|Year : 2020 | Volume
| Issue : 1 | Page : 160-168
|Clinical profile and outcomes of De novo posttransplant thrombotic microangiopathy
LP Saikumar Doradla1, H Lal2, Anupma Kaul1, D Bhaduaria1, M Jain3, N Prasad1, V Thammishetti1, A Gupta1, M Patel1, RK Sharma1
1 Departmenta of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Departmenta of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Departmenta of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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|Date of Submission||30-Jan-2019|
|Date of Decision||14-Mar-2019|
|Date of Acceptance||17-Mar-2019|
|Date of Web Publication||3-Mar-2020|
| Abstract|| |
Thrombotic microangiopathy (TMA) after kidney transplant is rather uncommon but an important reversible cause of graft loss. This retrospective study of biopsy-proven posttransplant TMA was done to identify the important etiological factors, clinical features, and outcomes of post transplant TMA in a tertiary care referral hospital in northern India. This retrospective study was conducted among all renal transplant recipients who presented with graft dysfunction between 1989 and 2015. All the cases were looked for their etiology, clinical course, treatment modalities, and renal outcomes. The study was conducted in accord with prevailing ethical principles and reviewed by our own institutional review board. Seventeen patients out of 2000 (0.008%) transplants done during the study period had posttransplant TMA, out of which all the patients had de novo TMA, and the median time of presentation after transplantation was four months. Systemic TMA was noted in only four patients. Biopsy revealed associated rejection in five patients and associated calcineurin inhibitor (CNI) toxicity in 12 patients. Patients with TMA due to CNI toxicity were managed with CNI reduction or switching to alternate CNI or mammalian target of rapamycin inhibitors. In addition, antithymocyte globulin and plasma exchange were used in rejection-associated TMA. While four out of 12 patients (33%) in CNI-related TMA developed end-stage renal disease (ESRD), all patients in rejection-associated TMA developed ESRD. The overall one-year graft survival was 47%, whereas five- and 10-year survival was 35%. There was no significant difference in graft survival between localized and systemic TMAs (P = 0.4). Posttransplant TMA should be suspected even if there are no systemic features of hemolysis and early graft biopsy and prompt action is needed. The occurrence of TMA in the setting of rejection is associated with grave prognosis.
|How to cite this article:|
Saikumar Doradla L P, Lal H, Kaul A, Bhaduaria D, Jain M, Prasad N, Thammishetti V, Gupta A, Patel M, Sharma R K. Clinical profile and outcomes of De novo posttransplant thrombotic microangiopathy. Saudi J Kidney Dis Transpl 2020;31:160-8
|How to cite this URL:|
Saikumar Doradla L P, Lal H, Kaul A, Bhaduaria D, Jain M, Prasad N, Thammishetti V, Gupta A, Patel M, Sharma R K. Clinical profile and outcomes of De novo posttransplant thrombotic microangiopathy. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Apr 4];31:160-8. Available from: http://www.sjkdt.org/text.asp?2020/31/1/160/279936
| Introduction|| |
Thrombotic microangiopathy (TMA) is a disorder of small vessels caused due to obstruction of vessel wall caused due to platelet and fibrin causing microangiopathic hemolytic anemia and thrombocytopenia leading to organ dysfunction depending on the vascular bed involved.
The incidence of TMA after kidney transplantation is 0.8% according to the United States Renal Data System (USRDS) data, and it is an important reversible cause of graft loss after kidney transplant. There are two types of posttransplant TMA. One is recurrent TMA which is due to recurrence of atypical hemolytic uremic syndrome (aHUS), of which the most common cause is factor H deficiency and the second type is de novo TMA which is mainly attributed to use of calcineurin inhibitors (CNIs), although many other causes have been described.
In a historical cohort study of USRDS data between 1998 and 2000 done by Reynolds et al, the incidence of recurrent TMA was high with 189 episodes/1000 person-years (29.4% of cases) when compared to 4.9 episodes/1000 person-years (0.8%) for de novo TMA. The major risk factors for de novo TMA include use of cyclosporine and tacrolimus.
Although the use of mammalian target of rapamycin (mTOR) inhibitors, marginal kid- neys, high panel-reactive antibody levels, cytomegalovirus (CMV), BK virus, parvo- virus B19, hepatitis C virus infection, and clopidogrel have all been described as uncommon factors for triggering de novo TMA.
Classification of patients with de novo TMA into localized and systemic forms of disease is found to be useful because patients with systemic TMA were found to have more need for plasmapheresis, more need for dialysis, and more chance of graft loss, whereas patients with localized form of disease were found to have no graft loss and did not require plasmapheresis and responded to CNI dose reduction, withdrawal, or conversion. Localized or systemic forms of TMA may represent the same disorder of different severity; it may initially present as localized form and subsequently progress to systemic form.
Prevention of posttransplant TMA in a patient with aHUS is unclear. However, plasmaphe- resis post and pretransplant, avoidance of CNI in early stages of the posttransplant period, use of eculizumab, and combined liver-kidney transplant were found to be beneficial.
Treatment of de novo TMA includes withdrawal of CNI completely or partially, although it may not lead to complete improvement, and sometimes, plasmapheresis in addition to CNI withdrawal may be necessary and it had led to graft survival to as high as 80%. In plasmapheresis-resistant cases, intravenous immunoglobulin may be used as a salvage therapy.
This retrospective study of biopsy-proven posttransplant TMA was done to identify the important etiological factors, clinical features, and outcomes of posttransplant TMA as published data is sparse from developing countries. This study may help in filling some of the gaps in knowledge of posttransplant TMA.
| Materials and Methods|| |
This single-center retrospective study was conducted among all renal transplant recipients who presented with graft dysfunction between 1989 and 2015 in the nephrology transplant unit of a tertiary care referral hospital in the northern part of India and were diagnosed as posttransplant TMA on the basis of their clinical presentation, laboratory investigations, and renal histology. We have included 17 renal transplant recipients with biopsy-proven TMA. All the cases were looked for their etiology, clinical course, treatment modalities, and renal outcomes. The study was conducted in accord with prevailing ethical principles and reviewed by our own institutional review board.
- Creeping rise of creatinine (Cr) - rise in serum Cr (SCr) over days or weeks but does not strictly fulfill the consensus criteria for acute kidney injury (AKI)
- Acute graft dysfunction - as there was no standard definition of AKI in transplant setting, standard AKI definition as per the Kidney Disease Improving Global Outcomes 2012 guidelines as increase in SCr by 0.3 mg/dL within 48 h or increase in SCr to 1.5 times from baseline which is known or presumed to have occurred within the prior seven days is used
- Response to therapy - Decrease of SCr by 50% or return to baseline
- End-stage renal disease (ESRD) was defined as an estimated glomerular filtration rate of less than 15 mL/min/1.73 m2 for more than three months
- Graft loss defined as ESRD or requirement of dialysis for more than three months, second transplant, or death.
All cases with biopsy-proven TMA were included in the study.
| Statistical Analysis|| |
Categorical variables were expressed as proportions and percentages. Continuous variables were expressed as means with standard deviations. Kaplan-Meier survival analysis was done to analyze the graft survival. All the statistical analyses were done using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA).
| Results|| |
Demographic characteristics are summarized in [Table 1]. Seventeen patients out of 2000 (0.008%) transplants done during 1989-2015 were identified to have posttransplant TMA.
|Table 1: Demographic characteristics and immunosuppression of patients with thrombotic microangiopathy.|
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All the patients had de novo TMA, and none of our patients had recurrent TMA. The duration of presentation after transplantation ranged from one month to 168 months, with a median of four months. Eight patients had creeping rise of Cr over weeks, whereas nine patients showed an acute rise in SCr. Cr at presentation ranged from 1.6 mg/dL to 5.3 mg/dL (2.6 ± 1.13 mg/dL). Systemic evidence of hemolysis was noted only in four (23.5%) patients. There was a statistically significant difference in hemoglobin, reticulocyte count, and lactate dehydrogenase (LDH) levels between systemic and localized TMAs.
Three (17.6%) patients presented with dialysis- dependent renal failure. Most of the patients in CNI-related TMA presented with creeping rise in Cr, whereas rejection-associated TMA presented with an abrupt rise in Cr.
Biopsy revealed associated rejection in five patients. Associated CNI toxicity was noted in twelve patients.
In patients with TMA due to CNI toxicity (n = 12), treatments used were CNI reduction or switching the CNI or switching to mTOR inhibitors. In patients with associated rejection (n = 5), in addition to the above measures, antithymocyte globulin (ATG) and plasma exchange were used in four patients; one patient received only ATG. Treatment regimens used are summarized in [Table 2].
|Table 2: Treatments used in the posttransplant thrombotic microangiopathy patients.|
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Out of 17 patients, nine patients developed ESRD within a mean period of 12.8 ± 7.3 months (4-26 months). While four out of 12 patients (33%) in CNI-related TMA developed ESRD, all patients in rejection-associated TMA developed ESRD. Individual patient details and their outcomes are shown in [Table 3]. The one- year graft survival was 47%, whereas five- and 10-year survival was 35%, as shown in [Figure 1]. Graft survival showed a statistically significant difference between the two causes of TMA, as shown in [Figure 2] (χ2 = 10.4, P= 0.01). There was no significant difference in graft survival between localized and systemic TMAs (P= 0.4), as shown in [Figure 3].
|Table 3: Data on types of transplant, cause, follow-up, and final outcome of patients with thrombotic microangiopathy.|
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|Figure 1: Cumulative graft survival of all the patients with posttransplant thrombotic microangiopathy.|
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|Figure 2: Kaplan–Meier survival analysis comparing graft survival in calcineurin inhibitor (CNI) and rejection (REJ) related thrombotic microangiopathy.|
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|Figure 3: Kaplan–Meier survival analysis comparing graft survival in systemic and localized thrombotic microangiopathies (TMA).|
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| Discussion|| |
In this retrospective study of 17 patients with biopsy-proven posttransplant TMA, the folio- wing important findings were noticed:
- All patients who had posttransplant TMA had de novo TMA, and none of them had recurrent TMA.
- Majority of them presented early in the posttransplant period and did not have systemic evidence of hemolysis
- CNI-associated TMA constitutes a majority of posttransplant TMA and commonly presents with creeping rise of SCr, whereas rejection-associated TMA presents with acute rise of SCr (acute graft dysfunction)
- Rejection-associated TMA was resistant to conventional treatment and was associated with poor graft outcomes.
Most (94.1%) of the renal transplant recipients were live related and ABO compatible when compared to a study done by Schwimmer et al where most of the cases were deceased renal transplants (81%). Most of the patients in our series presented in early posttransplant period which is similar to a study done by Caires et al (median time of presentation was 25 days), although the longest time of presentation in our study was 168 months posttransplant which is more when compared to older data showing posttransplant TMA presenting two to six years posttransplant.,, The patient who presented 168 months of transplant was a 54-year-old female who underwent live-related renal transplant on September 1, 1994, and presented 14 years after transplant with creeping rise of SCr without any systemic evidence of hemolysis, and graft biopsy was done which was suggestive of CNI toxicity with TMA and her SCr settled after CNI dose reduction.
The etiology for TMA in our case series is CNI related in 70% of cases and rest 30% of cases had rejection-associated TMA. One patient in our series had CMV disease (inclusion bodies) on biopsy along with TMA, and this patient had been treated with both anti-CMV treatments along with CNI dose reduction. This is important because although rare CMV disease is also associated with TMA.
Other rare risk factors for de novo TMA, found in previous data such as parvovirus, BK virus, disseminated histoplasmosis and drugs such as clopidogrel, antiviral treatments such as ribavirin, interferon, leflunomide, and valgan- ciclovir, an acquired disintegrin and metallo- proteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) deficiency, ischemia- reperfusion injury were not found in our study. Recent studies have found that there may be phenotypical shifts of native kidney disease which involve alternate complement pathway such as C3 glomerulopathy may transform to de novo HUS after transplant.
Le Quintrec et al had found mutations in complement factor H (CFH) and I (CFI) genes in 29% (7/24) of patients with posttransplant de novo TMA.
Onset and severity of graft dysfunction may predict the type of posttransplant TMA. In our series, patients with the rapid rise of SCr are likely to have rejection-associated TMA, whereas patients with slow creeping rise had CNI-associated TMA. In our series, three out of 17 patients presented with dialysis-dependent renal failure. Two of them who had rejection- associated TMA did not recover despite ATG or plasmapheresis, and they had eventual graft loss and progressed to ESRD. In the third patient who had TMA due to CNI toxicity, recovery occurred with CNI dose reduction and is on regular follow-up with normal graft function for three years. In a study done by Caires et al, 47% of patients needed dialytic support at diagnosis of TMA, among which 75% remained on dialysis.
Most (70%) of our patients had localized TMA. This is in correlation to a study done by Zarifian et al. However, Schwimmer et al had shown that majority of the patients had systemic evidence of hemolysis (61%). Caires et al found that patients with de novo posttransplant TMA markers of hemolysis such as anemia, thrombocytopenia, raised LDH, decreased haptoglobin, and schistocytes on peripheral smear were found in 53%, 41%, 70%, 64%, and 35%, respectively. Hence, systemic evidence of hemolysis might not be a reliable marker of posttransplant TMA.
Most of the patients in our series did not have high CNI levels at presentation or in the last three months even though biopsy revealed features of CNI toxicity. Hence, a normal CNI trough level does not rule out CNI-associated TMA.
The treatment options used for CNI-associated TMA were CNI dose reduction, conversion to alternative CNI, or conversion to mTOR inhibitors. These strategies were in agreement with previous studies.,, The graft loss on longterm follow-up in our series was high (52%) because of the inclusion of rejection-associated TMA. While ESRD occurred in all patients with rejection-associated TMA, 33% of CNI- related TMAs developed ESRD.
In our series, the incidence of graft loss was significantly high in rejection-associated TMA (all the 5 patients had graft loss despite the use of plasmapheresis and ATG) compared to CNI- associated TMA (4 out of 12); out of these four patients, two patients had graft loss at a later date after transplant due to reason other than TMA (resistant rejection). In a recent review, Abbas et al have proposed indications for the use of eculizumab in posttransplant TMA such as antibody-mediated rejection-associated TMA, patients who became PE-dependent, and patients with refractory hemolysis despite maximum doses of PE therapy. Eculizumab was not used in our patients due to nonavailability and high cost.
The limitations in our study include smaller sample size, heterogeneous nature of posttrans- plant TMA inclusion of rejection-associated TMA, retrospective nature of the study, and lack of studies evaluating genetic abnormalities of complement system such as CFH or CFI mutations. Further large-scale studies are needed to know the clinical characteristics and outcome of CNI-associated TMA and rejection- associated TMA individually.
| Conclusion|| |
Posttransplant TMA is a relatively uncommon disorder which occurs early in the posttrans- plant period and is one of the important reversible causes of early graft dysfunction, and it should be suspected even if there are no systemic features of hemolysis and early graft biopsy and prompt action is needed. The occurrence of TMA in the setting of rejection is associated with grave prognosis.
Conflict of interest: None declared.
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Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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