Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.

Functional activity of alveolar and peripheral cells in patients with human acquired immunodeficiency syndrome and pulmonary tuberculosis.

We compared the peripheral and pulmonary response to assess the phagocytic activity of monocytes/macrophages and neutrophils and the lymphoproliferative response (LPR) against Mycobacterium tuberculosis antigens from 21 AIDS patients, presenting at diagnosis with active pulmonary tuberculosis (TB), other non-TB pulmonary infection, or no pulmonary infection, as well as patients with active pulmonary TB and healthy control subjects. Alveolar lymphocyte analysis demonstrated that AIDS/TB patients had more markedly reduced percentages of CD4(+) lymphocytes than AIDS/TB patients and an increase in the percentage of CD8(+) lymphocytes, probably reflecting the impairment of CD4(+) T lymphocytes in peripheral blood at the lungs. Moreover, alveolar lymphocytes from AIDS/TB patients demonstrated a two- to fourfold decrease in LPR against M. tuberculosis antigens. Interestingly, it was observed an enhanced migration of natural killer cells to the lungs in all patients group. The phagocytic activity in alveolar macrophages and neutrophils showed that AIDS/TB patients had a twofold decreased capacity to ingest inert particles compared with AIDS patients. Comparing the alveolar and peripheral lymphocyte number and functional activity to M. tuberculosis-antigens it was possible to demonstrate that in both sites these cells had similar profile. However, the innate immune response in lungs showed a reduced activation in the presence of HIV infection, regarding the M. tuberculosis coinfection. These findings suggest that the advanced impairment of CD4(+) T lymphocyte in HIV-1 infection may lead to a deactivation of alveolar macrophages, enhancing bacilli burden and HIV replication in the lungs and furthering dissemination.