Acute renal allograft thrombosis in 'seronegative' antiphospholipid syndrome.

Sir,

We present a 32-year-old Asian female with ESRD secondary to lupus nephritis who received a deceased donor kidney transplant but lost the graft 5 days later. Her medical history was significant for a pregnancy complicated by hypertension and intra-uterine growth retardation with absent end diastolic flow. This necessitated emergency caesarian section at 28 weeks of gestation. Pathology of the placenta revealed vascular thrombosis and decidual necrosis.

At this hospitalization, the patient received a four-antigen match deceased donor kidney without intra-operative complications. The allograft functioned promptly after transplantation. However, on post-operative Day 5, she acutely decompensated with hypotension and diminished level of consciousness. Surgical exploration revealed a pale non-viable kidney necessitating a nephrectomy.

Histologic examination revealed that one of the hilar vessels had a luminal thrombus associated with haemorrhage (Figure 1A). Thrombi or endothelial swelling was also noted in afferent arterioles and glomerular capillaries (Figure 1B). Interstitial inflammation, tubulitis and arteritis were absent. Immunofluorescence was negative for immunoglobulins and C3 in the glomeruli and C4d in peritubular capillaries, ruling out recurrent lupus and humoral rejection. At the time of transplant, tests for lupus anti-coagulant and anti-cardiolipin antibody were negative on two separate occasions. However, her serum did show increased thrombotic activity in a new test performed in our laboratories, which is a proposed surrogate test in patients at risk for thrombosis (Figure 1C). A diagnosis of graft failure due to thrombotic microangiopathy and seronegative anti-phospholipid antibody syndrome was rendered.

Fig. 1

(A) Explant nephrectomy performed on Day 5. There is extravasation of red cells and fibrin in the muscular wall and thrombosis of the renal artery (H&E ×100). (B) Explant nephrectomy. Glomerular capillary thrombi and thickening and endothelial swelling in adjacent arteriole (H&E ×200). (C) Kinetics of kallikrein activation by negatively charged molecules. Patient serum (30 μl) or control human serum (30 μl) was incubated with 20 μl of oversulfated glycosaminoglycans (OS-GAG) at a final concentration of 0, 2, 20 and 200 μg/ml at 37°C for 5 min. Kallikrein amidolytic activity was assessed by addition of 150 μl of 50 mM N-Benzoyl-Pro-Phe-Arg-p-nitroanilide hydrochloride chromogenic substrate. O.D. readings were taken every minute for 60 min. The auto-activated kallikrein activities (without OS-GAG induction) in patient serum suggest the presence of a negatively charged contact system inducer in the patient's blood.

Thrombosis is the major cause of graft loss in the first year of survival following kidney transplantation. The APLS is a hypercoagulable state that predisposes patients to arterial and/or venous thromboses that can result in graft failure [1]. A 2006 consensus conference defined patients with definite APLS as having at least one laboratory criterion (e.g. persistent, elevated titres of APL) and one clinical criterion (e.g. deep vein thrombosis, pregnancy complications) [2]. However, APLS encompasses a wide range of clinical symptoms [3]. Notably, a subset of patients manifest thrombotic complications without detectable antiphospholipid titres. These patients are classified as having seronegative antiphospholipid syndrome (SNAPS) [2]. This patient's history of pregnancy complications was subtle, and the absence of LAC and ACA antibodies did not raise the possibility of APLS at the time of transplantation. We therefore propose the diagnosis of SNAPS in this patient. SNAPS increases the risk of graft thrombosis and necessitates anti-coagulation before and after the transplant operation [4]. Therefore, a second transplant operation in this patient would be considered high risk and would require peri-operative anti-coagulation [5]. This case highlights the difficulty of diagnosing ‘seronegative’ APLS within the current diagnostic guidelines. It also identifies a need for new diagnostic tests to identify at-risk patients.

Conflict of interest statement. None declared.