Role of the Skin Biopsy in the Diagnosis of Atypical Hemolytic Uremic Syndrome

Abstract

Introduction Atypical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. In the absence of complement inhibition, progressive clinical deterioration occurs. We postulated that a biopsy of normal skin could corroborate the diagnosis of aHUS via the demonstration of vascular deposits of C5b-9. Materials and methods Biopsies of normal skin from 22 patients with and without aHUS were processed for routine light microscopy as well as immunofluorescent studies. An assessment was made for vascular C5b-9 deposition immunohistochemically and by immunofluorescence. The biopsies were obtained primarily from the forearm and or deltoid. Results Patients with classic features of atypical HUS showed insidious microvascular changes including loose luminal platelet thrombi except in two patients in whom a striking thrombogenic vasculopathy was apparent in biopsied digital ulcers. Extensive microvascular deposits of the membrane attack complex (MAC)/ C5b-9 were identified excluding one patient in whom eculizumab was initiated prior to biopsy. In 5 of the 7 patients where follow-up was available, the patients exhibited an excellent treatment response to eculizumab. Patients without diagnostic clinical features of atypical HUS failed to show significant vascular deposits of complement except two patients with TTP including one in whom a Factor H mutation was identified. Conclusion In a clinical setting where aHUS is an important diagnostic consideration, extensive microvascular deposition of C5b-9 supports the diagnosis of either aHUS or a subset of TTP patients with concomitant complement dysregulation; significant vascular C5b-9 deposition predicts clinical responsiveness to eculizumab.

Post-bone marrow transplant thrombotic microangiopathy

“…However, the majority of these patients are at high risk for bleeding complications following biopsy of the kidney. In a recent study, Magro et al 26 used skin biopsies to diagnose aHUS, and they found extensive microvascular depositions of C5b-9, which supported the diagnosis.…”

Eosinophilic Granulomatosis With Polyangiitis With Thrombotic Microangiopathy

“…In our patient, a skin biopsy revealed C3 deposition on the vessel wall. Magro et al 9 reported that a skin biopsy is of value in establishing a diagnosis of TMA based on the microvascular deposition of complement in the dermis and subcutaneous fat. Because hypocomplementemia also existed in our patient, an alternative pathway of complement may have been associated with his TMA.…”

Routine complement blood tests are insensitive for alternative complement activation

“…Immunohistochemistry for C9 or membrane attack complex deposition is possible in some laboratories, and can be performed on random skin biopsies. 4 It is worth noting that alternative complement activation occurs in other chronic conditions, such as diabetic vasculopathy, 5 so clinical correlation is required in interpreting results. Currently available serological testing is not helpful in this area.…”

“…Tests to support alternative pathway activation are those detecting activation and/or depositions of complement factors C5–C9. Immunohistochemistry for C9 or membrane attack complex deposition is possible in some laboratories, and can be performed on random skin biopsies . It is worth noting that alternative complement activation occurs in other chronic conditions, such as diabetic vasculopathy, so clinical correlation is required in interpreting results.…”