Trimethoprim/sulfamethoxazole-induced acute renal failure: A case report

The patient was an 80-year-old man who arrived at the emergency room with breathing problems. He presented a history of chronic obstructive pulmonary disease (COPD), hypertension, diabetes mellitus and early (stage 1) chronic renal failure with normal levels of creatinine and no sign and symptoms of renal disease. A chest X-ray showed pneumonia. Therefore, he was first treated with 1 g daily of ceftriaxone IV. We did not observe any clinical improvement, and for this reason, a sputum culture was performed to guide the right antibiotic treatment. Subsequently, we started a new antibiotic therapy with trimethoprim/sulfamethoxazole (TMP/SMX) adjusted to renal functioning. Appropriate medical treatment was administered, as well as urine alkalinisation. After the first day of treatment, the patient’s clinical and laboratory status worsened very quickly, with an increased level of serum creatinine from 1.5 to 3.5 mg/dL. We stopped administering the antibiotic therapy immediately. However, we observed acute renal failure with a serum creatinine level of 9.0 mg/dL and four days after his admission, the patient died. Literature showed that patients can develop acute kidney injury (AKI) during or immediately following TMP/SMX therapy. Intrinsic renal impairment –rather, interstitial nephritis– appeared responsible for the great majority of cases, and impairment was transient if therapy was discontinued. In our study, despite the therapy with TMP/SMX was immediately discontinued, and our patient underwent appropriate medical treatment, urine alkalinisation and, then, haemodialysis, the AKI was rapidly fatal. In conclusion, particular attention should be paid to prescribing TMP/SMX to patients affected by chronic renal failure

Y chromosome loss in male patients with primary biliary cirrhosis

Lleo A, Oertelt-Prigione S, Bianchi I, et al. Y chromosome loss in male patients with primary biliary cirrhosis. Journal of Autoimmunity. 2013;41:87-91

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies

Human leukocyte antigen polymorphisms in Italian primary biliary cirrhosis: A multicenter study of 664 patients and 1992 healthy controls

Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between speci fic DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease. Copyright © 2008 by the American Association for the Study of Liver Diseases

Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis.

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 7 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 7 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 7 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC