Eculizumab Rescue Therapy in Patients With Recurrent Atypical Hemolytic Uremic Syndrome After Kidney Transplantation

Abstract

Introduction: Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study.

Methods: All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center.

Results: In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24-66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3-8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18-69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3-54 months after start of eculizumab), 6 patients had eGFR <30 ml/min per 1.73 m². Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%.

Conclusions: Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.

Keywords: atypical hemolytic uremic syndrome; eculizumab; kidney transplantation; thrombotic microangiopathy.

Graphical abstract

Figure 1

eGFR course of patient 3 and 7. Eculizumab was administered at a dose of 1200 mg biweekly (gray bar), or at a dose of 1200 mg with an extended interval (hatched bar). P3 (previously known with aHUS) received a second kidney transplant from a living unrelated donor at the age of 40 years. The transplantation protocol consisted of TAC, MMF, prednisolone, and induction therapy with basiliximab. On day (d) 68 laboratory signs of TMA were seen (T 124 × 10ꝰ/l, haptoglobin <0.10 g/l, LDH 427 U/l). A biopsy (d68) showed active TMA without signs of rejection (C4d negative) and eculizumab was started. After 8.8 months, eculizumab was discontinued. Two months after withdrawal, a slow loss of eGFR was seen (1.7 ml/min per 1.73 m² per month, over a period of 10 months). A kidney biopsy (d491) showed no abnormalities on light microscopy, but with electron microscopy (EM), a widened subendothelial lucent zone with platelet adhesion was seen. Despite discontinuation of tacrolimus, eGFR loss continued. A repeated kidney biopsy (d692) showed double contour formation of the GBM, with mild hyalinosis, and remnants of arteriolar thrombosis in the arterioles. C4d staining was negative. With EM, widening of the subendothelial zone with electron-lucent material was seen. Laboratory evaluation did not reveal consistent TMA signs. No increase in proteinuria (0.16 g/10 mmol) and no hematuria was observed. On d694 eculizumab was restarted, resulting in stabilization of eGFR. Treatment with eculizumab at extended dose interval targeting drug levels of 50−100 μg/ml was ongoing at last follow-up. P7 (previously known with aHUS) received a second DBD kidney transplant at the age of 30 years. The transplantation protocol consisted of TAC, MMF, prednisolone, and induction therapy with alemtuzumab. On d209, a biopsy was performed because of proteinuria (urine protein-creatinine ratio 3.3 g/10 mmol). The biopsy showed no abnormalities but was relatively small. A second biopsy (d212) showed active TMA, without signs of rejection (C4d negative). Tacrolimus was switched to belatacept. Because of eGFR loss and ongoing proteinuria, a third biopsy (d265) was performed, showing again active TMA. On d267 laboratory signs of TMA were observed (T 209 × 10ꝰ/l, haptoglobin <0.20 g/l, LDH 351 U/l) and eculizumab was started. A reduction in proteinuria was seen (urine protein-creatinine ratio <0.20 g/10 mmol). After 9.1 months, eculizumab was discontinued. After withdrawal of eculizumab, a slow loss of eGFR was observed (1.9 ml/min per 1.73 m² per month, over a period of 16 months). A biopsy (d1013) showed endothelial swelling without thrombi. C4d staining was negative. No EM was performed. There were no clinical signs of TMA, and no increase of proteinuria (0.07 g/l) or significant hematuria (1+). Eculizumab was restarted (d1030), resulting in improvement of eGFR. At last follow-up, the patient was still receiving treatment with eculizumab with an extended dose interval targeting drug levels of 50 to 100 μg/ml. eGFR, estimated glomerular filtration rate.