Hyperacute onset of haemolytic–uraemic syndrome associated with hyperacute rejection in the recipient of an ABO-incompatible kidney

Hiroshi Harada1,, Masaki Togashi2, Toshimori Seki2, Junri Shindo1, Naohiko Shimoda1, Yayoi Ogawa3, Akio Takada3, Masatoshi Tateno3, Hidetoshi Sato3 and Tetsuo Hirano1

Departments of 1 Renal Transplantation, 2 Urology and 3 Pathology, Sapporo City General Hospital, Sapporo, Japan

Keywords: ABO-incompatible; complication; haemolytic–uraemic syndrome; hyperacute rejection; renal transplantation



   Introduction
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 Introduction
 Case
 Discussion
 References
 
Haemolytic–uraemic syndrome (HUS), characterized by microangiopathic haemolysis, thrombocytopenia and renal dysfunction, is uncommon but can result in serious complications in transplantations of kidneys, and even other organs [1]. Any factors that damage vascular endothelial cells can trigger HUS [2,3]. Humoral vascular rejection and calcineurin inhibitors such as cyclosporin A (CSA) and tacrolimus are recognized as factors that instigate HUS in organ transplantation [4,5]. Meanwhile, an extreme shortage of organ donors necessitates widening the sources of donated organs, e.g. to ABO-incompatible donors [6]; well-refined pre- and post-operative treatments, including powerful immunosuppresion and diminution of anti-A and -B antibodies using plasmapheresis, make this possible [7,8]. The major cause of early graft loss is hyperacute and acute humoral rejection brought on by abundant antibodies against surface A or B antigens ubiquitously expressed on cell surfaces [68]. Whereas HUS associated with hyperacute rejection (HAR) in ABO-incompatible transplantations has never been reported, this kind of devastating rejection would result in immediate graft necrosis because of the complete occlusion of the vessels. We report a unique case of acute-onset HUS caused by HAR in a recipient of an ABO-incompatible renal graft who was rescued by plasma exchange [9] and nafamostat mesilate [10].



   Case
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 Introduction
 Case
 Discussion
 References
 
A 28-year-old Japanese male, with end-stage renal disease caused by biopsy-proven group III IgA nephropathy, after 11 months of maintenance haemodialysis underwent an HLA 2/6-mismatched and ABO-incompatible (blood type B into type A) living, related kidney transplantation (the donor was his 60-year-old father). The standard NIH method of complement-dependent lymphocytotoxicity testing by the dye exclusion technique was used, with some modifications for the pre-transplantation cross-match, to detect anti-donor HLA, and the results were totally negative (T warm, B warm and B cold). Double filtration plasmapheresis was performed four times pre-operatively, and his titres of IgG 256x and IgM 64x against blood type B antibody were reduced to 32x and 8x, respectively. We used an immunosuppression induction regimen consisting of 0.3 mg/kg per day of tacrolimus p.o. (from day -3 to day -1 ), 0.05 mg/kg per day tacrolimus i.v. (from day 0 to day 7), 75 mg of azathiopurine p.o. (from day -3 to the present) and 60 mg per day prednisolone p.o. (from day 0 tapered gradually to the present). Tacrolimus administration was switched from p.o. to i.v. on day 8 and adjusted according to trough blood levels (target trough 15–20 ng/ml to day 14, then tapered gradually). In addition, antilymphocyte globulin was overlapped intravenously from day 0 to day 7. The graft was implanted in the right iliac fossa after an ex vivo vascular reconstruction using an autologous hypogastric artery graft for double graft arteries. Total ischaemic time was 152 min, and the graft functioned promptly. Splenectomy immediately followed transplantation. Frozen sections of the 1 h graft biopsy did not show any changes of HAR. The titres of anti-B antibodies just before transplantation during the operation turned out to be unexpectedly higher (IgG 128x, IgM 16x) than the pre-operative titres (32x and 8x, respectively).

On day 1 after transplantation, his platelet count was markedly reduced from 12.9x104/mm3 to 1.8x104/mm3, and red blood cell count had fallen from 3.41x106/mm3 to 1.48x106/mm3, with the appearance of schistocytes. Serum lactate dehydrogenase (LDH) rose strikingly from 203 to 1539 mg/dl. The total bilirubin level rose from 0.2 to 1.7 mg/dl, and serum haptoglobin level fell to an undetectable range. Coagulation tests revealed: prothrombin time, >100% of normal; activated partial thromboplastin time, 41 s; Thrombo test, 41% of normal; fibrinogen, 110 mg/dl; and fibrinogen degradation products (FDP), 5.9 µg/ml. Urine output did not deteriorate; however, serum creatinine did not decrease ideally. 99mTc-DTPA reno-scintigraphy did not indicate a cessation of the blood perfusion of the graft, even though it was severely affected. The concentration of tacrolimus in whole blood was 19.1 ng/ml, within the target range (15–20 ng/l). The data taken together suggested the clinical diagnosis of HUS, and plasma exchange with fresh frozen plasma was performed from day 1 to day 5, and on day 12. Nafamostat mesilate, a synthetic serine protease inhibitor, was administrated continuously (5–mg/kg/day, i.v.) from day 1 to day 16 to inhibit various serine proteases generated during the coagulation cascade and the inflammatory process [10]. During this period, LDH rose to 2350 mg/dl and the nadirs of platelet and red blood cell counts were 0.3x104 and 0.81x106/mm3, respectively. Ten units of blood and 40 units of concentrated platelets were transfused. Haemodialysis was initiated again, due to the reduced urine output and consequent anasarca on day 3 after transplantation, and was required 10 times (Figure 1Go). The patient remained afebrile and did not report diarrhoea during this period. Vital signs also were thoroughly stable. The final pathological diagnosis of the 1 h graft biopsy was HUS. The diffuse C3 staining in the peritubular capillaries indicated the effect of humoral factors, so we judged that HAR had caused HUS (Figure 2Go).



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Fig. 1.  The course of the presenting case. TAC, tacrolimus; AZ, azathiopurine; PD, prednisolone; ALG, antilymphocyte globulin; GCV, ganciclovir; NM, nafamostat mesilate; HD, haemodialysis; PEX, plasma exchange; HP, haptoglobin (mg/dl); LDH, lactate dehydrogenase (mg/dl); RBC, red blood cell (x106/mm3); PLT, platelet (x104/mm3); S-Cr, serum creatinine (mg/dl); U-Prot, urinary protein (g/day); RTx, renal transplantation.

 


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Fig. 2.  (A) One hour graft biopsy. The attachment of eosinophilic substances, partial occlusion of glomerular capillary and disappearance of brush border in tubules can be seen. There was no evidence of interstitial lymphocyte infiltration (H&E, original magnification x20). (B) Fluorescent study proves the diffuse attachment of C3 along the peritubular capillaries (original magnification x10). (C) Forty days graft biopsy. Thickening and double contours can be seen in the glomerular capillary and capillary walls. There is infiltration of a few lymphocytes in each tubule, which is identical to the borderline change of the Banff classification (H&E, original magnification x10).

 
On day 6 after transplantation, the signs of haemolysis abated just after the cessation of plasma exchange, judged by the elevation of the platelet and red blood cell counts. The reticulocyte count was >100%. LDH and total bilirubin levels normalized on day 15 and day 11, respectively. The graft gradually started to function after the discontinuation of haemodialysis. A repeat graft biopsy on day 40 showed the existence of changes of HUS and borderline changes (according to the Banff classification) (Figure 2Go). The haptoglobin level had normalized on day 50. He enjoyed his life at home for a few weeks. Suggesting that he had a reactivation of cytomegalovirus (CMV) on day 58 was the fact that the out-patient screening by the antigenaemia method for CMV infection was strongly positive (401/383), although this test had been negative pre-operatively. He then was treated with intravenous ganciclovir (5 mg/kg, b.i.d) for 3 weeks. On day 98 after transplantation, his serum creatinine fell to its lowest level (1.9–2.0 mg/dl) and became stable. Nevertheless, he required ganciclovir (5 mg/kg/day) therapy due to asymptomatic elevation of CMV antigenaemia from day 106 to day 160. After this episode, his course was uneventful except for continuous moderate proteinuria, which had manifested since day 30 (1.5–3.2 g/day), and his serum creatinine level was steady even 2 years after transplantation (1.8–2.0 mg/dl) (Figure 1Go). A 2-year protocol biopsy demonstrated the persistent focal glomerular sclerosis-like change, the recurrence of IgA nephropathy, and CAN I in the Banff classification.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
HUS is a drastic intravascular platelet-clumping disorder characterized by microangiopathic haemolysis, thrombocytopenia and renal dysfunction. The renal arterial cell injury and consequent subendothelial exudation of serum, including fibrinogen, complement, etc., explain the pathogenesis. The cause of HUS varies. Circulating factors that can damage the renal endothelial cells can trigger HUS. Bacterial and viral infections (Shigella dysenteriae serotype I and various Escherichia coli serotypes, human immunodeficiency virus, CMV, etc.), various toxic agents, pregnancy, malignant hypertension, anti-endothelial antibodies and immune complex are provoking factors [2,3,9]. CSA, which has the potential to injure vascular endothelial cells, is very well known as a cause of HUS after allogeneic organ transplantation. An alternative calcineurin inhibitor, tacrolimus, also can cause HUS, although the incidence is somewhat lower (1%) compared with CSA (3–5%) [4]. At the time of vascular rejection in kidney grafts, antigen–antibody complexes can be responsible for triggering the coagulation process and producing vascular damage that could lead to HUS.

Meanwhile, an extreme shortage of organs requires expanding the sources of donors, which could result in ABO-incompatible combinations [6]. Immunomodulation, including a powerful immunosuppresion regimen and diminution of anti-A and -B antibodies with plasmapheresis, make it possible to resort safely to these challenging combinations [7]. Recipient and long-term graft survival of ABO-incompatible transplants does not differ significantly from that of ABO-compatible ones; nevertheless, the rate of early graft loss is higher in the former. Actuarial patient and graft survival rates in the ABO-incompatible setting are 92 and 77% at 1 year, and 89 and 51% at 10 years, respectively [8]. The cause of early graft loss is mostly HAR and acute humoral rejection—brought on by abundant antibodies against surface A or B antigen on the endothelial cell surface—and follows activation of complements [6]. However, HUS caused by HAR or acute humoral rejection has not been reported so far. The rapidity of the process would preclude the development of microangiopathy since the affected areas are promptly excluded from the renal circulation in those harsh types of vascular rejection in ABO-incompatible transplantation.

Our case implies that there are two problems to be elucidated. To begin with, are there any causes of HUS apart from HAR? From the pathogenetic standpoint, any factor that damages renal endothelial cells should be taken into consideration. Tacrolimus might be responsible; usually, however, drug-induced thrombotic microangiopathy develops weeks to months after exposure and is dose dependent. The trough level of tacrolimus in our patient was within the ideal range, at least on day 0. CMV infection, which could be another factor inducing HUS, was negative, at least at the onset, judging from the pre-operative CMV antigenaemia level. The fact that pathological changes of HUS already had been seen in the 1 h biopsy specimen does not point to either of these causes. The presence of antibodies against donor HLA may be a humoral factor to induce vascular rejection; however, the direct cross-match test was negative pre-operatively in this case. Thus, it is not difficult to postulate that HAR was caused by incompletely diminished pre-existing anti-A antibody, which triggered HUS. Unexpectedly high anti-B antibody titres and the diffuse attachment of complement along the peritubular capillaries in a 1 h graft biopsy would support this notion. Nafamostat mesilate, which is used in Japan for treating patients with disseminated intravascular coagulation (DIC) and acute pancreatitis, could play a role in inhibiting not only coagulation and fibrinolysis, but also the complement system [10]. HUS associated with vascular rejection generally happens days later than it did in our case, even in recurrent cases [11,12]. Our case is the only observed case of HUS with hyperacute onset.

Secondly, we should discuss why HAR did not result in the total cessation of blood flow to the kidney and subsequent graft necrosis in this case. Immunomodulation, comprising strong immunosuppressants, splenectomy and plasmapheresis, can prevent HAR altogether or delay its occurrence [7]. The modulated strength of an anti-A antibody might result in the partial occlusion of renal circulation with microangiopathy, but not in the total occlusion of vessels by obliterating clots. In conclusion, we present this unique case of HUS with hyperacute onset in an ABO-incompatible renal transplant recipient, which implies that HUS is another serious complication caused by pre-existing anti-A/B antibodies. Longer follow-up is warranted because CAN was proven by a 2-year protocol biopsy. The acute phase of HUS, however, is salvageable by means of intensive care, comprising frequent plasma exchange and administration of a serine protease inhibitor [10]. Pre-operative elimination of anti-A/B antibodies is crucial for the success of ABO-incompatible transplantation.

Conflict of interest statement. None declared.



   Notes
 
Correspondence and offprint requests to: Dr Hiroshi Harada, Department of Renal Transplantation, Sapporo City General Hospital, Kita 11-Jo, Nishi 13-Chome, Chuou-Ku, Sapporo 060-8604, Japan. Email: oyaji-1{at}rf6.so-net.ne.jp Back



   References
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 Introduction
 Case
 Discussion
 References
 

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