T-cell receptor signaling in Schimke immuno-osseous dysplasia is SMARCAL1-independent.

Schimke immuno-osseous dysplasia (SIOD) caused by mutations in SMARCAL1 is an ultra-rare disease characterized by specific facial features, skeletal dysplasia, and steroid-resistant nephrotic syndrome, which often leads to kidney failure and requires transplantation. Cellular (T-cell) deficiency, lymphopenia, and infections have been frequently reported, but whether they are due to T-cell-intrinsic defects in T-cell receptor (TCR) signaling associated with SMARCAL1 deficiency or to T-cell-extrinsic effects such as the impaired proliferation of hematopoietic precursors or T-cell-specific immunosuppression after renal transplantation remains unknown. We have explored the effects of SMARCAL1 deficiency on T-cell receptor signaling in primary and immortalized T cells from a 9-year-old SIOD patient under immunosuppression treatment when compared to healthy donors. Immortalized T cells recapitulated the SMARCAL1 deficiency of the patient, as judged by their impaired response to gamma irradiation. The results indicated that TCR-mediated signaling was normal in SIOD-derived immortalized T cells but strongly impaired in the primary T cells of the patient, although rescued with TCR-independent stimuli such as PMA + ionomycin, suggesting that SIOD-associated T-cell signaling is not intrinsically defective but rather the result of the impaired proliferation of hematopoietic precursors or of T-cell-specific immunosuppression. The lack of early thymic emigrants in our patients may support the former hypothesis.

Functional Assessment of Fatigue and Other Patient-Reported Outcomes in Patients Enrolled in the Global aHUS Registry.

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients. METHODS: In this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment. RESULTS: Patients who started eculizumab after the baseline visit (n = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment (n = 295) and those never treated (n = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment. CONCLUSION: These real-world findings confirm the detrimental effects of aHUS on patients' daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.

Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available. CASE-DIAGNOSIS/TREATMENT: We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis. CONCLUSION: Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene.