Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA. Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency. 983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5th decade and women after the 6th. Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05. This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.

Tubulointerstitial damage is a common histopathological feature of acute and chronic renal diseases and a prognostic indicator of renal function outcome. Monocytes infiltrating the interstitium, through the release of cytokines and/or growth factors, may play a key role in the pathogenesis of tubulointerstitial damage. Monocyte chemotactic peptide-1 (MCP-1) is a specific and powerful chemoattractant and activating factor for monocytes. This study investigated MCP-1 expression and its correlation with monocyte infiltration and tubulointerstitial damage in biopsies of patients with acute interstitial nephritis (AIN) and a chronic glomerulonephritis, namely immunoglobulin. A nephropathy (IgAN), often characterized by tubulointerstitial involvement. Six patients with AIN and 20 patients with IgAN, nine with mild (G1 to 2) and 11 with moderate to severe histologic lesions (G3 to 5), were studied. MCP-1 gene and protein expression were evaluated by in situ hybridization and immunohistochemistry. Infiltrating CD68-positive cells were identified as monocytes. MCP-1, weakly expressed in normal kidneys, was clearly upregulated in AIN biopsies. The gene and the protein expression were primarily localized in tubular and glomerular parietal epithelial cells, as well as in infiltrating mononuclear cells. In IgAN, a striking increase in MCP-1 mRNA and protein expression was observed only in the biopsies with moderate to severe lesions, with a pattern of expression similar to AIN. The MCP-1 expression strictly correlated with monocyte infiltrates and tubulointerstitial damage. In addition, the urinary excretion of this chemokine was studied in 17 IgAN patients. MCP-1 protein concentration was higher, compared with healthy subjects, in IgAN patients, especially in the G3 to 5 group, and directly correlated with the renal MCP-1 gene expression. In conclusion, these data suggest that production of MCP-1 in the tubulointerstitial compartment may play a key role in modulating monocytes influx and, consequently, tubulointerstitial damage.

Increasing evidence demonstrates a phenotypic plasticity of endothelial cells (ECs). Endothelial-to-mesenchymal transition (EndMT) contributes to the development of tissue fibrosis. However, the pathogenic factors and signalling pathways regulating this process in ischaemia/reperfusion (I/R) injury are still poorly understood. We investigated the possible role of complement in the induction of this endothelial dysfunction in a swine model of renal I/R injury by using recombinant C1 inhibitor in vivo. Here, we showed that I/R injury reduced the density of renal peritubular capillaries and induced tissue fibrosis with generation of CD31⁺/α-SMA⁺ and CD31⁺/FPS-1⁺ cells indicating EndMT. When we inhibited complement, the process of EndMT became rare, with preserved density of peritubular capillaries and significant reduction in renal fibrosis. When we activated ECs by anaphylatoxins in vitro, C3a and C5a led to altered endothelial phenotype with increased expression of fibroblast markers and decrease expression of specific endothelial markers. The activation of Akt pathway was pivotal for the C3a and C5a-induced EndMT in vitro. In accordance, inhibition of complement in vivo led to the abrogation of Akt signalling, with hampered EndMT and tissue fibrosis. Our data demonstrate a critical role for complement in the acute induction of EndMT via the Akt pathway. Therapeutic inhibition of these systems may be essential to prevent vascular damage and tissue fibrosis in transplanted kidney.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures. To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS). The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE. In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 [41.7%] vs 38 of 58 [65.5%], respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001). From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment. ClinicalTrials.gov: NCT01034969.