A clinicopathologic study of thrombotic microangiopathy in IgA nephropathy.

Thrombotic microangiopathy (TMA) occurs in IgA nephropathy, but its clinical significance is not well described. We retrospectively examined a series of 128 patients diagnosed with IgA nephropathy between 2002 and 2008 who had a mean follow-up of 44±27 months. In our series, 53% presented with lesions of TMA, acute or organized, in arteries and/or arterioles. Among patients with TMA, 4% were normotensive, 25% had controlled hypertension, and 71% had uncontrolled hypertension. Of those with uncontrolled hypertension, 26% had malignant hypertension. Histologically, the group with TMA had a significantly greater percentage of sclerotic glomeruli and worse tubulointerstitial fibrosis than those of the group without TMA. However, a significant minority of patients had near-normal histology, with minimal tubular atrophy (20%) and/or <20% interstitial fibrosis (24%). TMA rarely occurred in the absence of significant proteinuria. During follow-up, a doubling of serum creatinine or ESRD occurred in all patients with laboratory evidence of TMA, in 42% of those with morphologic evidence but no laboratory evidence of TMA, and in 11% of those without TMA. In summary, lesions of TMA are frequent in IgA nephropathy and may occur in normotensive patients with near-normal renal histology. Although the pathophysiologic mechanisms involved remain undetermined, the current study rules out severe hypertension or advanced renal disease as sole causes.

Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies.

It is well known that lesions morphologically identical with focal segmental glomerulosclerosis (FSGS) may appear in IgA nephropathy (IgAN). Capsular adhesions without underlying abnormalities in the tuft, often the first sign of FSGS, are frequent in IgAN. In this retrospective study, a new cohort of 128 adult patients with IgAN was used to validate the new Oxford classification system of IgAN, and shown to have highly significant associations with clinical and outcome parameters. We then used these patients to determine the extent to which IgAN could be accounted for in terms of FSGS. Some form of lesion consistent with FSGS, notably hyalinosis and collapsing glomerulopathy, was found in 101 of these patients. No glomerular lesions were found in 16 patients, and 11 had mild lesions not definable as FSGS. Those with FSGS had significantly worse renal survival at 80 months than those without. Comparison of pure forms of FSGS (excluding collapsing glomerulopathy) with cases of FSGS having other glomerular lesions (mesangial hyperplasia, endocapillary hypercellularity, glomerular necroses, extracapillary proliferation) revealed that those with FSGS and other superimposed lesions did significantly worse than cases of pure FSGS at 80 months following diagnosis. Importantly, patients with pure FSGS had relatively poor survival even without other superimposed glomerular abnormalities. Thus, the majority of cases of IgAN can be interpreted as representing one or another variant of FSGS. Hence, interpreting IgAN in terms of FSGS emphasizes the role that podocyte lesions may play in the pathogenesis and progression of this disease.

Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.

Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D(254)G and K(325)N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase.