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Published ahead of print on June 14, 2006
Clin J Am Soc Nephrol 1: 811-819, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01781105
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ICU Nephrology

Clinical Outcome of Thrombotic Microangiopathy after Living-Donor Liver Transplantation Treated with Plasma Exchange Therapy

Hiroshi Nishi*,{dagger}, Norio Hanafusa*,{dagger}, Yasushi Kondo*,{ddagger}, Masaomi Nangaku{dagger}, Yasuhiko Sugawara§, Masatoshi Makuuchi§, Eisei Noiri*,{dagger},||, and Toshiro Fujita*,{dagger}

* Department of Hemodialysis and Apheresis, {dagger} Department of Nephrology and Endocrinology, {ddagger} Department of Urology, § Department of Surgery, || Center for NanoBio Integration, University of Tokyo, Tokyo, Japan

Address correspondence to: Dr. Eisei Noiri, Department of Nephrology & Endocrinology 107 Lab, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. Phone: +81-3-3815-5411; Fax: +81-3-5800-8725; E-mail: noiri-tky{at}umin.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Thrombotic microangiopathy (TMA) is a well-documented but severe complication that occurs after solid-organ transplant. Administration of calcineurin inhibitors is considered a major cause of this fatal complication; prompt initiation of plasma exchange therapy after reduction or conversion of calcineurin inhibitors has been recommended. Nevertheless, little is known about clinical evidence of this strategy against TMA after solid-organ, especially non–renal-organ, transplantation. Medical records of 63 patients who were hospitalized at Artificial Organ and Transplantation Division in Tokyo University Hospital and underwent blood purification therapy between January 1999 and May 2005 were reviewed. Twenty-eight living-donor liver transplantation (LDLT) recipients who received plasma exchange therapy were identified, and 18 of them were found retrospectively to receive a diagnosis of having TMA. Of the 18 patients, 10 (56%) responded to this therapy and survived after the treatment was stopped, whereas eight (44%) patients died before improvement. Subsequent follow-up of patients clarified that 1-yr survival rate of post-LDLT TMA was approximately 30%. Multivariate Cox proportional-hazards regression analysis demonstrated that the interval between transplant surgery and onset of TMA (hazard ratio 1.35 per 30 d; 95% confidence interval 1.07 to 1.71; P = 0.021) and pretreatment blood urea nitrogen level (hazard ratio 1.39 per 10 mg/dl; 95% confidence interval 1.02 to 1.90; P = 0.037) predicted mortality. Analyses identified post-LDLT recipients with TMA as being at high risk for poor prognosis. Effective strategies are needed for late-onset TMA after LDLT to improve treatment response and survival.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Thrombotic microangiopathy (TMA) includes syndromes of microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, fever, neurologic deficits, and associated organ impairments (1). Development of TMA has been documented also in organ transplant recipients, the majority of which presumably are associated with calcineurin inhibitors (CNI) that typically are administered to prevent rejection. Vascular rejection or viral infection might exaggerate TMA in some cases. Plasma exchange (PE) along with dose reduction, discontinuation, or conversion of CNI has been a widely used therapy to treat posttransplantation TMA (1–5). Karthikeyan et al. (6) reported that 23 (79%) of 29 kidney transplant recipients who had TMA and were treated with PE recovered graft function at a single institute. However, according to an analysis based on a national database in the United States, the 3-yr survival rate of TMA after renal transplantation was approximately 50% (7). These seemingly conflicting data suggest that this strategy might not yet be sufficiently effective against TMA in renal transplant recipients.

Clinical outcome of TMA that is treated with PE after nonrenal organ transplantation is less understood. Although living-donor liver transplantation (LDLT) has emerged as a clinically safe alternative to cadaver transplantation because of organ shortage, post-LDLT TMA has been reported in infrequent cases (8–10) and in a case series at our hospital (11).

In a clinical setting, therapeutic PE to treat post-LDLT TMA is problematic. The immediate accurate diagnosis of TMA sometimes is extremely difficult despite a substantial need for prompt initiation of plasma therapy, mainly for the following reasons: (1) Minimal hematologic disorder or organ involvement is apparent, which also might lack characteristic organ failures of typical TMA, or (2) differential diagnosis is required to distinguish post-LDLT TMA from liver graft failure and disseminated intravascular coagulation. These reasons explain why PE treatment has been initiated before definite diagnosis of TMA is established in LDLT (1–5). This study reviews medical records of adult LDLT recipients who were treated with PE and screens out posttransplantation TMA using laboratory data through the PE treatment period in our hospital. We also observed their clinical outcomes and clarified pretreatment prognostic factors that might be useful for predicting mortality in this strategy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
This study enrolled adult LDLT recipients who were treated with PE between January 1, 1999, and May 31, 2005, at Tokyo University Hospital. These patients were followed up to May 31, 2005. Written informed consent was obtained from all patients before initiation of the study. The entire protocol of this study was designed in accordance with the Declaration of Helsinki.

LDLT and Postoperative Immunosuppressive Care
The LDLT surgical technique that is used at our institute has been described elsewhere (12). Patients received the following immunosuppressive regimens. Immediately after transplant surgery, patients were given tacrolimus by continuous intravenous infusion (2.5 µg/kg per h) to maintain a whole-blood level of 17 to 18 ng/ml. The dose was adjusted to maintain the target level during the first week. Then, tacrolimus was administered orally to maintain a trough level of 14 to 16 ng/ml on postoperative days (POD) 8 to 14, 10 to 15 ng/ml on POD 15 to 90, 8 to 10 ng/ml on POD 91 to 180, and 5 to 10 ng/ml on POD 181 onward (13).

Post-LDLT TMA
PE therapy was initiated immediately when TMA was clinically suspected by experienced transplant surgeons on the basis of all or some of the following: Microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. For this study, a retrospective definite diagnosis of TMA was rendered by hemolytic microangiopathic anemia (hemoglobin level of ≤8 g/dl with elevated serum lactate dehydrogenase [LDH]) level, reduced serum haptoglobin level, or microscopic emergence of fragmented erythrocytes), thrombocytopenia (platelet count ≤ 10 x 104/mm3), and progressive renal failure (serum creatinine level ≥ 1.2 mg/dl) during treatment. Differential diagnosis of disseminated intravascular coagulation was made on the basis of the lack of laboratory findings suggestive of the consumption of clotting factors with prothrombin time of 15 s or longer.

PE Therapy for TMA
Plasma was separated using a 0.8-m2 polyethylene membrane (Plasmaflo OP-08W; Asahi Medical Co. Ltd., Tokyo, Japan) and replaced by the same volume of fresh-frozen plasma (0.1 L/kg). All PE sessions were performed in combination with hemodialysis to correct imbalances of electrolytes and sodium citrate (14). Drug substitution of tacrolimus with cyclosporine was attempted also in some cases (15). For those cases, after discontinuation of tacrolimus, cyclosporine was initiated intravenously at the dose of 2 to 3 mg/h at 12 h. On the basis of whole-blood concentration, the dose then was titrated to maintain the target level of 250 to 350 ng/ml during the first week. It subsequently was administered orally to maintain a trough level of 200 to 250 ng/ml on POD 8 to 14, 150 to 200 ng/ml on POD 15 to 90, 100 to 150 ng/ml on POD 91 to 180, and 100 ng/ml on POD 181 onward (15). Treatment was continued until recovery was indicated by a stable decrease in the serum LDH level or until the patient died.

Statistical Analyses
Survival or death from any cause during treatment was evaluated as a response to PE. During follow-up, survival or death from any cause was evaluated as a clinical outcome of PE. Cox regression tests were performed for statistical analyses of pretreatment parameters that can predict responses during treatment and for analyses of mortality during follow-up. Pretreatment factors that were examined in this study were gender, age, common native liver disease (in two or more patients), CNI (tacrolimus or cyclosporine use at onset, conversion strategy, and the highest trough blood concentration during 5 d before onset), interval days between transplant surgery and TMA onset, blood laboratory data about TMA and liver function, or concurrent cytomegalovirus (CMV) infection. Some of them were used as covariates. Therefore, multiple Cox proportional-hazards regression analyses were performed after removal of nonsignificant variables (P > 0.10) through univariate Cox proportional-hazards regression analysis. All data were interpreted using two-sided tests. Survival curves were estimated using the Kaplan-Meier method followed by log-rank tests. For all statistical tests, we inferred P < 0.05 as statistically significant. Data were analyzed using computer software (SPSS for Windows version 12.0; SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients
We reviewed medical records of 63 patients who were hospitalized at Artificial Organ and Transplantation Division and underwent blood purification therapy at our unit, Center for Department of Hemodialysis and Apheresis, between January 1, 1999, and May 31, 2005. The cases included 18 patients who were treated with PE only before transplant surgery, 10 patients who had hepatic failure and finally could not undergo transplant surgery, three patients who underwent transplantation before the study period, two pediatric recipients, and two patients who were treated with hemodialysis or continuous renal replacement therapy but without any PE session. Therefore, we identified 28 adult patients who were treated with empiric PE after LDLT. Of those recipients, 18 (12 men and six women) received a diagnosis of TMA, retrospectively. The median age of these 18 patients was 51 yr (range 24 to 63 yr; see Table 1 for patient baseline characteristics).


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  		Table 1. Clinical and laboratory baseline characteristicsa

 
During the study period, 238 adult patients underwent LDLT at our institute; 539 patient-years of observation were included. The overall rate of TMA after LDLT was 3.34 cases per 100 patient-years of observation. Of the other 10 patients who were treated with PE and did not meet our TMA criteria, six finished PE of six or fewer sessions. The other four needed additional PE sessions (range 14 to 98 sessions) because of severe hepatic failure; two of them died.

Post-LDLT TMA and PE
The 18 enrolled patients had no medical history of hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), systemic lupus erythematosus, scleroderma, cryoglobulinemia, or malignant hypertension. The most common indication for LDLT was viral cirrhosis in 10 (hepatitis B virus in one and hepatitis C virus [HCV] in nine), followed by primary biliary cirrhosis in two (one HCV positive), autoimmune hepatitis, biliary atresia, fulminant hepatic failure, multiple liver cyst, post-LDLT graft failure (HCV positive), and cirrhosis attributable to unknown cause in one each. Pretransplantation hepatocellular carcinoma was noted in seven (39%), all of which were removed at surgery. One patient with HCV cirrhosis had HIV infection under medical control. Tacrolimus had been administered after transplant surgery in 17 (94%) patients and cyclosporine in one (6%) patient to prevent rejection response.

The PE therapy was initiated with a median interval of 20 d (range 1 to 334 d) after transplantation. In all, 17 patients were treated initially with tacrolimus, which was substituted with cyclosporine during the PE period in six patients. In two patients among the remaining patients, tacrolimus was substituted with cyclosporine because of possible tacrolimus-induced seizure that occurred 8 and 15 d before PE, respectively. In one of those two, cyclosporine was substituted with tacrolimus 1 d before PE started (Figure 1). Withdrawal of CNI was observed in none.


Figure 1
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  		Figure 1. Drug profile of calcineurin inhibitors (CNI) tacrolimus and cyclosporine in the enrolled patients (n = 18). Ovals indicate newly started drugs after CNI conversion, and squares indicate no CNI conversion.

 
The initial laboratory data of those 18 patients exhibited median hemoglobin of 6.6 g/dl (range 3.2 to 9.3 g/dl), a median serum LDH level of 853 U/L (range 277 to 1969 U/L), a median platelet count of 4.9 x 104/mm3 (range 2.2 to 58.4 x 104/mm3), and a median serum creatinine level of 1.4 mg/dl (range 0.7 to 3.6 mg/dl). Fragmented erythrocytes were noted microscopically in nine (50%) patients, and reduced serum haptoglobin level was noted in 12 (67%) patients. Liver function data showed a median level of serum albumin of 3.3 g/dl (range 2.4 to 4.1 g/dl), prothrombin of 61% (range 38 to 100%), and total bilirubin of 8.8 mg/dl (range 1.7 to 16.7 mg/dl). CMV antigenemia was confirmed serologically at the onset of TMA in four (22%) patients.

Courses of PE therapy lasted for a median of 15 sessions (range 1 to 54). During that treatment, the median of hemoglobin was decreased to 4.4 g/dl (range 3.2 to 7.3 g/dl) at bottom, serum LDH increased to 1689 U/L (range 464 to 10,026 U/L), the platelet count decreased to 1.5 x 104/mm3 (range 0 to 8.7 x 104/mm3), and serum creatinine increased to 1.8 mg/dl (range 1.3 to 3.7 mg/dl; Table 2).


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  		Table 2. Data at follow-upa

 
Response to PE
Of those recipients, 10 (56%) survived, whereas eight (44%) died during treatment or within 7 d after that period (Table 2). Onset POD (hazard ratio [HR] 1.39 per 30 d; 95% confidence interval [CI] 1.04 to 1.87; P = 0.034) and platelet count (HR 1.04 per 1 x 104/mm3; 95% CI 0.99 to 1.10; P = 0.098) calculated through a univariate analysis were included in multivariate analyses. Multivariate analyses revealed that neither onset POD (HR 2.05 per 30 d; 95% CI 0.96 to 4.41; P = 0.054) nor platelet count (HR 0.92 per 1 x 104/mm3; 95% CI 0.81 to 1.05; P = 0.218) was capable of significantly predicting the response to therapy.

Clinical Outcome
Of those recipients, six (33%) survived and 12 (67%) died during the follow-up (Table 2). Overall, recipients who developed TMA and underwent PE (n = 18) survived for a shorter period after LDLT than those who did not (n = 220; log-rank test, P < 0.001; Figure 2). A median follow-up of 66 d (range 4 to 1611 d) demonstrated a median survival time of 66 d (95% CI 27 to 105 d) and a 1-yr survival rate of 30.6% after initiation of PE therapy against post-LDLT TMA (Figure 3). The Kaplan-Meier curve demonstrated a remarkable decrease in patient survival with post-LDLT TMA soon after initiation of the follow-up period.


Figure 2
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  		Figure 2. Posttransplantation cumulative survival for adult living-donor liver transplantation (LDLT) recipients without thrombotic microangiopathy (TMA; n = 220) and those with TMA that was treated with plasma exchange (PE; n = 18) during the same study period (log-rank test, P < 0.0001). The 1-yr survival rate was much higher in the non-TMA group than in the TMA group (95.5 versus 30.0%).

 

Figure 3
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  		Figure 3. Cumulative survival for the entire studied cohort of LDLT recipients who developed TMA and were treated with PE therapy, during follow-up after initiation of treatment (n = 18). It seemed shorter than that of recipients who received PE therapy and did not meet TMA criteria during the same period (n = 10), but the difference did not reach a statistically significant level (log-rank test, P = 0.0584).

 
A univariate analysis demonstrated that a median onset POD (HR 1.31 per 30 d; 95% CI 1.04 to 1.66; P = 0.010) and initial urea nitrogen level (HR 1.34 per 10 mg/dl; 95% CI 1.04 to 1.72; P = 0.027) were associated significantly with mortality during the observation period (Table 3). In addition, the initial albumin level (HR 0.28 per 1 g/dl; 95% CI 0.07 to 1.05; P = 0.059) was included in subsequent multivariate analyses. Multivariate analyses demonstrated that only onset POD (HR 1.35 per 30 d; 95% CI 1.07 to 1.71; P = 0.021) and initial urea nitrogen level (HR 1.39 per 10 mg/dl; 95% CI 1.02 to 1.90; P = 0.037) predicted mortality (Table 4). Because the onset of TMA seemed to be related most closely to survival, its influence was evaluated further as follows. Recipients who developed post-LDLT TMA before the median of onset POD of 20 d were defined as a group with early-onset TMA (n = 9), whereas those who developed TMA after 20 d were defined as a group with late-onset TMA (n = 9). Figure 4 showed that the Kaplan-Meier estimate of 1-yr cumulative survival was 11.1% for patients with late-onset TMA and 51.9% for those with early-onset TMA (log-rank test, P = 0.032).


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  		Table 3. Cox proportional hazards univariate regression analysis for mortality during the follow-up perioda

 

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  		Table 4. Cox proportional hazards multivariate regression analysis for mortality during the follow-up period

 

Figure 4
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  		Figure 4. Cumulative survival after PE therapy for early-onset (within 20 d after transplantation) TMA group (n = 9) and late-onset (>20 d after transplantation) TMA group (n = 9) in adult LDLT recipients who were treated with PE (log-rank test, P = 0.0315). The 1-yr survival rate was higher in the early-onset TMA group than in the late-onset TMA group (51.9 versus 11.1%).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
TMA after Solid-Organ Transplantation
In pathogenesis of TMA, vascular endothelial injury and platelet aggregation seem to play a pivotal role (1,5), as demonstrated also experimentally by TMA model rat with Ig-induced endothelial injury (16). Along with primary HUS/TTP, numerous systemic diseases, such as systemic lupus erythematosus and malignant hypertension, are known to predispose to TMA. Nevertheless, 18 cases in this study involved none of them and most likely were classified into posttransplantation TMA. In the majority of posttransplantation TMA induction, the association of cyclosporine or tacrolimus has been inferred because the agents can be directly toxic to endothelial cells and can induce vasoconstriction of the microvasculature and platelet aggregation (17,18). Trimach et al. (19) reported in a review of the literature that nine (43%) patients of 21 cases of posttransplantation tacrolimus-induced TMA responded to reduction of tacrolimus alone. Schwimmer et al. (20) also reported in a case series of a single institute that seven (88%) of eight kidney or pancreas-kidney transplant recipients with posttransplantation, biopsy-proven renal TMA improved only with reduction or withdrawal of CNI. More recently, Øyen et al. (21) reported in their prospective but uncontrolled 4-yr study that no recurrence of TMA occurred in seven kidney allograft recipients with HUS as primary renal disease and seven with posttransplantation de novo TMA, all of whom thereafter had been maintained on CNI-free immunosuppression regimens. These clinical reports demonstrated that CNI should be a major offender in posttransplantation TMA. Furthermore, several viruses, including CMV (22,23), HIV (24), and parvovirus B19 (25), also were implicated. In our case series, administration of CNI seems to be the most responsible for development of post-LDLT TMA, although infection of HCV in nine cases, HIV in one case, and CMV in four cases might be associated. High titer of anticardiolipin antibodies was observed in a small subset of HCV-positive renal allograft recipients with posttransplantation TMA (26), but these antibodies were not analyzed in the enrolled patients.

Incidence
Incidence of posttransplantation TMA was reported collectively after kidney transplantation (6,7,20,27,28), suggesting that recurrent TMA among renal transplant recipients with native kidney HUS/TTP should be distinguished from posttransplantation de novo TMA among those with other native renal disorders: Incidence of the former tends to be much higher than that of the latter (Table 5). Incidence of TMA after nonrenal organ transplantation remains poorly discussed in a few papers (29–31), but TMA in nonrenal transplant recipients seems to be more common than de novo TMA in renal transplant recipients. The overall rate of post-LDLT TMA in our report, 3.34 cases per 100 patient-years of observation, was high and nearly equivalent to that reported of TMA after lung transplantation by Hachem et al. (29). These higher rates of TMA in nonrenal allograft recipients might be explained partly by diagnostic criteria that are based on blood data without renal biopsy.


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  		Table 5. Literature review of TMA after solid-organ transplantationa

 
Outcome
Treatment of posttransplantation TMA relies on removal of any precipitating factors, relief of symptoms, and PE or plasma infusion (17). Our review of recent studies indicated that graft survival or recipient mortality differed profoundly between TMA after kidney transplantation and TMA after nonrenal "vital" organ transplantation (Table 5); TMA can be life-threatening in recipients after heart or lung transplantation. Survival of patients who had TMA and were treated with PE and/or CNI conversion after LDLT in our report was poorer than that of overall TMA (2,3) and even less than that of TMA after renal transplantation (6,7,20,27,28). That considerable difference is not surprising because the burden of comorbid disease in the liver transplantation population negatively affects survival when compared with that of patients after kidney transplantation. Indeed, the 1-yr survival rate of total adult-to-adult LDLT recipients was recently reported as 80 to 90% (32,33), whereas that of cadaveric kidney transplant recipients was estimated as >95% (34).

A small series of TMA after kidney or liver transplantation reported a favorable response with intravenous Ig infusion therapy (35). This approach might be particularly effective in TMA cases with hypogammaglobulinemia because of repetitive PE sessions with albumin replacement.

Prognostic Analyses
Very few analyses have examined prognostic factors to predict the response to treatment or survival of TMA that is treated with PE. Pereira et al. (36) reported from a retrospective study that included 32 patients that delay in initiating PE, neurologic symptoms, and baseline renal disorder can predict treatment failure. In two other studies that included 44 (37) and 24 (38) patients who were treated with PE-based regimens, no clinical feature at diagnosis was reported as predictive of response or survival. However, these reports evaluated varying subgroups of TMA together. To our knowledge, this study is the first prognostic analysis to take up TMA that was treated exclusively with PE after nonrenal transplantation.

Results of our analyses indicated that late onset of TMA after transplantation can predict high mortality. Tacrolimus or cyclosporine was administered successively to every LDLT recipient after surgery, but it remains unknown whether long exposure to the agents might affect the prognosis. This subgroup was likely to require more PE sessions and a larger quantity of fresh-frozen plasma.

PE, sometimes in combination with several devices such as hemodialysis or sorbent hemoperfusion, has long been used as a clinical approach to failing liver in the absence of orthotopic liver transplantation surgery (39–41). The baseline laboratory data including liver function (Table 1) showed extraordinary values and seemed to complicate graft failure at the initiation of PE therapy. In our analysis, however, baseline liver function was not identified as a potential prognostic factor. Another important result of our study was the lack of significant association of CMV seropositivity at the onset of TMA with response to PE. One case report suggested that this viral infection might forestall treatment response or invoke relapse of TMA after liver transplantation (23). The reason for this discrepancy is unknown, but either direct or indirect involvement of viral infection with posttransplantation TMA should be investigated further.

Recent studies have shown a deficiency in the activity of the von Willebrand factor–cleaving metalloprotease, ADAMTS13, as a cause of a significant number of familial or acquired TTP (1,42–45). Therefore, the efficacy of plasma therapy probably depends on replenishing the missing ADAMTS13 metalloprotease or removing the inhibitory antibodies. It is interesting that several groups have suggested that varying assays of ADAMTS13 activity and inhibitors are useful to predict clinical outcomes of patients who have TMA and are treated with plasma therapy (46,47). Nevertheless, it remains controversial whether a similar mechanism or clinical approach can be valid with patients who develop TMA after solid-organ transplantation, according to case reports that have evaluated this enzyme activity in blood samples of these patients (48,49). Unfavorable responses to PE in this report might be explained by different pathophysiology from deficiency in those factors, but these molecules were not examined in our study.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Although our retrospective study involved a small cohort of patients who were examined at a single institute, the results suggest the need to evaluate proper treatment and prognoses of patients who develop TMA after nonrenal organ transplantation. This study demonstrated that the survival of LDLT recipients with late-onset TMA that was treated with PE is poor and should prompt consideration of alternative therapeutic strategy.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.

Received November 19, 2005. Accepted May 2, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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