非典型溶血性尿毒症症候群

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder that affects individuals of any age. It is caused by genetic abnormalities of the alternative complement pathway, arising from inherited or de novo mutations, or from acquired factors such as autoantibodies against complement proteins, including complement factor H. Clinically, aHUS is characterized by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. However, its clinical presentation may be difficult to distinguish from typical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. aHUS is driven by uncontrolled activation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis. Atypical HUS may also occur after kidney transplantation, either as recurrence of the native disease or as de novo post-transplant thrombotic microangiopathy. The diagnosis of post-transplant aHUS relies on the presence of the above-mentioned classic triad and the exclusion of secondary causes such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS. The pathophysiology is similar, involving either genetic mutations affecting complement proteins or acquired dysregulation due to autoantibodies. Historically, plasma exchange was used to replace dysfunctional complement regulators and remove circulating autoantibodies, with variable success. After transplantation, the disorder may either recur or develop de novo. In the past, plasmapheresis was considered beneficial. More recently, the availability of eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, has become the treatment of choice, either as monotherapy or with plasma exchange. However, uncertainties remain regarding the optimal duration and dosing of long-term therapy, particularly in transplant recipients.

The complement cascade is part of the innate immune system, and it provides an important line of defense against infections. Inappropriate or excessive activation of this system, however, is also a driver of kidney inflammation in many diseases. Complement inhibitory drugs have now been approved by the US Food and Drug Administration for the treatment of 5 renal diseases: atypical hemolytic uremic syndrome, C3 glomerulopathy, immune-complex membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibody-associated vasculitis, and IgA nephropathy. Ongoing clinical trials are testing new anticomplement drugs and additional renal indications for complement inhibitors. Most immunosuppressive drugs do not directly block complement activation, and the use of complement inhibitors for renal indications is likely to expand in the coming years. Complement activation in renal diseases also generates plasma, urine, and tissue biomarkers, and laboratory evaluation of the complement system is an important part of the clinical work-up of patients with these inflammatory and autoimmune conditions. It is essential, therefore, that nephrologists are familiar with the available anticomplement drugs and with complement diagnostics.

BACKGROUND: Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. METHODS: We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. RESULTS: Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. CONCLUSIONS: PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.

Venous thrombosis is initiated by endothelial cell activation triggered by reduced blood flow and venous stasis. Innate immune cells (neutrophils and monocytes) and platelets adhere to activated endothelial cells via P-selectin and von Willebrand factor multimers, respectively. Platelet activation involves integrin activation, P-selectin expression, and the release of ADP, polyphosphates, and soluble complement regulators. Neutrophils bind to the activated platelets and endothelial cells and release neutrophil extracellular traps. Activated monocytes express tissue factor. The interplay of these exacerbated immune and thrombotic events ultimately results in thrombosis, a process now referred to as immunothrombosis. Atypical hemolytic uremic syndrome, aHUS, is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement. Genetic analyses of Japanese patients with aHUS predominantly identified a unique gain-of-function C3 variant, p.Ile1157Thr. Patients with this variant showed favorable outcomes despite frequent relapses.

The complement system, which plays a key role in innate immunity, facilitates the elimination of foreign and endogenous substances in the body. Consequently, while a balance between complement activation and regulation is typically maintained, a disruption of this balance can lead to various diseases. Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS) are diseases in which abnormal complement regulatory factors cause excessive complement activation. To accurately diagnose diseases such as aHUS, international standard complement tests including activation markers such as Ba and sC5b-9 are used. The Japanese Society for Complement Research has contributed to the standardization of the International Complement Society and has established this testing system in Japan. In the present study, we revealed that the Ba level serves as a good predictive marker for the onset of thrombotic microangiopathy, a complication that typically occurs following hematopoietic stem cell transplantation. We also showed that complement activation levels rise more frequently postpartum than during pregnancy. Considering the growing number of drugs targeting the complement pathway, it is speculated that these complement markers will become available for testing in clinical settings in Japan.