its successful use in transplant recipients with CsA-associated HUS18McCauley J. Bronsther O. Fung J. Treatment of cyclosporin-induced haemolytic uraemic syndrome with FK506.Lancet. 1989; 2: 1516Abstract PubMed Scopus (64) Google Scholar. As tacrolimus has become more widely used, however, cases of tacrolimus-induced HUS also have been recognized19Holman M.J. Gonwa T. Cooper B. FK506-associated thrombotic thrombocytopenic purpura.Transplantation. 1992; 55: 205-206Google Scholar. 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 higher6Pham P.T.T. Peng A. Wilkinson A.H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy.Am J Kidney Dis. 1999; 36: 556-560Google Scholar. 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 full-blown pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic signs, fever, and renal failure6Pham P.T.T. Peng A. Wilkinson A.H. Cyclosporine and tacrolimus-associated thrombotic microangiopathy.Am J Kidney Dis. 1999; 36: 556-560Google Scholar. 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 thrombosis20Frishberg Y. Kaplan B.S. Bone marrow transplantation-associated thrombotic microangiopathy,.Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura. edited by Kaplan BS, Trompeter RS, Moake JL. New York, Marcel Dekker1992: 187-198Google Scholar. 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 HUS21Baid S. Pasqual M. Williams Jr, W.W. Renal thrombotic microangiopathy associated with anti-cardiolipin antibodies in hepatitis C-positive renal allograft recipients.J Am Soc Nephrol. 1999; 10: 146-153PubMed Google Scholar. 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 CsA22Zoja C. Furci L. Ghilardi F. Cyclosporin-induced endothelial cell injury.Lab Invest. 1986; 55: 455-462PubMed Google Scholar, and a reduction of both prostacyclin synthesis and the prostacyclin-to-thromboxane A2 ratio; these changes lead to vasoconstriction, platelet aggregation, and thrombus formation23Remuzzi G. Bertani T. Renal vascular and thrombotic effects of cyclosporine.Am J Kidney Dis. 1989; 13: 261-272Abstract Full Text PDF PubMed Scopus (181) Google Scholar. 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 process23Remuzzi G. Bertani T. Renal vascular and thrombotic effects of cyclosporine.Am J Kidney Dis. 1989; 13: 261-272Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 24Garcia-Maldonado M. Kaufman C.E. Comp P.C. Decrease in endothelial cell-dependent protein C activation induced by thrombomodulin by treatment with cyclosporine.Transplantation. 1991; 51: 701-705Crossref PubMed Scopus (39) Google Scholar, 25Carlsen E. Flatman A. Prydz H. Cytokine-induced procoagulant activity in monocytes and endothelial cells.Transplantation. 1988; 46: 575-580Crossref PubMed Scopus (75) Google Scholar. Although less systemically studied, similar mechanisms have been involved in the pathogenesis of tacrolimus-induced HUS26Collins P. Wilkie M. Razak K. Cyclosporine and cremaphor modulate von Willebrand factor release from cultured human endothelial cells.Transplantation. 1993; 56: 1218-1223Crossref PubMed Scopus (34) Google Scholar. Moreover, both CsA and tacrolimus have direct and indirect preglomerular constricting properties, the latter through a stimulatory effect on endothelin secretion27Moutabarik A. Ishibashi M. Fukunaga M. FK506 mechanism of nephrotoxicity: Stimulatory effect on endothelin secretion by cultured kidney cells and tubular cell toxicity in vitro.Transplant Proc. 1991; 23: 3133-3136PubMed Google Scholar, which in turn can result in increased vascular shear stress, abnormal vWF fragmentation, and platelet activation, with further amplification of the microangiopathic process1Ruggenenti P. Noris M. Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura.Kidney Int. 2001; 60 (10.1046/j.1523-1755.2001.060003831.x): 831-846Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar. 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-α release9Abramowicz D. Pradier O. Marchant A. Induction of thromboses within renal grafts by high-dose prophylactic OKT3.Lancet. 1992; 339: 777-778Abstract PubMed Scopus (88) Google Scholar,28Chatenoud L. Ferran C. Reuter A. Systemic reaction to anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma.N Engl J Med. 1989; 320: 1420-1421Crossref PubMed Scopus (245) Google Scholar. 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 disease29Verburgh C.A. Vermeij C.G. Zijlmans JMJM Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature.Nephrol Dial Transplant. 1996; 11: 1332-1337Crossref PubMed Scopus (20) Google Scholar. Several viruses, including influenza A virus30Asaka M. Ishikawa I. Nakazawa T. Hemolytic uremic syndrome associated with influenza A virus infection in an adult renal allograft recipient: Case report and review of the literature.Nephron. 2000; 84: 258-266Crossref PubMed Google Scholar, parvoviruses31Murer L. Zacchello G. Bianchi D. Thrombotic microangiopathy associated with Parvovirus B 19 infection after renal transplantation.J Am Soc Nephrol. 2000; 11: 1132-1137PubMed Google Scholar, and cytomegalovirus7Waiser J. Budde K. Rudolph B. De novo hemolytic uremic syndrome post renal transplant after Cytomegalovirus infection.Am J Kidney Dis. 1999; 34: 556-560Abstract Full Text Full Text PDF PubMed Google Scholar,32Hochstetler L.A. Flanigan M.J. Lager D.J. Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy.Am J Kidney Dis. 1994; 23: 444-450Abstract Full Text PDF PubMed Google Scholar 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 transplantation31Murer L. Zacchello G. Bianchi D. Thrombotic microangiopathy associated with Parvovirus B 19 infection after renal transplantation.J Am Soc Nephrol. 2000; 11: 1132-1137PubMed Google Scholar. 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 vWF7Waiser J. Budde K. Rudolph B. De novo hemolytic uremic syndrome post renal transplant after Cytomegalovirus infection.Am J Kidney Dis. 1999; 34: 556-560Abstract Full Text Full Text PDF PubMed Google Scholar,32Hochstetler L.A. Flanigan M.J. Lager D.J. Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy.Am J Kidney Dis. 1994; 23: 444-450Abstract Full Text PDF PubMed Google Scholar. 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 thrombosis33Talatsuka H. Takemoto Y. Yamada S. Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome.Bone Marrow Transplant. 2000; 26: 419-426Crossref Scopus (87) Google Scholar. 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 dysfunction33Talatsuka H. Takemoto Y. Yamada S. Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome.Bone Marrow Transplant. 2000; 26: 419-426Crossref Scopus (87) Google Scholar. 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. The first reported case of recurrent HUS was a 51-year-old man who received a living-related renal allograft from his son 5 months following the onset of post-HUS 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 period34Hebert D. Kim E.M. Sibley R.K. Mauer S.M. Post-transplantation outcome of patients with hemolytic-uremic syndrome: Update.Pediatr Nephrol. 1991; 5: 162-167Crossref PubMed Scopus (38) Google Scholar. 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 al35Grino J.M. Caralps A. Carreras L. Apparent recurrence of hemolytic uremic syndrome in azathioprine-treated allograft recipients.Nephron. 1988; 49: 301-304Crossref PubMed Google Scholar, 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)36Eijgenraam F.J. Donckerwolcke R.A. Monnens L.A.H. Renal transplantation in 20 children with hemolytic-uremic syndrome.Clin Nephrol. 1990; 33: 87-93PubMed Google Scholar. In fact, an extremely variable rate of recurrence, ranging from 9% to 54%, has been reported in different series [reviewed in37Doucloux D. Rebibou J.M. Semhoun-Ducloux S. Recurrence of hemolytic-uremic syndrome in renal transplant recipients.Transplantation. 1998; 65: 1405-1407Crossref Scopus (59) Google Scholar. 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
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