No association between renin-angiotensin system gene polymorphisms and early and long-term allograft dysfunction in kidney transplant recipients.

BACKGROUND: Genes determining the activity of the renin-angiotensin system (RAS) may be alloantigen-independent factors influencing kidney allograft function. We determined if gene polymorphisms of the RAS are associated with early and long-term post-transplantation graft dysfunction in 405 Caucasian kidney recipients with graft survivals of >2 years. METHODS: We calculated the slopes of serum creatinine(-1)/year and urinary protein excretion/year to follow graft function over time. Subjects were genotyped for the deletion (D) polymorphism of the gene encoding angiotensin I-converting enzyme, the angiotensin II-receptor type1 gene 1166A-C polymorphism and the M235T polymorphism of the angiotensinogen gene. RESULTS: The frequencies of factors predicting graft function were similar in patients with different genotypes. None of the polymorphisms influenced need for dialysis in the first week after transplantation, occurrence of at least one rejection episode, the slope of serum creatinine(-1)/year or the slope of urinary protein excretion/year. Results were independent of blood pressure or the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers or calcineurin inhibitors. The combination of genotypes did not influence the indicators of early and long-term graft dysfunction. CONCLUSIONS: Neither the investigated gene polymorphisms of the RAS in kidney allograft recipients nor their combinations have an impact on early and long-term graft dysfunction.

Activity of the endothelin system in kidney allograft recipients is not associated with progression of chronic graft dysfunction.

Endothelin (ET) A receptor antagonists have been shown to be beneficial in rat models of chronic kidney allograft dysfunction. We investigated urinary and plasma ET-1 (uET-1, pET-1) and BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble ET-converting enzyme (ECE) concentration in 310 adult Caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. All patients were on cyclosporine A- or FK506-based immunosuppression protocols. From all available measurements since transplantation, we calculated the slope of serum creatinine(-1)/year (slopeCrea) as a parameter for progression of chronic graft dysfunction, as well as the mean of serum creatinine (meanCrea) from most recent year before measurements as a parameter for actual graft function. The slope of urinary protein excretion/year (slopeProt) and mean of urinary protein concentration (meanProt) from most recent year was calculated analogue. uET-1 and uBigET-1 were adjusted for protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Blood and urine probes for measurements were always drawn immediately before morning dosage of immunosuppressants. There was no significant correlation of any measured component of the ET system with slopeCrea or slopeProt. MeanCrea (mg/dl) was significantly correlated with pBigET-1 (fmol/ml) and pET-1 (fmol/ml) (pBigET-1: r=0.179, P=0.001; pET-1: r=0.161, P=0.009). The other measured components of the ET systems were not significant correlated with meanCrea. In conclusion, the actual graft function is associated with elevated pET-1 and BigET-1 concentrations as it is well known from other forms of impaired kidney function. However, the actual concentration of ET-1, soluble ECE, and BigET-1 in urine and plasma in our study is not associated with parameters for progression of chronic graft dysfunction.

Interaction of the endothelin system and calcineurin inhibitors after kidney transplantation.

Plasma endothelin (ET)-1 concentrations have been shown to be elevated in patients receiving calcineurin-inhibitors (CI). We investigated urinary and plasma ET-1 (uET-1, pET-1), BigET-1 (uBigET-1, pBigET-1) concentrations, and plasma soluble endothelin-converting enzyme (ECE) concentrations in 381 adult caucasian kidney allograft recipients with graft survival of more than 2 years from the outpatients department of our clinic. Blood and urine probes were always drawn immediately before morning dosage of immunosuppressants. Mean of urinary protein excretion (meanProt) and mean of serum creatinine (meanCrea) were calculated from all available measurements in the most recent year. uET-1 and uBigET-1 were adjusted for urinary protein excretion by calculating uET-1/meanProt and uBigET-1/meanProt. Patients (n=310) were on a cyclosporine A or FK506 (CI-group) based immunosuppression protocol, and 71 patients were immunosuppressed without use of CI (nonCI group). Time since transplantation was similar in both groups (mean+/-S.D.; CI-group: 7.55+/-2.50; nonCI-group: 7.74+/-3.06 years, P=0.240) as well as meanCrea (mean+/-S.D.; CI-group: 1.97+/-1.34; nonCI-group: 1.77+/-1.29 mg/dl, P=0.326). pET-1 was significantly higher in the CI-group, compared with nonCI (mean+/-S.D.; 0.87+/-1.4 versus 0.56+/-0.76 fmol/ml, P=0.011). pBigET-1 was similar (mean+/-S.D.; 0.85+/-1.41 versus 0.70+/-1.21 fmol/ml, P=0.33). ECE concentrations were higher in the CI group (mean+/-S.D.; 14.30+/-18.02 versus 9.23+/-7.42 ng/ml, P=0.001). uET-1/meanProt and uBigET-1/meanProt concentration were similar in the CI-group compared with the nonCI-group (mean+/-S.D.; uET-1/meanProt: 15+/-24 versus 21+/-40 pmol/g, P=0.139; uBigET-1/meanProt: 34+/-55 versus 19+/-23pmol/g, P=0.248). pET-1 elevation in patients receiving CI might be more likely to be due to elevated conversion of pBig-ET-1 by more ECE, and not to higher concentrations of pBigET-1.