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Table of Contents
Year : 2020  |  Volume : 14  |  Issue : 3  |  Page : 213-218

Thrombotic microangiopathies postrenal transplantation

1 Department of Nephrology and Renal Transplantation, VPS Lakeshore Hospital and Research Centre, Kochi, Kerala, India
2 Department of Pathology, VPS Lakeshore Hospital and Research Centre, Kochi, Kerala, India

Date of Submission18-Jul-2019
Date of Acceptance15-Mar-2020
Date of Web Publication30-Sep-2020

Correspondence Address:
Dr. Kartik Ganesh
Department of Nephrology and Renal Transplantation, VPS Lakeshore Hospital and Research Centre, Kochi - 682 040, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_29_19

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Aims: The aim of the study was to describe 12 cases of thrombotic microangiopathy (TMA) postrenal transplantation and study the causes, treatment, and outcomes. Materials and Methods: A retrospective observational study was conducted among renal transplants conducted from 2005 to 2018. Results: Of a total number of 1210 transplants, 12 patients (1%) developed posttransplant thrombotic complications. The mean age of recipients was 36.75 years, and the male-to-female ratio was 9:3. Native kidney diseases included diabetic nephropathy, chronic glomerulonephritis, chronic interstitial nephritis, lupus nephritis, atypical hemolytic uremic syndrome (HUS), and immunoglobulin A nephropathy. Treatment options included plasmapheresis, intravenous immunoglobulin, and everolimus. Seven (58.3%) were associated with an acute rejection, 2 (16.6%) had associated histopathological evidence of calcineurin toxicity, 1 (8.3%) had an unknown etiology, 1 (8.3%) had recurrent HUS in the graft, and 2 (18.2%) patients developed glomerular microthrombi, both of which resolved spontaneously. Graft loss was 50% within the 1st year. Six patients (50%) had a good 1-year graft survival. Two patients succumbed (16.6%). Conclusion: TMA in the posttransplant period may be commonly associated with drug toxicities, antibody-mediated rejection, or recurrent HUS. There is no correlation between drug levels and extent or prognosis of TMA. Empirical plasma exchange may be tried even in cases with no evident cause for TMA. Graft loss is common.

Keywords: CNI toxicity,thrombotic microangiopathy, rejection, renal transplantation

How to cite this article:
Ganesh K, Abraham AM, Kumar JS, Paul RS, Simon S, Harshan N. Thrombotic microangiopathies postrenal transplantation. Indian J Transplant 2020;14:213-8

How to cite this URL:
Ganesh K, Abraham AM, Kumar JS, Paul RS, Simon S, Harshan N. Thrombotic microangiopathies postrenal transplantation. Indian J Transplant [serial online] 2020 [cited 2021 Jul 30];14:213-8. Available from: https://www.ijtonline.in/text.asp?2020/14/3/213/296888

  Introduction Top

Thrombotic microangiopathy (TMA) is a specific pathologic lesion in which abnormal arteriolar and capillary vessel walls lead to microvascular thrombosis.[1] TMA is a pathologic diagnosis made by tissue biopsy. The pathological diagnosis of TMA requires the presence of one or more of the following: (i) microvascular thrombi, (ii) a glomerular capillary occlusion which results from subendothelial deposits of the electron-lucent material, and (iii) a severe subendothelial widening TMAs may be primary or secondary. In this study, we attempted to study the causes and outcomes of TMA seen in the postrenal transplant scenario.

  Materials and Methods Top

A retrospective observational study conducted at VPS Lakeshore Hospital and Research Center among 1210 renal transplants conducted from 2005 to 2018. Out of these 12 patients with histopathology in graft biopsies suggestive of thrombotic microangiopathy were identified. Informed consent was taken from all patients. Parameters studied were etiology, management, graft survival and patient survival.

Statistical methods

Data was filled in excel charts. Descriptive statistics was performed. Variables were presented as mean and standard deviation or as frequencies (percentage).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Ethics statement

It was a retrospective, observational study and did not involve any human intervention and hence EC approval was waived. Study was done according to principles of declaration of Helsinki.

  Results Top

Of a total number of 1210 transplants, 12 patients (1%) developed posttransplant thrombotic complications. The mean age of recipients was 36.75 years and the male-to-female ratio was 9:3. The mean time of presentation was 62.6 weeks posttransplant. Of these, one patient presented 10-year posttransplantation and another 2-year posttransplant, excluding whom, the mean time of presentation was 12.6 weeks posttransplant, with the earliest being 1 week postrenal transplant. Native kidney diseases included diabetic nephropathy, chronic glomerulonephritis, chronic interstitial nephritis, lupus nephritis, atypical hemolytic uremic syndrome (aHUS), and immunoglobulin A nephropathy [Table 1]. Induction agents used were interleukin-2 receptor blockers (basiliximab and daclizumab) in 5 patients (41.6%) and anti-thymocute globulin in 7 patients (58.3%), according to the institution protocol at the time. Seven (58.3%) were associated with an acute rejection, 2 (16.6%) had associated histopathological evidence of calcineurin toxicity, 1 (8.3%) had an unknown etiology, 1 (8.3%) had recurrent HUS in the graft, and 2 patients (18.2%) developed glomerular microthrombi, both of which resolved spontaneously. Graft loss was 50% within the 1st year. Six patients (50%) had good 1-year graft survival. Two patients succumbed (16.6%) of which 1 (9%) was in the immediate postoperative period and 1 (9%) was 9 years posttransplant, of a cause unrelated to the TMA process. The results are summarized in [Table 1] and [Table 2].
Table 1: General characteristics

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Table 2: Transplant details

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  Discussion Top

TMA syndromes can be broadly classified into primary and secondary syndromes. Primary TMA syndromes are thrombotic thrombocytopenia purpura (hereditary or acquired), Shiga toxin-mediated HUS, drug-induced TMA, complement-mediated TMA, and rare hereditary disorders of Vitamin B12 metabolism or factors involved in hemostasis. Treatment of these disorders involves targeting the corresponding metabolic pathways. TMA can also be secondary to disorders such as preeclampsia, severe hypertension, systemic infections, malignancies, systemic lupus erythematosus, and complications of hematopoietic stem cell or organ transplantation. Treatment in these cases involves the treatment of the underlying disorders.

Posttransplant TMA may ensue de novo, i.e., for the first time with no prior history, or may affect patients whose primary cause of ESRD was HUS (recurrent posttransplant TMA). In our case population, we had one case of recurrent HUS, while the others were presumed de novo HUS.

TMAs are usually diagnosed with concurrent evidence of microangiopathic hemolytic anemia, manifested by anemia, thrombocytopenia, schistocytes on peripheral smear, raised LDH, and low haptoglobin levels. None of our patients however showed these systemic features. The TMA was limited to the graft, and thus, a graft biopsy was the only way to diagnose these cases. Studies have shown a prevalence of 30% of graft limited TMA,[2] which was borne out in our population. Studies have described de novo HUS in 3% to 14% of kidney transplant recipients.[3],[4],[5] The causes specific to the posttransplant patient include medications (calcineurin inhibitors [CNIs], mammalian target of rapamycin [mTOR] inhibitors, and clopidogrel), antibody-mediated rejections, and infections (HIV, parvovirus B19, and cytomegalovirus). All the nontransplant causes of TMA can also occur.

CNIs may cause TMA through various proposed mechanisms. CNIs cause an imbalance between vasoconstrictors (endothelin and thromboxane A2) and vasodilators (PGE2 and prostacyclin), favoring renal arteriolar vasoconstriction, and thereby endothelial injury.[6],[7] They also have platelet-activating, procoagulant, and antifibrinolytic properties which contribute to TMA evolution.[7],[8],[9] A third mechanism is by microparticle production from endothelial cells, a known effect of Cyclosporin A that can result in TMA.[10] The timing of CNI-induced TMA could be at any point, but the risk is theoretically higher in the first 6 months of transplantation when drug levels are maintained at a high level. However, CNI-induced TMA appears to be relatively rare, borne out by the fact that 95% of kidney transplant recipients are on CNI and TMA due to CNI is a relatively rare complication. In our group of patients, we found evidence of CNI toxicity in two patients. Biopsies in these patients showed notable isometric vacuolization and nodular arteriolar hyalinosis [Figure 1] and [Figure 2] which is considered a feature of CNI toxicity. CNI was withdrawn slowly and substitution with everolimus was tried in this case, but the graft could not be salvaged. Reduction or withdrawal of CNI or switching to mTOR inhibitors have been attempted to limit drug-related nephrotoxic insult. However, 60%–100% graft loss has been reported with these procedures.[11] Suggested strategies include reducing CNI during TMA and restoring the dose after clinical recovery.[12] In the aforementioned study, plasmapheresis was used as a bridge to cover the immediate posttransplant TMA after discontinuing CNI, with lymphocyte-depleting agents used in the interim. CNIs were reinstituted once TMA resolved. Ninety-five percent of the patients tolerated the reinstitution of CNI. There are plenty of caveats to CNI withdrawal. CNI withdrawal raises the risk of rejection. The recurrence rate after switching from cyclosporine to tacrolimus or vice versa is unknown; TMA developing after switching, either way, has been described.[13] Furthermore, there are well-documented cases of continued TMA despite CNI withdrawal.[14] CNI withdrawal in de novo TMA does not always guarantee a favorable graft outcome.[15] Drug levels are of limited value in diagnosing CNI-induced TMA. CNI levels correlate with neither development nor progression of TMAs as shown in various studies and case reports.[2],[16] Switching over to everolimus has been suggested as a possible solution.[17] Animal models[18] have shown relative safety of everolimus in TMA, and therefore, CNIs are thought to have more TMA-producing potential than everolimus. A long-term combination is best avoided. In our case, the switch was ineffective leading to graft loss.
Figure 1: Hematoxylin and eosin stain (40X): CNI toxicity: Isometric vacuolization of tubular epithelial cells

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Figure 2: Periodic acid Schiff stain (40X): CNI toxicity: Periodic acid Schiffpositive nodules in the outer muscle layer of an arteriole (periodic acid Schiff)

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TMA is often associated with antibody-mediated rejection [Figure 3]. Seven of our patients had TMA associated with acute rejection, one of which (Case 8) developed TMA following an acute rejection, while in the other cases, TMA and AMR occurred concurrently. Two patients lost their grafts and three had good graft survival at 1 year. Few studies have reported some level of correlation between TMA and C4d staining in 16.2%[19] and 55%[15] of biopsied recipients, respectively. Two studies also demonstrated that clustering of AMR and TMA predicted worse graft outcome.[15],[20] All our patients were C4d negative however. Graft loss rate of 40% has been reported in de novo TMA within a few years of diagnosis.[21] A report presented by Reynolds et al.[19] reported a patient mortality rate of 50% after 3 years of diagnosis.
Figure 3: Hematoxylin and eosin stain (40X): Antibody Mediated Rejection: Glomerulitis with infiltrating leukocytes and hilar arteriole with fibrinoid necrosis

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In case number 2 in [Table 2], a patient of aHUS with negative pretransplant complement genetic workup lost his graft due to recurrent HUS after being treated for a combined rejection. The timing of an aHUS episode is difficult to predict. The minimal list of genetic screening should include complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), complement factor B (CFB), membrane cofactor protein (MCP), and C3.[22] CFB mutations have a 100% risk of relapse posttransplant, whereas the risks of recurrence in mutations of CFH, CFI, MCP, and C3 were 75%–90%, 45%–80%, <20%, and 40%–70%, respectively.[23] A reduced C3 level is commonly seen in mutations of CFB, C3, and anti-CFH antibodies.[23] C3 levels may be normal or decreased in CFH, CFI, and MCP mutations.[23] All of them have normal C4 levels.[23] The choice of donor is important – risks associated with living-related kidney donation are recurrent disease in the recipient and de novo disease in the donor if he/she is a genetic mutation carrier.[24] A living-related donor without complement gene abnormalities can be permitted.[25] Liver transplantation may be offered for patients with liver-derived complement protein abnormalities and in patients poorly responding to complement blockade.[26] Prophylactic use of rituximab along with plasma exchange[27],[28] and the anti-C5 monoclonal antibiody, eculizumab, has been reported to be used successfully to prevent aHUS recurrence in patients with CFH, CFH/CFHR1 hybrid genes as well as with C3 gene mutations.[29],[30]

Treatment of posttransplant TMA involves assessing for reversible factors such as drug withdrawal, the implications of which have been discussed already. In addition, plasmapheresis and intravenous immunoglobulin may have a role in the empirical treatment of TMA, based on the proven efficacy in the treatment of thrombotic thrombocytopenia,[31],[32] and previous choice as a first-line therapy for aHUS. The 2003 study by Karthikeyan et al.[12] reported a graft salvage rate approaching 80% with plasma exchange. The beneficial effects are thought to be due to the removal of the platelet aggregation factors and simultaneous replenishment of the deficient factors, for example, PGI2-stimulating factor.[12] In AMR-associated TMA, improved outcomes have been attributed to removal of the anti-HLA antibodies.[15],[33] Most of our cases were treated with a combination of plasma exchange and intravenous immunoglobulin. Case 11 had significant associated cortical necrosis, and hence, plasma exchange was not done.

A curious phenomenon we observed was the seemingly uneventful presence of few glomerular microthrombi [Figure 4] with no other evidence of TMA or rejection in cases 7 and 10 described in [Table 1]. The graft dysfunction in case 7 improved spontaneously with no therapy, whereas in case 10, these were observed after treatment of an antibody-mediated rejection. Both grafts have shown good 1-year graft survival. Graft microthrombi have been described in multiple reports of deceased-donor kidney transplantation,[34],[35] the cause of which has been ascribed to some form of disseminated intravascular coagulation. Batra et al.[35] reported a large number of pre-existing fibrin thrombi in the preimplantation biopsy of deceased donors but concluded that they had no influence on future graft function. An older study by McCall et al.[36] found an increased risk of delayed graft function but no influence on 2-year graft function. Both our cases however had fibrin thrombi post a living donor transplant. Both were observed carefully and graft function improved spontaneously. Whether these microthrombi could be predictive of impending AMR or a manifestation of thrombotic disorders like APLA syndromes are questions worth considering; however, this was not the case in both our patients.
Figure 4: Hematoxylin and eosin stain (40X): Glomerulus with thrombi

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Study was limited by small sample size.

  Conclusions Top

TMA in the posttransplant period may be commonly associated with drug toxicities, antibody-mediated rejection, or recurrent HUS. An exact etiology is difficult to identify in most cases even after a biopsy because of overlapping features, suggesting the possibility of multiple etiological processes occurring concurrently. There is no correlation between drug levels and extent or prognosis of TMA. There was no correlation between graft survival and differing histopathological features (C4d staining) in patients with TMA and antibody-mediated rejection. Empirical plasma exchange may be tried even in cases with no evident cause for TMA. Graft loss is common.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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