Prognostic value of donor cytotoxic T-lymphocyte precursor frequencies for acute graft-versus-host disease in hematopoietic stem cell transplantation from HLA-matched siblings: a single center experience in a cohort of 92 patients

We investigated the prognostic value of cytotoxic T-lymphocyte precursor frequencies (CTL-p-f) for the development of graft-versus-host disease (GvHD) in a cohort of 92 recipients of a hematopoietic stem cell transplantation from HLA-matched sibling donors. CTL-p-f and clinical variables were correlated with acute GvHD and chronic GvHD in univariate and multivariate analyses. CTL-p-f resulted an independent risk factor for severe acute GvHD. Moreover, a trend towards a correlation between CTL-p-f and chronic GvHD was observed. In summary CTL-p-f may be considered as a functional assay useful for identifying patients at high risk of severe GVHD.     

Early reduced liver graft survival in hepatitis C recipients identified by two combined genetic markers

HLA and IL‐28B genes were independently associated with severity of HCV‐related liver disease. We investigated the effects of these combined genetic factors on post‐transplant survival in HCV‐infected recipients, aiming to provide new data to define the optimal timing of novel antiviral therapies in the transplant setting. HLA‐A/B/DRB1 alleles and IL‐28B rs12979860 (C > T) polymorphism frequencies were determined in 449 HCV viremic recipients and in their donors. Median follow‐up was 10 years; study outcome was graft survival. HLA‐DRB1*11 phenotype and IL‐28B C/C genotype were significantly less frequent in recipients than donors (27.8% vs. 45.9% and 27.4% vs. 44.9%, respectively, P < 0.00001). Ten‐year graft survival was better in patients with HLA‐DRB1*11 (P = 0.0183) or IL‐28B C/C (P = 0.0436). Conversely, concomitant absence of HLA‐DRB1*11 and IL‐28B C/C in 228 (50.8%) predicted worse survival (P = 0.0006), which was already evident at the first post‐transplant year (P = 0.0370). In multivariable Cox analysis, absence of both markers ranked second as risk factor for survival (HR = 1.74), following donor age ≥ 70 years (HR = 1.77). In the current era of direct‐acting antiviral agents, the negative effects of this common immunogenetic profile in HCV‐infected recipients could be most effectively neutralized by peri‐transplant treatment. This should be particularly relevant in countries where elderly donors represent an unavoidable resource.     

Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and an important cause of ESRD. Familial clustering of cases suggests genetic predisposition to this disease. Two recent genome-wide studies in IgAN have identified a major susceptibility locus on chromosome 6q22 (IGAN1) and two additional loci with suggestive linkage signals on chromosomes 4q26-31 and 17q12-22. A large four-generation family with 14 affected individuals has been clinically ascertained and excluded from linkage to these loci. A genome-wide linkage scan was performed on this family with GeneChip Mapping 10K 2.0 Arrays using an "affected-only" strategy. By nonparametric analysis, two regions of suggestive linkage (multipoint logarithm of odds [LOD] scores >2) were identified on chromosomes 2q36 and 13p12.3. By parametric analysis (assuming an autosomal dominant inheritance, a disease allele frequency of 0.001, phenocopy rate of 0.01, and penetrance of 75%), a significant linkage to chromosome 2q36 (maximum multipoint LOD score 3.47) was found. Nine simple sequence repeat markers then were genotyped in 21 members (included all of the affected individuals), and significant linkage to chromosome 2q36 over a region of 12.2 cM (maximum multipoint LOD score 3.46) was confirmed. Recombination events in two affected individuals, as detected by haplotype analysis, delineated a critical interval of approximately 9 cM (equivalent to approximately 7 Mb) between D2S1323 and D2S362. Taken together, these data provide strong evidence for a novel disease susceptibility locus for familial IgAN.     

Screening for cerebral aneurysms in the ADPKD population: mandatory or potentially harmful?

Cerebral aneurysm in autosomal dominant polycystic kidney disease (ADPKD) is an uncommon event (documented in 6-13% of cases) but frequently characterized by severe neurological sequelae and potentially fatal in case of rupture. The arterial vascular wall of the anterior cerebral circulation is most frequently involved. Experimental data showed the expression of polycystins (the proteins modified by the mutation in this disease) in the affected arterial vascular wall and some mutations apparently give rise to greater susceptibility to the complication. The risk factors that cause the predisposition to this condition and the natural history are poorly understood. This lack of information complicates the clinical management of these patients because many pivotal questions still need an answer: Are cerebral aneurysms to be screened for in the ADPKD population? If so, at which intervals? In which cases where an aneurysm has been detected is correction needed? Which type of correction technique is to be preferred, interventional neuroradiology or neurosurgery? The three authors compare their partially discordant positions on this highly controversial topic.     

Epidermal growth factor receptor polymorphism and autosomal dominant polycystic kidney disease

BACKGROUND: The clinical variability in the rate of progression of autosomal dominant polycystic kidney disease (ADPKD) has been attributed to genetic heterogeneity, though environmental factors and modifying genes very likely play an important role as well. We examined the association between clinical outcome, defined by age at onset of end-stage renal disease (ESRD) in 46 ADPKD patients, and a polymorphism in the epidermal growth factor receptor (EGFR) gene, a candidate modifying gene. EGFR is a key element in renal tubular proliferation. METHODS: This study comprised 46 unrelated patients with ADPKD and ESRD, and 58 healthy controls. The patients had prevalently PKD 1 mutations. The EGFR microsatellite polymorphism was genotyped according to Gebhardt et al (11). RESULTS: The allele frequencies of the EGFR polymorphism were different in the ADPKD sample and the control population (G2=17.19; P=0.009). In particular, the frequencies of the 122 and 118bp length alleles had a different distribution (P=0.010 and P=0.047 respectively). Patients with the 122bp length polymorphism had ESRD at an earlier age,but this finding was not statistically significant. CONCLUSIONS: These findings suggest an association between the EGFR microsatellite polymorphism and ADPKD. However, it is difficult to establish which alleles are protective and which harmful. A larger, multicenter study may help clarify these results and is also required to replicate our preliminary finding of an association between ADPKD and the EGFR polymorphism.