Impact of genetic polymorphisms of the renin-angiotensin system and of non-genetic factors on kidney transplant function--a single-center experience.

Renin-angiotensin-aldosterone system (RAAS) polymorphisms such as the angiotensinogen-gene-M235T-, the angiotensin-conversion enzyme (ACE)-gene I/D- and the angiotensin-II-type 1-receptor-(AT1R)-A1166C-polymorphism have been implicated in renal insufficiency and hypertension. We studied the association of these RAAS genotypes and non-genetic factors with transplant function and hypertension after renal graft transplantation (NTX). A total of 229 renal graft recipients, transplanted at a single center, were monitored up to 54 months and genotyped using polymerase chain reaction. The prevalence of the genotypes was comparable to a control group of healthy volunteers. Genotype and clinical outcome was analyzed using ANOVA, while the k-nearest neighbor method was used for a pattern recognition analysis of the complete database. Hypertension after NTX was not influenced by the RAAS polymorphisms. The DD-genotype of the ACE-I/D-polymorphism was associated with significantly deteriorated renal transplant function during the months 18 to 30 after transplantation according to ANOVA at p < 0.05, as were non-genetic factors like long hospitalization, poor primary transplant function, and frequent rejections. Pattern recognition identified, the use of cyclosporine (odds ratio of 4.25) and the use of Ang II-receptor-blockers at discharge indicating the need of effective antihypertensive treatment (odds ratio of 3.26) as risk factors for transplant function loss. Altogether, the significant impact of the DD-genotype on the outcome after renal transplantation emphasizes the early identification of RAAS genotypes.

Influence of interleukin-6 G-174C gene polymorphism on coronary artery disease, cardiovascular complications and mortality in dialysis patients.

BACKGROUND: Inflammation is a well recognized central component of atherosclerotic processes in chronic kidney disease. Interleukin-6 (IL-6) levels are a strong determinant of cardiovascular mortality in dialysis patients. We evaluated the impact of IL-6 gene G-174C polymorphism associated with modified IL-6 production on the development of coronary artery disease (CAD), cardiovascular events and mortality in chronic dialysis patients. METHODS: We studied n = 463 patients on chronic dialysis with angiographically confirmed (n = 218) or excluded (n = 245) CAD followed up for 65 months after initiation of dialysis. Monitored were arterial hypertension, diabetes mellitus, hyperlipidemia, smoking, CRP and fibrinogen. IL-6 gene G-174C polymorphism was determined by PCR amplification. RESULTS: The CC genotype was associated with an impaired patient survival (p < 0.05) remaining an independent risk factor for death in multivariate analysis (HR for CC genotype: 3.58, CI: 1.41-9.07, p < 0.01). CC genotype carrying CAD patients suffered significant frequently cardiovascular events (revascularization, myocardial infarction, death) compared to GG/GC genotype carriers (85.2% vs. 66.5, p < 0.05). However, the IL-6 gene G-174C polymorphism was not related to the onset and development of CAD itself (ns) and the inflammation parameters CRP and fibrinogen did not differ between the genotypes under investigation (ns). CONCLUSIONS: Our results suggest that IL-6 gene G-174C polymorphism is associated with the incidence of cardiovascular events and mortality in chronic dialysis patients.

Influence of cytokine gene polymorphisms on IgA nephropathy.

Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 +/- 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 78) and group B (fast progressors, n = 49). TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-beta1, 92.3%; TNFalpha, 25.6%; IL-6, 74.4%; fast progressors: TGF-beta1, 85.7%; TNFalpha, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.

Influence of cytokine genes polymorphisms on long-term outcome in renal transplantation.

BACKGROUND: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of interleukin-10 (IL-10) gene G-1082A, tumour necrosis factor alpha (TNFalpha) gene G-308A and IL-6 gene G-174C polymorphisms on the rejection rate, renal function and long-term outcome in renal transplantation. PATIENTS AND METHODS: We studied n = 224 consecutive patients, who underwent renal transplantation at our centre from 1998 to 2001 (cadaveric: n = 175, living related: n = 49) followed up for 4.9 +/- 2.0 yr and n = 100 healthy volunteers. IL-10 gene G-1082A, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by polymerase chain reaction (PCR) amplification. RESULTS: The genotype distribution of the investigated polymorphisms was similar in patients and controls (ns). The age of donor and the recipient, the number of HLA mismatches and cold and warm ischemic time did not differ among patients with different genotypes (ns). No association between cytokine polymorphisms and the incidence of acute rejection episodes was detected (ns). The cytokine genotypes did not correlate with serum creatinine or creatinine clearance at any time during follow up (ns). Furthermore, there was no significant difference in the genotype frequencies among patients experiencing graft failure (ns). Patients with different cytokine gene polymorphisms showed similar outcomes in the Kaplan-Meier analysis of graft survival (ns). Finally, cytokine polymorphisms had no influence on the acute rejection rate or graft outcome also in the subgroup of HLA-DR mismatched grafts (ns). CONCLUSION: Our results suggest that IL-10 gene G-1082A, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms are no major risk factors in renal transplantation.

Tumor necrosis factor-alpha gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a major pro-inflammatory cytokine. Recently, the G-308A polymorphism of the TNF-alpha gene has been associated with modified gene expression and increased TNF-alpha production in the -308A allele. We evaluated its influence on the incidence and clinical course of membranous glomerulonephritis. METHODS: We studied 53 patients with biopsy-proven primary membranous glomerulonephritis followed up for 5.7 +/- 4.9 years. 100 volunteers were analyzed as controls. According to the slope of the curve of reciprocal serum creatinine against time, group A (slow progressors, n = 35) and group B (fast progressors, n = 18) were defined. TNF-alpha G-308A polymorphism was determined by polymerase chain reaction amplification. RESULTS: The frequency of the A-allele (associated with higher TNF-alpha levels) was significantly higher in patients than control subjects (patients: G-allele: 0.66, A-allele: 0.34; controls: G-allele 0.85, A-allele 0.15, p < 0.001). Similarly, the genotype distribution differed significantly between our study and control populations (patients: GG-genotype: 41.5%, GA: 49.1%, AA 9.4%; controls: GG: 71%, GA: 27%, AA 2%, p = 0.001). Age, renal function, proteinuria and blood pressure were similar at the time of renal biopsy between patients with different genotypes (NS). There was also a tendency towards an overpresentation of the A-allele in group B indicating a possible impact on the progression of membranous nephropathy, but a significance was not reached. Furthermore, no impact on renal survival in the Kaplan- Meier analysis was detected (NS). CONCLUSION: Our results suggest that TNF-alpha gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis.

Influence of beta3 integrin gene Leu/Pro33 polymorphism on primary glomerulonephritis.

BACKGROUND: Beta3 integrin subunit is expressed as alpha(IIb)beta3 integrin on platelets and as alpha(v)beta3 integrin on a variety of cells including renal endothelial, mesangial and tubular cells. Leu33/Pro33 polymorphism of beta3 integrin has been associated with altered platelet functions, cardiovascular complications and the incidence of acute rejection episodes in renal transplantation. We investigated its influence on IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). METHODS: We studied 251 patients with biopsy-proven primary glomerulonephritis (IgAN n = 127, FSGS n = 71, MGN n = 53) followed up for 6.3 +/- 5.3 years and 100 control subjects. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 162) and fast progressors (n = 89). Leu33/Pro33 polymorphism was determined by PCR amplification followed by restriction with the endonuclease Bcnl. RESULTS: The genotype frequencies were similar in patients and controls (n.s.). Initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The genotype frequencies were similar in slow and fast progressors (n.s.). Furthermore, Leu33/Pro33 polymorphism had no impact on renal survival in the Kaplan-Meier analysis (n.s.). CONCLUSION: Our results indicate that beta3 integrin Leu33/Pro33 polymorphism is not a risk factor or a marker of progression in primary glomerulonephritis.

Influence of cytokine gene polymorphisms on focal segmental glomerulosclerosis.

BACKGROUND: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of focal segmental glomerulosclerosis (FSGS). METHODS: The clinical course of 71 patients with biopsy-proven primary FSGS followed up for 6.0 +/- 4.4 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 49) and fast (n = 22) progressors. One hundred healthy volunteers were analysed as controls. Genetic polymorphisms were determined by PCR amplification. RESULTS: The genotype distribution of the studied polymorphisms was similar in patients and controls (n.s.). Age, initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The investigated polymorphisms were not associated with the progression of FSGS as shown by the similar genotype frequencies among slow and fast progressors (n.s.) and the renal survival in the Kaplan-Meier analysis (n.s.). CONCLUSION: Our results indicate that TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in focal segmental glomerulosclerosis.