Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA-TMA; approximately 60% of TA-TMA patients have complement dysregulation. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal membrane-attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post-transplant. We present two cases of kidney TA-TMA due to unknown causes, suspected antibody-mediated rejection, or calcineurin inhibitor (CNI)-related toxicity that developed on day 1 or 2 post-kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA-TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA-TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA-TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA-TMA as early as the diagnosis of refractory to PE.

Ikeda T ，Okumi M ，Unagami K ，Kanzawa T ，Sawada A ，Kawanishi K ，Omoto K ，Ishida H ，Tanabe K ... -  《-》

Prevention and treatment of atypical haemolytic uremic syndrome after kidney transplantation.

Atypical haemolytic uraemic syndrome is a rare disorder characterized by an over-activated, dysregulated alternative complement pathway due to genetic mutation and environmental triggers. Atypical haemolytic uraemic syndrome is a serious, life-threatening disease characterized by thrombotic microangiopathy, which causes haemolytic anaemia, thrombocytopaenia, and acute renal failure. Since recurrences of atypical haemolytic uraemic syndrome frequently lead to end-stage kidney disease even in renal allografts, kidney transplantation for patients with end-stage kidney disease secondary to atypical haemolytic uraemic syndrome has long been contraindicated. However, over the past several years, advancements in the management of atypical haemolytic uraemic syndrome have allowed successful kidney transplantation in these patients. The key factor of this success is eculizumab, a humanized anti-C5 monoclonal antibody, which inhibits terminal membrane-attack complex formation and thrombotic microangiopathy progression. In the setting of kidney transplantation, there are different possible triggers of post-transplant atypical haemolytic uraemic syndrome recurrence, such as brain-death related injury, ischaemia-reperfusion injury, infections, the use of immunosuppressive drugs, and rejection. Principal strategies are to prevent endothelial damage that could potentially activate alternative complement pathway activation and subsequently lead to atypical haemolytic uraemic syndrome recurrence in kidney allograft. Published data shows that prophylactic eculizumab therapy is highly effective for the prevention of post-transplant atypical haemolytic uraemic syndrome recurrence, and prompt treatment with eculizumab as soon as recurrence is diagnosed is important to maintain renal allograft function. Further study to determine the optimal dosing and duration of prophylactic therapy and treatment of post-transplant atypical haemolytic uraemic syndrome recurrence is needed.

Okumi M ，Tanabe K 《-》

Eculizumab in secondary atypical haemolytic uraemic syndrome.

Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.

Cavero T ，Rabasco C ，López A ，Román E ，Ávila A ，Sevillano Á ，Huerta A ，Rojas-Rivera J ，Fuentes C ，Blasco M ，Jarque A ，García A ，Mendizabal S ，Gavela E ，Macía M ，Quintana LF ，María Romera A ，Borrego J ，Arjona E ，Espinosa M ，Portolés J ，Gracia-Iguacel C ，González-Parra E ，Aljama P ，Morales E ，Cao M ，Rodríguez de Córdoba S ，Praga M ... -  《-》

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy accompanied by renal arteriolar C4d deposition.

HSCT-associated thrombotic microangiopathy (TA-TMA) is a severe complication with a poor prognosis. Recently, it has been reported that complement system dysregulation, such as CFH autoantibodies and deletions CFH-related genes 3 and 1, induced TA-TMA. In addition, C4d-positive renal arterioles are both a good marker of complement system activation and a useful diagnostic tool for TA-TMA. Because dysregulation of the complement system is associated with TA-TMA, the complement system might be a therapeutic target, such as eculizumab, a terminal complement inhibitor. Herein, we describe an eight-yr-old boy who developed TA-TMA accompanied by severe renal dysfunction. His renal specimen showed diffuse C4d deposition in the renal arterioles, which is consistent with TA-TMA. Although the patient gradually improved without eculizumab, renal arteriolar C4d staining in sample with TA-TMA shows the complement system activation and may guide the target therapy using the eculizumab.

Sakamoto K ，Imamura T ，Osone S ，Nishimura A ，Nishida M ，Ishida H ，Hosoi H ... -  《-》

Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome - a case report.

Nunius C ，Büttner-Herold M ，Bertz S ，Schiffer M ，Buchholz B ... -  《BMC Nephrology》