非典型溶血性尿毒症症候群

BACKGROUND: Complement dysregulation is a key mechanism underlying atypical hemolytic uremic syndrome and complement-mediated thrombotic microangiopathy in kidney transplantation, and is associated with post-transplant recurrence, graft dysfunction, and graft loss. Although Western cohort data are well established, integrated transplant outcome data combining genetic analysis, anti-factor H (AFH) antibody profiling, and individualized therapy from Indian and other South Asian populations remain limited, despite a distinct biologic profile in this region. AIM: To evaluate clinical characteristics, complement biologic profile, post-transplant recurrence, and graft outcomes in kidney transplant recipients with complement dysregulation managed at a tertiary transplant center in Central India, with particular emphasis on genotype-phenotype correlation and outcomes in a resource-constrained setting. METHODS: This single-center retrospective cohort study included kidney transplant recipients with evidence of complement dysregulation identified from January 2018 to March 2025 at a tertiary transplant center in Central India. Complement dysregulation was defined as the presence of a pathogenic or likely pathogenic complement gene variant, AFH antibody positivity, or both. Genetic testing was performed using multiplex ligation-dependent probe amplification and/or clinical exome sequencing covering the alternative complement pathway gene panel, and AFH antibodies were measured using enzyme-linked immunosorbent assay. All patients underwent comprehensive evaluation including hematological, biochemical, and complement (C3, C4) profiling, with kidney biopsy when clinically feasible. The primary outcome was post-transplant recurrence of thrombotic microangiopathy; secondary outcomes included graft loss, patient survival, renal function, and treatment response. Median post-transplant follow-up was approximately 12 months. RESULTS: Of the 335 patients evaluated for complement abnormalities, 136 had complement dysregulation, of whom 38 underwent kidney transplantation and constituted the study cohort. Mean age was 36.3 ± 9.3 years, 84.2% were male, and 97.4% had hypertension; 73.7% were on maintenance hemodialysis at diagnosis. Complement genetic abnormalities were identified in 34/38 recipients (89.5%), with CFHR1-CFHR3 structural variants predominating (78.9%) and complement factor H abnormalities in 18.4%; no pathogenic variants were detected in CFI, C3, CD46, THBD, or DGKE. AFH antibodies were detected in 15 patients (39.5%), with 11 having concomitant genetic abnormalities. Pre-transplant immunomodulation with plasma exchange and rituximab reduced mean AFH antibody levels from 179.9 AU/mL to 59.7 AU/mL (approximately 67% reduction). Post-transplant recurrence occurred in 7/38 recipients (18.4%), all biopsy-confirmed, donor-specific antibody and C4d-negative, and clustered within 1-3 weeks of transplantation; recurrence occurred exclusively in patients with complement genetic abnormalities, and not in those with isolated AFH antibody positivity. All 7 recipients with recurrence maintained functioning grafts after disease-directed therapy. Overall patient survival was 94.7%; two deaths (5.3%) were attributable to severe infections, and one graft loss followed invasive mucormycosis unrelated to recurrent disease. CONCLUSION: In this Indian transplant cohort with complement dysregulation, CFHR1-CFHR3 structural variants and AFH antibody positivity defined the predominant biologic substrate, post-transplant recurrence clustered within the early weeks after transplantation, and disease-directed therapy with plasma exchange, rituximab, and selective eculizumab achieved durable graft preservation despite limited access to long-term complement inhibition. Comprehensive pre-transplant complement evaluation and biologic risk stratification are essential for safe transplantation in complement-mediated kidney disease, particularly in resource-limited settings.

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.