EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Thrombotic microangiopathy refers to a spectrum of conditions that share a common underlying pathologic mechanism that result in endothelial damage and microangiopathic hemolytic anemia. De novo thrombotic microangiopathy after kidney transplant is often triggered by immunosuppressive drugs, and studies most often implicate calcineurin inhibitors and/or mammalian target of rapamycin inhibitors; however, muromonab and alemtuzumab also reportedly cause thrombotic microangiopathy. In addition, thrombotic microangiopathy may be triggered by acute antibody-mediated rejection and infections like cytomegalovirus and parvovirus.

Here, we present a case series of 3 patients without any apparent risk factors (eg, acute antibody-mediated rejection) who developed de novo thrombotic microangiopathy immediately following kidney transplant, but before the introduction of calcineurin inhibitors. Two of these 3 patients were successfully managed with plasma exchange, and calcineurin inhibitors were successfully introduced without the recurrence of thrombotic microangiopathy.

Key words : Thrombotic microangiopathy, Hemolytic uremic syndrome, Kidney transplant

Thrombotic microangiopathy describes a spectrum of conditions that share a common underlying pathologic mechanism that causes endothelial damage and microangiopathic hemolytic anemia. Thrombotic microangiopathy is a serious complication of kidney transplant that can often causes allograft failure. Thrombotic microangiopathy may develop de novo or reoccur in patients with a previous history of hemolytic uremic syndrome. De novo thrombotic microangiopathy is often triggered by immunosuppressive drugs, and studies often implicate calcineurin inhibitors and/or mammalian target of rapamycin inhibitors; however, muromonab and alemtuzumab are also reported causes. Additionally, thrombotic microangiopathy may be triggered by acute antibody-mediated rejection and other infections.

Here, we present a case series of 3 patients who developed de novo thrombotic microangiopathy immediately after kidney transplant, but before the initiation of immunosuppressive therapy (ie, calcineurin inhibitors or sirolimus). Two of these 3 patients were successfully managed with plasma exchange, and calcineurin inhibitors were sub-sequently introduced without the recurrence of thrombotic microangiopathy.

Case Presentations

Patient 1
A 42-year-old woman with end-stage renal disease caused by polycystic kidney disease presented for de novo kidney transplant. Her medical and surgical history was significant and included polycystic kidney disease, hypertension, seizure, depression, and bilateral native nephrectomy. Her panel reactive antibody score was 4%. She had been receiving dialysis for 2350 days. She received a right iliac fossa kidney transplant from a 51-year-old deceased standard-criteria donor who died of anoxic brain injury. Before surgery, her hemoglobin, serum creatinine, and platelet count were 117 g/L, 884 mmol/L, and 150 x 10⁹/L. Intraoperatively, she received cefazolin, 400 mg methylprednisolone, and 125 mg thymoglobulin according to our institution’s protocol. Postoperatively, the patient was tapered off methylprednisolone and was started on mycopheno-late mofetil, clotrimazole, cotrimoxazole, heparin, docusate, senna, ranitidine, and hydromorphone. She also continued receiving her home medications, which included levetiracetam, escitalopram, carisoprodol, and oxycodone.

On postoperative day 2, the patient’s platelet count decreased to 39 x 10⁹/L. Peripheral blood smear revealed schistocytes. Her hemoglobin, lactate dehydrogenase, and haptoglobin concentrations were 71 g/L, 482 U/L, and < 80 mg/L. She also was anuric and hyperkalemic. She received hemodialysis and therapeutic plasma exchange, which consisted of 1 volume of fresh frozen plasma that was initiated because thrombotic microangiopathy was suspected. Her induction therapy was changed to a single dose of 30 mg of alemtuzumab. Heparin and cotrimoxazole were continued, and a hematology consultation was requested. On postoperative day 3, her platelet count had decreased to 27 x 10⁹/L and hemoglobin had decreased to 61 g/L. Plasma exchange and hemo-dialysis were continued (Figure 1A).

The possibility of hyperacute antibody-mediated rejection was considered low, especially because the patient had no preformed donor-specific antibodies and the donor was ABO compatible. Kidney biopsy could not be performed because there was a high risk of bleeding. Subsequent work-ups, including cytomegalovirus and parvovirus B19 polymerase chain reaction, were negative. Complement levels were within normal limits. Antinuclear antibody and lupus anticoagulant were negative. Factor H and I mutations were assessed to diagnose atypical hemolytic uremic syndrome, but were not detected. ADAMTS 13 was > 90%. The assay to detect antibodies to heparin and platelet 4 complexes was negative, ruling out heparin induced thrombocytopenia.

On postoperative day 6, tacrolimus, cotrimoxazole, valganciclovir, and heparin were initiated. The patient’s platelet count was 43 x 10⁹/L. On postoperative day 12, she received her last hemodialysis (urine output = 1400 mL/24 h) and therapeutic plasma exchange treatments, after which she received 30 g intravenous immunoglobulin. She was discharged on postoperative day 17 with a hemoglobin, serum creatinine, platelet, lactate dehydrogenase, and hapto-globin levels of 77 g/L, 380.12 mmol/L, 166 x 10⁹/L, 265 U/L, and 1270 mg/L. Her serum creatinine and platelet count continued to improve and have remained stable at 132.6 mmol/L and > 150 x 10⁹/L, for the past 6 months. She is currently receiving tacrolimus, mycophenolate mofetil, and prednisone.

Patient 2
A 71-year-old African American woman with end-stage renal disease (presumably caused by hyper-tension) presented for de novo kidney transplant. Her medical history was significant and included hypertension and hypothyroidism. Her panel reactive antibody score was 13%. She had been receiving dialysis for 964 days. She received dual intra-abdominal kidney transplant from a 72-year-old deceased extended-criteria donor who died from intracranial hemorrhage. Before transplant, the patient’s hemoglobin, platelet count, and serum creatinine were 112 g/L, 298 x 10⁹/L, and 388.96 mmol/L. Intraoperatively, she received cefa-zolin, 400 mg methylprednisolone, 1000 mg mycophenolate mofetil, and 100 mg thymoglobulin. On postoperative day 1, her platelet count was 149 x 10⁹/L and she was administered 100 mg thymoglobulin, methylprednisolone, mycophenolate mofetil, clotrimazole, cotrimoxazole, valganciclovir, metoprolol, ranitidine, and heparin.

On postoperative day 2, her platelet count and hemoglobin were 39 x 10⁹/L and 82 g/L. Thrombotic microangiopathy was suspected and later confirmed by the presence of schistocytes, elevated serum lactate dehydrogenase (1568 units/L), and low serum haptoglobin (< 70 mg/L). She demonstrated a negative heparin-induced thrombocytopenia assay. She received hemodialysis for oliguria and hyper-kalemia. Her induction therapy was changed to 20 mg basiliximab on postoperative days 2 and 6. Daily therapeutic plasma exchange, which consisted of 1 volume of fresh frozen plasma, was started on postoperative day 2. On postoperative day 4, her platelet count reached a nadir of 10 x 10⁹/L, after which it increased to 150 x 10⁹/L on postoperative day 9 (Figure 1B).

Tacrolimus was initiated on postoperative day 7. Therapeutic plasma exchange was continued through postoperative day 12. The patient was discharged on postoperative day 14 when her platelets, lactate dehydrogenase, hemoglobin, and serum creatinine were 228 x 10⁹/L, 368 U/L, 80g/L, and 238.68 mmol/L. The possibility of hyperacute antibody-mediated rejection was low given that she had no preformed donor-specific antibodies and the donor was ABO-compatible. Kidney biopsy could not be performed because of a high risk of bleeding. Her creatinine subsequently decreased to her baseline value of 132.6 mmol/L and has been stable for the last 3 years. She is currently receiving mycophenolate mofetil, tacrolimus, and prednisone.

Patient 3
A 46-year-old Asian woman with end-stage renal disease due to polycystic kidney disease presented for de novo kidney transplant. Her medical history was significant and included polycystic kidney disease and hypertension. Her panel reactive antibody score was 0%. She had been receiving dialysis for 1737 days. She received a kidney transplant from a 51-year-old deceased standard criteria donor who died from an opioid overdose. Before transplant, hemoglobin, serum creatinine, and platelet count were 128 g/L, 601.12 mmol/L, and 132 x 10⁹/L. Intraoperatively, she received cefazolin, 400 mg methylprednisolone, 1000 mg myco-phenolate, and 125 mg thymoglobulin. On postoperative day 1, her platelet count was 89 x 10⁹/L. She was administered 75 mg thymoglobulin, methyl-prednisolone, mycophenolate mofetil, ranitidine, heparin, cotrimoxazole, clotrimazole, valganciclovir, metoprolol, and morphine. She also received hemodialysis due to delayed graft function.

On postoperative day 2, her platelet count decreased to 39 x 10⁹/L. She later received a single dose of 1 mg tacrolimus, which was then discontinued. Thrombotic microangiopathy was suspected and later confirmed by presence of schistocytes, elevated serum lactate dehydrogenase (1376 U/L), and low serum haptoglobin (< 80 mg/L). Her heparin-induced thrombocytopenia assay was negative. Daily therapeutic plasma exchange with 1 volume of fresh frozen plasma was initiated. Her induction therapy was changed to 20 mg basiliximab on postoperative days 3 and 7. On postoperative day 5, her platelet count reached a nadir of 17 x 10⁹/L, after which it increased to > 90 x 10⁹/L by postoperative day 14 (Figure 1C).

Tacrolimus was initiated on postoperative day 5. On postoperative day 18, kidney biopsy revealed fibrin thrombi in the glomerular capillaries and areas with fibrinoid necrosis, which are consistent with thrombotic microangiopathy. The biopsy was negative for acute cellular and antibody-mediated rejection. Therapeutic plasma exchange was continued until postoperative day 25, which is when the platelet count was consistently > 100 x 10⁹/L. The patient was discharged on postoperative day 35 when her platelet, lactate dehydrogenase, hemoglobin, and serum creatinine levels were 141 x 10⁹/L, 246 U/L, 87 g/L, and 751.40 mmol/L. She remained anuric, and on discharge she had to continue receiving hemodialysis because of a nonfunctioning allograft. She was weaned off tacrolimus over a 2-month period, and her platelet count remained stable during that time.

The aforementioned cases describe the development of de novo thrombotic microangiopathy immediately after kidney transplant but before the introduction of calcineurin inhibitors. The patients were managed with therapeutic plasma exchange and subsequently the introduction of calcineurin inhibitors, but thrombotic microangiopathy did not reoccur. One of our patients (patient 3) received a single dose of tacrolimus before the diagnosis of thrombotic micro-angiopathy. However, considering her laboratory values and overall clinical picture, we believe throm-botic microangiopathy was present before adminis-tration. Two of our 3 patients demonstrated good allograft outcomes. However, 1 patient developed allograft loss due to thrombotic micro-angiopathy.

Thrombotic microangiopathy is defined by histopathologic lesions in the arteriole, capillary wall thickening, platelet thrombosis, and luminal obstruction. Platelets and erythrocytes are consumed in the microvasculature of the kidneys and other organs.1 Thrombotic microangiopathy is also characterized by microangiopathic hemolytic anemia, thrombo-cytopenia, and acute kidney injury. Unlike thrombotic thrombocytopenic purpura (which is characterized by defective ADAMTS 13 activity) and atypical hemolytic uremic syndrome (which is characterized by dysregulated complement pathways), the mechanism responsible for thrombotic microangiopathy remains unknown. The mainstay treatment consists of therapeutic plasma exchange and fresh frozen plasma as the replacement fluid.²

The incidence of de novo thrombotic micro-angiopathy after kidney transplant is reportedly 3% to 6%^3-6 however, the follow-up is variable in published studies. In a large series reported by Schwimmer and associates 2.8% of kidney transplant recipients developed de novo thrombotic microangiopathy over a 15-year period and the rate of allograft loss was 22%.⁷ De novo and recurrent thrombotic microangiopathy/hemolytic uremic syndrome are independently associated with the increased risk of graft loss.⁸ A United States Renal Data System analysis of patients who received kidney transplant between 1998 and 2000 reported a dismal survival rate of 50%, and a 3-year incidence of 0.8% was reported for thrombotic microangiopathy.⁹ This analysis also identified multiple additional risk factors, including young recipient, old donor, female recipient, long duration of dialysis before transplant, previous renal transplant, delayed graft function, allograft rejection, high peak panel-reactive antibody, and treatment with mammalian target of rapamycin inhibitors.

Calcineurin inhibitors are a well-established risk factor for developing thrombotic microangiopathy and may cause or aggravate the endothelial injury due to vasoactive, necrotic, and profibrotic activities. Calcineurin inhibitor-induced thrombotic micro-angiopathy has been associated with endothelial damage from tissue ischemia at the time of transplant.¹⁰ There are multiple reports on the association between calcineurin inhibitors and thrombotic microangiopathy, though improvement in some patients has been reported following the withdrawal of calcineurin inhibitors and conversion to belatacept.^11-15While numerous studies suggest that mammalian target of rapamycin inhibitors can be safely used to treat calcineurin inhibitor-associated thrombotic microangiopathy, Yilmatz and associates reported a case of thrombotic micro-angiopathy in association with everolimus,¹⁶ and Saikali, Barone, and Crew have each published reports stating an association between de novo hemolytic uremic syndrome and sirolimus.^17-19 Additionally, several studies associate the concomitant use of sirolimus and calcineurin inhibitors with an augmented risk of developing thrombotic microangiopathy.^20-22 The mechanism responsible for sirolimus’ attenuation or causation of thrombotic microangiopathy may be partially affected by its antiangiogenic effects, that is, inhibition of the repair of injured endothelial cells.^19,20 Alemtuzumab induction therapy was reportedly associated with de novo hemolytic uremic syndrome in a single case, although the patient concomitantly received tacrolimus.²³ Muromonab induction is associated with both de novo and recurrent hemolytic uremic syndrome in several studies.^24-26 Plasma analysis of prothrombin fragments and fibrin degradation products by Pradier and associates indicates that the coagulation cascade is activated and fibrinolytic processes are active during the first 24 hours after administering muromonab.²⁷ Cytomegalovirus²⁸ and parvovirus infections²⁹ and acute antibody-mediated rejection^30,31 also are reportedly associated with posttransplant de novo thrombotic microangiopathy.

The exact mechanism and risk factors for throm-botic microangiopathy could not be determined in this case series. Our patients received thymoglobulin induction therapy, but its association with thrombotic microangiopathy is not apparent. Using the validated Naranjo adverse drug reaction probability scale to analyze these cases, we determined that it is possible that thymoglobulin led to the development of de novo thrombotic microangiopathy in our three patients.³²

However, we cannot entirely rule out other causes of thrombotic microangiopathy. We did not attempt rechallenge with thymoglobulin. Our patients subsequently received induction therapy that consisted of basiliximab or alemtuzumab followed by maintenance therapy with tacrolimus, prednisone, and myco-phenolate mofetil, and thrombotic microangiopathy did not reoccur. Ceasing thymoglobulin and administering therapeutic plasma exchange therapy, with or without intravenous immunoglobulin, resolved microangiopathic hemolytic anemia and thrombocytopenia. Two of our patients continue to demonstrate stable allograft function; however, one patient developed a nonfunctional primary allograft.

This case series describes the development of de novo thrombotic microangiopathy immediately after kidney transplant in patients without any apparent risk factors. Thrombotic microangiopathy resolved after administering standard therapeutic plasma exchange, with or without intravenous immuno-globulin. Induction therapy was changed from thymoglobulin to alemtuzumab or basiliximab, and calcineurin inhibitors were successfully introduced without recurrence.

Volume: 14 Issue: 2 April 2016

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