Homocysteine and B-group vitamins in renal transplant patients

Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.

Annotated Chromosome Maps for Renal Disease

A combination of linkage analyses and association studies are currently employed to promote the identification of genetic factors contributing to inherited renal disease. We have standardized and merged complex genetic data from disparate sources, creating unique chromosomal maps to enhance genetic epidemiological investigations. This database and novel renal maps effectively summarize genomic regions of suggested linkage, association, or chromosomal abnormalities implicated in renal disease. Chromosomal regions associated with potential intermediate clinical phenotypes have been integrated, adding support for particular genomic intervals. More than 500 reports from medical databases, published scientific literature, and the World Wide Web were interrogated for relevant renal-related information. Chromosomal regions highlighted for prioritized investigation of renal complications include 3q13-26, 6q22-27, 10p11-15, 16p11-13, and 18q22. Combined genetic and physical maps are effective tools to organize genetic data for complex diseases. These renal chromosome maps provide insights into renal phenotype-genotype relationships and act as a template for future genetic investigations into complex renal diseases. New data from individual researchers and/or future publications can be readily incorporated to this resource via a user-friendly web-form accessed from the website: www.qub.ac.uk/neph-res/CORGI/index.php.

Genetic analysis of coronary artery disease single nucleotide polymorphisms in diabetic nephropathy

Background. Diabetic nephropathy is a leading cause of end-stage renal disease. Premature mortality is common in patients with nephropathy, largely due to cardiovascular disease. Genetic variants implicated in macrovascular disease are therefore excellent candidates to assess for association with diabetic nephropathy. Recent genome-wide association studies have identified a total of 15 single-nucleotide polymorphisms (SNPs) that are reproducibly associated with cardiovascular disease.

Methods. We initially assessed these SNPs for association in UK type 1 diabetic patients with (cases; n = 597) and without (controls; n = 502) nephropathy using iPLEXTM and TaqMan® assays. Replication studies were performed with DNA genotyped in a total of 2668 individuals from the British Isles.

Results. One SNP (rs4420638) on chromosome 19q13 was found to be significantly associated with diabetic nephropathy before (P = 0.0002) and after correction for multiple testing (Pcorrected = 0.002). We replicated this finding in a phenotypically similar case–control collection comprising 709 individuals with type 1 diabetes (P = 0.002; combined P < 0.00001; OR = 1.54, 95% CI: 1.29–1.84).

Conclusions. Our case–control data suggest that rs4420638, or a functional SNP in linkage disequilibrium with this SNP, may be associated with diabetic nephropathy.

Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy

Background: Haem oxygenase-1 (HO-1) is a cytoprotective molecule that is reported to have a protective role in a variety of experimental models of renal injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO-1 promoter, regulates HO-1 gene expression; a short number of repeats (S-allele <25) increases transcription. We report the first assessment of the role of this HO-1 gene promoter polymorphism in chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD) and IgA nephropathy (IgAN).

Methods: The DNA from 160 patients (99% Caucasian) on renal replacement therapy (RRT) was genotyped. The primary renal disease was ADPKD in 100 patients and biopsy-proven IgAN in 60 patients.

Results: Overall, the mean age at commencement of RRT was not significantly different between patients with and without an S-allele (44.1 years versus 45.0 years, P = 0.64). In patients with ADPKD, the age at commencement of RRT was comparable regardless of the HO-1 genotype (47.7 years versus 46.7 years, P = 0.59). The same was true in patients with IgAN (38.3 years versus 42.2 years, P = 0.28).

Conclusion: This suggests that the functional HO-1 promoter polymorphism does not influence renal survival in CKD due to ADPKD or IgAN.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

AIMS
The aim of this study was to investigate the in?uence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation.
METHODS
Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular ?ltration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes.
RESULTS
The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls,P = 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%,P = 0.057). Carriers of the G2677->T variant allele also had a signi?cant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P = 0.031). Haplotype analysis showed a signi?cant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P = 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were signi?cantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation.
CONCLUSIONS
These ?ndings suggest that ABCB1 polymorphisms in the native intestine signi?cantly in?uence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the ?rst year posttransplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety