Metastatic lung adenocarcinoma- associated thrombotic microangiopathy in a renal transplant recipient

Abstract

Thrombotic microangiopathy (TMA) after renal transplantation can be a diagnostic challenge. TMA can occur with calcineurin inhibitors, allograft rejection, infection, mutations in complement regulatory proteins and autoimmunity. A 52-year-old male renal transplant recipient presented with extensive deep vein thrombosis. He developed transfusion-dependent microangiopathic haemolytic anaemia with thrombocytopenia. He did not respond calcineurin inhibitor cessation, eculizumab or plasma exchange. ADAMTS13 and complement levels were normal. Infection and autoimmune screens were negative. A diagnosis of metastatic adenocarcinoma was made on bone marrow biopsy. This represents a rare case of malignancy-associated TMA in a renal transplant recipient. Early diagnosis can facilitate the prompt initiation of chemotherapy which is the only treatment option.

Background

Thrombotic microangiopathy (TMA) after renal transplantation is a diagnostic dilemma. Post-transplant TMA can occur with medications, allograft rejection, infection, autoimmunity and mutations in complement regulatory proteins. The authors present a rare case of malignancy-associated TMA in a renal transplant recipient, a phenomenon that has not been described previously. Associated with a high mortality rate, the only therapeutic option for malignancy-associated TMA is chemotherapy. The prompt initiation of chemotherapy may alter the disease course.

Case presentation

A 52-year-old male renal transplant recipient presented with right lower limb oedema. His medical history was significant for hypertension-induced renal failure with a dialysis vintage of 6 years. He had a 40 pack-year history of smoking and quit 7 years prior. Pretransplant malignancy screening including chest X-ray, CT of the abdomen with contrast and renal ultrasound were unremarkable. Prostate specific antigen (PSA) was 0.6 ng/mL and prostate examination was normal. Deceased donor dual renal transplant occurred 4 months prior with 4/6 human leukocyte antigen mismatch, low and moderate titres of class 1 and class 2 donor-specific antibodies (DSAs), respectively. While T and B complement-dependent cytotoxicty crossmatches were negative, due to the presence of DSAs he received thymoglobulin, plasma exchange (PLEX) and intravenous immunoglobulin for induction. Tacrolimus, mycophenolate and prednisone were used for maintenance immunosuppression. He achieved a creatinine of 110 micromoles/L 1 week after transplant.

Investigations

Doppler ultrasound of the right lower limb revealed extensive deep vein thrombosis involving the saphenous and common femoral veins. The patient was admitted for warfarin initiation and received bridging intravenous heparin.

Two weeks later, he developed severe anaemia with a haemoglobin of 5.8 g/dL (table 1), thrombocytopenia and graft dysfunction with a creatinine of 184 micromoles/L (table 2). His regular antihypertensive medications (prazosin and diltiazem) were ceased due to borderline low blood pressure. Serological testing demonstrated high lactate dehydrogenase (LDH), bilirubin and reticulocytes with a low haptoglobulin and fibrinogen (tables 2 and 3). Repeated blood films reviewed by a haematologist revealed schistocytosis. Coombs test and heparin-induced thrombocytopenia screening were negative (table 3). According to the 4T score, the patient was at low risk for heparin-induced thrombocytopenia.¹ Antiphospholid syndrome screening was negative. ADAMTS13 and complement levels (C3, C4, complement factor I and complement factor H) were normal (tables 3 and 4). Repeated bacterial and viral screens, including cytomegalovirus PCR, were negative. While the fibrinogen normalised within 48 hours, the severe haemolysis continued with transfusion-dependent anaemia without any further change in fibrinogen. Transthoracic echocardiography revealed a large pericardial effusion with normal ventricular function. No valvular vegetations were identified.

Table 1.

Haematology results during admission

Full blood count	Normal range	Presentation	2 weeks	5 weeks
White cell count (109/L)	4.0–11.0	5.8	4.4	7.0
Haemoglobin (g/dL)	13.0–18.0	10.2	5.8	5.8
Haematocrit (L/L)	0.380–0.490	0.296	0.168	0.170
Mean cell volume (fL)	80–100	90	87	70
Mean cell haemoglobin (pg)	27–32	31	30	31
Platelets (109/L)	150–400	203	108	51
Neutrophils (109/L)	1.8–7.7	4.5	2.5	5.5
Lymphocytes (109/L)	1.0–4.0	0.8	0.3	0.5
Monocytes (109/L)	0.1–0.8	0.2	0.2	0.6
Eosinophils (109/L)	<0.6	0.0	0.0	0.0
Basophils (109/L)	<0.3	0.0	0.0	0.0
Film comment		Elliptocytes	Red cell fragments	Red cell fragments

Table 2.

Biochemistry results during admission

Biochemistry	Normal range	Presentation	2 weeks	5 weeks
Sodium (mmol/L)	135–145	137	134	132
Potassium (mmol/L)	3.5–5.2	3.6	4.3	3.3
Chloride (mmol/L)	95–110	101	94	96
Bicarbonate (mmol/L)	22–32	20	25	19
Urea (mmol/L)	2.1–8.1	9.8	12.7	27.8
Creatinine (μmol/L)	60–110	113	184	296
GFR estimate (mL/min)	>60	64	36
Albumin (g/L)	35–52	40	42	30
Urate (mmol/L)	0.24–0.48	0.26
Corrected calcium (mmol/L)	2.10–2.60	2.50	2.47	2.48
Magnesium (mmol/L)	0.59	0.59	0.68	0.71
Phosphate (mmol/L)	0.75–1.50	1.06	1.26	1.55
Tacrolimus trough (ng/mL)	5–15	5.4	<2
Folate (nmol/L)	9.3–52.6		18.5
Vitamin B12 (pmol/L)	138–652		764
Iron (μmol/L)	11–30		9
Ferritin (μg/L)	30–300		4024
Transferrin (g/L)	1.7–3.6		2.0
Transferring saturation (%)	20–50		17
Haptoglobin (g/L)	0.30–2.00		<0.08	<0.08
Reticulocytes (109/L)	10–100		168	270
Bilirubin (μmol/L)	3–20		23	65
Lactate dehydrogenase (U/L)	120–250		1263	13 529

Table 3.

Coagulation profile during admission

Coagulation	Normal range	Presentation	2 weeks	5 weeks
International normalised ratio	<1.2	1.2	1.8	1.6
Prothrombin time	12–16	16	21	19
Activated Partial Thromboplastin Time	24–36	35	38	72
Fibrinogen (g/L)	2.0–4.0		1.7	4.3
Anticardiolipin antibodies (U/mL)	<15	<9	<9
Lupus anticoagulant		Not detected
Factor 5 Leiden		Not detected
Homocysteine (μmol/L)	5.5–16.2	8.9
Beta 2 glycoprotein (EU)	<20		3
Coombs test			Negative
Heparin-dependent platelet antibodies			Negative
ADAMTS-13 activity (%)	40–130		90

Table 4.

Complement levels

Complement	Normal range	2 weeks
Complement C3 (g/L)	0.82–1.85	1.78
Complement C4 (g/L)	0.15–0.53	0.35
Complement factor H (mg/L)	>70	791.00
Complement factor I (mg/L)	>7	44.20

Graft function deteriorated further. Doppler ultrasound did not reveal thrombus in transplant arteries or veins and a renal biopsy was performed. Renal histology showed tubulitis (t1) and interstitial infiltrates (i2) suspicious for cellular rejection with no features of antibody-mediated rejection (AMR) with negative C4d staining. There was evidence of interstitial oedema and ischaemic wrinkling of the glomeruli though no glomerular thrombi were seen. Laboratory testing supported a diagnosis of TMA causing microangiopathic haemolytic anaemia (MAHA).

Differential diagnosis

Disseminated intravascular coagulation causing coagulopathy, haemolysis and thrombocytopenia is an important differential in the context of cancer. However, such profound haemolysis with high LDH requiring multiple blood transfusions is rare in DIC. Moreover, the hypofibrinogenaemia was mild with resolution within 48 hours. The fibrinogen remained normal with ongoing transfusion-dependent haemolysis. Therefore, DIC was considered less likely.

TMA following renal transplantation has a wide differential diagnosis. Drug-induced TMA is common.² The patients’ regular tacrolimus and trimethoprim-sulfamethoxazole were ceased due to the known association. An infective insult was another possible cause. Extensive infective screens were negative and broad-spectrum antibiotics were provided. AMR was postulated; however, the lack of histological features of AMR and C4d on renal histology opposed this. Given potential cellular rejection on histology, pulse intravenous methylprednisolone was administered. Investigations for autoimmune and complement-mediated diseases were negative.

The patient’s native kidney biopsy was reviewed which showed evidence of microvascular thrombi with fibrointimal hyperplasia. The possibility of recurrent atypical haemolytic uraemic syndrome (aHUS) was considered and he was given PLEX followed by eculizumab. Despite five PLEX treatments followed by eculizumab, he remained transfusion dependent and deteriorated on day 30 (figure 1).

Figure 1.

Clinical course and treatment through admission.

Outcome and follow-up

The patient worsened clinically with fevers to 39 degrees celsius, dyspnoea and back pain. Disseminated fungal infection was considered and he had a CT of the chest. Imaging showed a right lower lobe spiculated opacity, mediastinal lymph nodes with pleural and pericardial effusions. MRI of the back revealed a diffuse infiltrative process involving the spine and bony pelvis. Pleural aspirate and bronchoalveolar lavage were non-diagnostic. Bone marrow trephine demonstrated extensive marrow necrosis with a focus of malignant cells in keeping with metastatic adenocarcinoma (figure 2). Cells were positive for thyroid transcription factor 1 supporting primary lung malignancy. The patient continued to deteriorate and, due to his poor Eastern Cooperative Oncology Group performance status, was unsuitable for chemotherapy. He was then palliated, dying a week after the diagnosis.

Figure 2.

Bone marrow trephine revealing a cluster of malignant cells on a background of necrotic bone marrow.

Discussion

We report a case of probable TMA causing MAHA in the setting of a recent renal transplant. In retrospect, the MAHA was potentially a paraneoplastic phenomenon secondary to disseminated adenocarcinoma of the lung. To our knowledge, this is the first report of cancer-related MAHA (CR-MAHA) in the setting of solid organ transplantation. While the clinical course, laboratory, imaging and histology results make cancer-related TMA the most likely cause, there were other possible contributing factors.

TMA in the setting of renal transplant is a diagnostic dilemma with multiple potential aetiologies.^{3 4} Reported incidence of TMA after renal transplant varies from 1% to 14%.^{5 6} Potential causes include medications,^{2 7 8} AMR,^{9 10} infection and haemolytic uraemic syndrome or complement mutations causing aHUS.^{11 12} Although complement levels were normal, due to rapid deterioration, we were unable to test for mutations. However, the lack of response to eculizumab suggests that this is less likely. This report extends the differential to include CR-MAHA, a paraneoplastic syndrome resulting in Coombs’ negative haemolytic anaemia with thrombocytopenia.

The patients’ pretransplant malignancy screen in the form of a chest X-ray, CT scan of the abdomen and PSA were normal. A CT of the chest was not done prior as he was asymptomatic with no suspicious findings on chest X-ray. Chest CT should be considered in future patients with significant smoking history as immunosuppression following transplant may have contributed to the development of a metastatic malignancy.¹³ While in hospital, the patient deteriorated rapidly, from functioning independently to being bed bound requiring assistance with most activities by week 3 of his admission. The authors believe that the swift functional decline provides clinical support for the diagnosis of CR-MAHA.

The largest review of CR-MAHA showed metastatic adenocarcinoma of the lung made up 8.4% of cases.¹⁴ The patient had classical clinical and laboratory features of CR-MAHA with venous thrombosis, dyspnoea, bone pain, normal ADAMTS13 and bone marrow metastases. The pathogenesis of CR-MAHA remains unclear. One theory proposes that malignant cell infiltration into bone marrow causes intraluminal thrombi, red cell fragmentation and platelet destruction.¹⁵ The prognosis of patients with CR-MAHA is poor with 46.5% of patients dying within a month after diagnosis. Chemotherapy directed at the underlying malignancy offers the only potential treatment. There are reports of complete MAHA resolution within just one cycle of chemotherapy.¹⁴

A component of medication-related TMA cannot be excluded. TMA caused by calcineurin inhibitors occurs in 1% of patients after transplant and is typically restricted to the kidneys.¹⁶ This disease can mimic AMR and a biopsy is required to exclude this. The mechanism of tacrolimus-related TMA is not fully understood, however, may be related to a dose-dependent inhibition of prostacyclin, leading to vasoconstriction.^{17 18} With elevated drug levels, some centres advocate for drug conversion and others alter dosing to aim for normal levels.¹⁶ Management is controversial in the presence of normal drug levels. In the setting of severe renal dysfunction with uncertainty about the diagnosis of drug-induced TMA, PLEX and eculizumab may be considered.¹⁹ While drug-induced TMA may be associated with incomplete and slow renal recovery, it is rarely associated with the rapidly progressive and treatment-resistant course seen in this case.²⁰

This case demonstrates the diagnostic challenge of TMA and MAHA in the setting of renal transplant. MAHA may rarely be the presenting manifestation of an underlying malignancy. Bone marrow biopsy may be a useful diagnostic tool to acquire a histological diagnosis. Earlier recognition of CR-MAHA may result in better outcomes through the timely administration of chemotherapy.¹³

Learning points.

• Bone marrow biopsy may be a helpful investigation in the setting of microangiopathic haemolytic anaemia of unclear cause.

• Metastatic cancer should be a considered differential diagnosis in patients presenting with thrombotic microangiopathy.

• High index of suspicion with prompt diagnosis may facilitate the early administration of chemotherapy, the only disease-modifying intervention.