Association of Functional Heme Oxygenase-1 Gene Promoter Polymorphism with Renal Transplantation Outcomes

Heme oxygenase-1 (HO-1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO-1 promoter, regulates gene expression; a short number of repeats (S-allele

Is screening for Factor V Leiden and Prothrombin G20210A Mutations in Renal Transplantation worthwhile? Results of a large single-center U.K. study

This single center study is the largest series of renal transplant recipients and donors screened for the commonest prothrombotic genotypes. A total of 562 transplant recipients and 457 kidney donors were genotyped for the factor V Leiden and prothrombin G20210A mutations. The prevalence of heterozygous factor V Leiden was 3.4% and 2.6% and prothrombin G20210A was 2.0% and 1.1% in recipients and donors, respectively, similar frequencies to that of the general U.K. population. The 30-day and 1-year graft survival rates in recipients with thrombophilic mutations were 93% and 93%, compared with 88% and 82% in patients without these mutations (log-rank P =0.34). Thrombophilia in recipients (odds ratio 0.55; confidence interval 0.06-2.29; P =0.56) or in donors (odds ratio 1.53; confidence interval 0.27-5.74; P =0.46) did not correlate with graft loss at 30 days after transplantation. In contrast to recent reports, this study did not demonstrate an association between thrombophilia and renal allograft loss, and routine screening is not recommended.

Level of renal function and serum erythropoietin levels independently predict anaemia post-renal transplantation

Background. Post-renal transplant anaemia is a potentially reversible cardiovascular risk factor. Graft function, immunosuppressive agents and inhibition of the renin-angiotensin system have been implicated in its aetiology. The evaluation of erythropoietin (EPO) levels may contribute to understanding the relative contributions of these factors. Methods. Two-hundred and seven renal transplant recipients attending the Belfast City Hospital were studied. Clinical and laboratory data were extracted from the medical records and laboratory systems. Results. Of the 207 patients (126 male), 47 (22.7%) were found to be anaemic (males, haemoglobin (Hb) <12 g/dl, females Hb <11g/dl). The anaemic group had a significantly higher mean serum creatinine level (162.8 µmol/l vs 131.0 µmol/l, P <0.001) and lower mean estimated glomerular filtration rate (eGFR) (41.5 ml/min vs 54.9 ml/min, P <0.001) than the non-anaemic group. Individual immunosuppressive regimens were comparable between those with and those without anaemia. Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) administration was not more prevalent in those with anaemia compared with those without (36.2 vs 38.8, P = 0.88). There was a significant inverse correlation between Hb levels and serum EPO levels (R = -0.29, P <0.001), but not between EPO levels and eGFR (R = 0.02, P = 0.74). Higher EPO levels were predictive of anaemia, independent of eGFR in multivariate analysis. Conclusion. Anaemia is common in post-renal transplant patients. The levels of renal function and serum EPO and not immunosuppressive regimens or ACE-I/ARB use, are strong and independent predictors of anaemia. © The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Outcome of pregnancy following renal transplantation

Successful renal transplantation improves fertility with 1 in 50 women of childbearing age becoming pregnant. Pregnancy following renal transplantation is associated with increased maternal and fetal complications. In Belfast 118 women of childbearing age (15-45 yrs) have received a renal allograft and of these 14 (12%) have become pregnant. Twenty-seven pregnancies have resulted in 23 live births (including one set of identical twins), 1 still birth and 4 first trimester abortions. The most frequent complications were hypertension and prematurity. In this group of patients, whose sole immunosuppressive therapy was azathioprine and prednisolone, pregnancy post transplantation was associated with frequent successful outcome and a low incidence of maternal and fetal complications.

Renal replacement therapy in multiple myeloma and systemic amyloidosis

Renal failure frequently complicates both multiple myeloma and systemic amyloidosis. Renal replacement therapy (RRT) may be poorly tolerated and its role in such patients is not clearly defined. Of fifty patients (26 males and 24 females) referred to a single centre because of renal failure associated with multiple myeloma or systemic amyloidosis 37 progressed to end-stage renal failure and 30 of these patients received RRT. Nine patients have been treated by CAPD, 13 by haemodialysis, and 8 patients have required both forms of dialysis. Overall one year and two year survival rates were 66% and 57% respectively. The median duration on RRT was 7.5 months (range 1-96 months) with a 51% one year, and a 46% two year survival rate. Of 7 patients with amyloidosis who underwent renal transplantation, 3 died within 6 months of transplantation. Undiagnosed cardiac involvement contributed to this early mortality. We conclude that renal replacement therapy is appropriate for some patients with multiple myeloma and systemic amyloidosis who develop endstage renal failure. Careful assessment and selection of patients is necessary prior to renal transplantation.

Genetics of New-Onset Diabetes after Transplantation

New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic ß-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in ß-cell apoptosis. These results corroborate recent clinical evidence implicating ß-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect ß cells in the post-transplant period.

Tacrolimus is not associated with gingival overgrowth in renal transplant patients

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients.

METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models.

RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension.

CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus

Background: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA), Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement.

Improved prognosis for congenital nephrotic syndrome of the Finnish type in Irish families

Congenital nephrotic syndrome of the Finnish type is a rare autosomal recessive disease with a high infant mortality without aggressive treatment. The biochemical basis of the disease is not understood fully but the disease locus has been mapped recently to chromosome 19q12-q13.1 in Finnish families. This paper describes the clinical features and outcome of 20 patients in Ireland with congenital nephrotic syndrome of the Finnish type who have presented since 1980. Before 1987, all infants died by the age of 3 years. After the introduction of daily intravenous albumin infusion, nutritional support, elective bilateral nephrectomy, and renal transplantation, mortality in the past decade has fallen to 30%, with no deaths in the past five years. Genetic linkage analysis was performed in six families in whom DNA was available and the locus responsible was mapped to the same region on chromosome 19 as in Finnish families, suggesting that Irish families share the same disease locus.

Genetic polymorphisms and kidney transplant outcomes

Purpose of review: Gene polymorphism studies are growing at a quasiexponential rate and aim to improve immediate and long-term outcomes in renal transplantation. This review highlights recent evidence and potential future directions for genetic research studies.

Recent findings: Studies are largely based on immunity, inflammation and pharmacogenetics, investigating mostly 'surrogate' outcomes with sometimes conflicting results. However, the last 12 months has also heralded the emergence of important genome-wide association studies on transplantation, more robust replicated multicentre analyses of candidate gene variants, meta-analyses, and an increasing interest in copy number variation and donor genetics.

Summary: These studies set the scene for further investigation, aiming to understand pathways of disease and biomarkers of risk, and are leading to a greater understanding of the biology of transplantation. Future studies will require focus on donor : recipient and gene : environment interactions, and an integrated approach of 'transplantomics' to evaluate long-term outcomes in multinational collaborations.

Elevated serum phosphate predicts mortality in renal transplant recipients

BACKGROUND.: High serum phosphate has been identified as an important contributor to the vascular calcification seen in patients with chronic kidney disease (Block et al., Am J Kidney Dis 1998; 31: 607). In patients on hemodialysis, elevated serum phosphate levels are an independent predictor of mortality (Block et al., Am J Kidney Dis 1998; 31: 607; Block, Curr Opin Nephrol Hypertens 2001; 10: 741). The aim of this study was to investigate whether an elevated serum phosphate level was an independent predictor of mortality in patients with a renal transplant.
METHODS.: Three hundred seventy-nine asymptomatic renal transplant recipients were recruited between June 2000 and December 2002. Serum phosphate was measured at baseline and prospective follow-up data were collected at a median of 2441 days after enrolment.
RESULTS.: Serum phosphate was significantly higher in those renal transplant recipients who died at follow-up when compared with those who were still alive at follow-up (P<0.001). In Kaplan-Meier analysis, serum phosphate concentration was a significant predictor of mortality (P=0.0001). In multivariate Cox regression analysis, serum phosphate concentration remained a statistically significant predictor of all-cause mortality after adjustment for traditional cardiovascular risk factors, estimated glomerular filtration rate, and high sensitivity C reactive protein (P=0.036) and after adjustment for renal graft failure (P=0.001).
CONCLUSIONS.: The results of this prospective study are the first to show that a higher serum phosphate is a predictor of mortality in patients with a renal transplant and suggest that serum phosphate provides additional, independent, prognostic information to that provided by traditional risk factors in the risk assessment of patients with a renal transplant.