Analysis of L-myc gene polymorphism in patients with renal failure outcome to renal transplant

BACKGROUND: Abnormalities of cell numbers and apoptosis have been observed in renal failure. As uncontrolled expression of c-myc is known to induce apoptosis, we thought that polymorphism in the other myc gene, L-myc gene, which is structually similar to c-myc and reported to be expressed in the kidney, may have a role in the induction of apoptosis and thus have role in chronic renal failure. The aim of this study was to investigate the relationship between the distribution of L-myc genotypes and renal failure. METHODS: In the present study we examined 101 chronic renal failure patients who had either live or cadaveric renal transplants and 105 healthy individuals, for L-myc gene polymorphism by polymerase chain reactions and restriction fragment length polymorphism techniques. RESULTS: Among our patient group, the distribution of the LL, LS, and SS genotypes was 24% (n=25), 71% (n=71), and 5% (n=5), respectively, versus 41% (n=43), 47% (n=49), and 12% (n=13) in our control group. The distribution of genotypes was significantly different between our patients and the control group (chi2=12.281; P=.002). The frequency of the S allele was significantly higher in the patient group (chi2=6.122; P=.013). CONCLUSION: Our study showed that having an S allele in the L-myc gene may increase the risk of renal failure.     

p53 gene codon 72 polymorphism but not tumor necrosis factor-alpha gene is associated with prostate cancer

OBJECTIVE: A polymorphism of gene p53 codon 72 is associated with various cancer formations. Tumor necrosis factor-alpha (TNF-alpha) one of the cytokines secreted by macrophages in response to inflammation and is also related to cancer formation. We aimed to evaluate the association between prostate cancer and the polymorphisms of the TNF-alpha gene promoter -308 and p53 gene codon 72. PATIENTS AND METHODS: In our study, a normal control group of 126 healthy people and 96 patients with prostate cancer were examined. The polymorphism (G/A) of TNF-alpha gene was detected by polymerase chain reaction (PCR)-based restriction analysis (Nco I endonuclease) and the polymorphism of p53 gene was detected by two PCRs (one for proline and one for arginine form). RESULTS: There was a significant difference in the distribution of codon 72 polymorphism the p53 gene between prostate cancer patients and the normal controls (p < 0.001). The proline form of p53 gene codon 72 was significantly higher than the arginine form, with an odds ratio of 2.606 (95% CI = 1.052-6.455). This difference was also revealed in the tumor staging (p = 0.035) as the proline form was significantly higher in the metastasis group of prostate cancer. There were no statistical differences in the distribution of -308 polymorphism of the TNF-alpha gene between cancer patients and the control subjects (p = 1.0). CONCLUSION: Prostate cancer appears to be associated with the p53 gene codon 72 polymorphisms, but not with the TNF-alpha gene. The proline form of p53 gene codon 72 might be a more significant risk factor for the development of metastasis than the arginine form.     

Serum uric acid level is associated with cardiac hypertrophy in renal transplant recipients

Caliskan Y, Gorgulu N, Yelken B, Akturk F, Yazici H, Turkmen A, Sever MS. Serum uric acid level is associated with cardiac hypertrophy in renal transplant recipients.
Clin Transplant 2011: 25: 368–374. © 2010 John Wiley & Sons A/S. Abstract: Background: Serum uric acid (UA) level as a significant and independent risk factor for cardiovascular disease, and the link between this marker and left ventricular hypertrophy (LVH) in renal transplant recipients remains to be clarified. Methods: A total of 141 renal transplant recipients (83 men), between ages of 18 and 69 (mean age 37 ± 11), were included in this single center study. In addition to demographic, clinical, and laboratory parameters, serum UA concentrations were evaluated. LVH was determined by two‐dimensional and M‐mode echocardiography. Results: Serum UA levels were significantly higher (6.14 ± 1.15 mg/dL) in patients with LVH (n = 54) when compared to patients (n = 87) who did not have this abnormality (5.29 ± 1.43 mg/dL) (p = 0.006). Serum UA levels were significantly correlated with septal wall thickness, LV posterior wall thickness, LV mass index (LVMI), and pulmonary arterial pressure. Multiple linear regression analysis revealed that UA predicted LVMI (r² = 0.150, β = 0.369, p = 0.001). However, serum creatinine (β = 0.060, p = 0.593) and age (β = 0.146, p = 0.175) were not predictors of LVMI. Conclusion: High serum UA levels are associated with LVH in renal transplant recipients, which underlines the importance of treating hyperuricemia.     

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy

BACKGROUND.: There is agreement that a family history of hypertension (HT),is a predictor for the risk of diabetic nephropathy (DN) inpatients with type 2 diabetes, and possibly also type 1 diabetes.It follows that genes related to the risk of hypertension mustalso be considered candidate genes for DN. The 235T allele ofthe angiotensinogen gene was found to be related to primaryHT. METHODS.: To examine whether it is predictive for DN as well, we examinedthe angiotensinogen gene polymorphism in 230 healthy local controls,423 patients with type 1 diabetes (n=180 with DN; n=243 withoutDN) and 663 patients with type 2 diabetes (n=310 with DN; n=353without DN). The angiotensinogen gene M235T polymorphism wasdetermined using PCR amplification. RESULTS.: The following results were obtained (i) no significant differenceof genotype distribution (type 1: MM/MT/TT(%) 27.6/57.2/15.2vs. 27.2/56.1/16.7 (P=0.92); type 2: MM/MT/TT (%) 31.7/48.2/20.1vs. 32.9/46.8/20.3 (P=0.93)) or allele frequencies (type 1:M 0.56 vs. 0.55 (P=0.795); type 2: M 0.56 vs. 0.56 (P=0.86))was found, between diabetic patients with or without DN, (ii)no difference was found between normotensive and hypertensivediabetic patients. CONCLUSION.: The data argue against a role of the angiotensinogen gene M235Tpolymorphism in the manifestation of diabetic nephropathy orhypertension in diabetic patients.     

Plasminogen activator inhibitor-1 polymorphism is associated with progressive renal dysfunction after acute rejection in renal transplant recipients

BACKGROUND: Plasma level of plasminogen activator inhibitor (PAI)-1 is genetically determined by a polymorphism in the promoter region, involving two alleles, 4G and 5G. Plasma PAI-1 concentrations are higher in subjects homozygous for the 4G allele than other genotypes (5G/5G and 4G/5G). Such genetic variation in fibrinolytic system may affect the long-term renal transplant outcome. METHODS: We determined PAI-1 4G/5G-promoter genotype polymorphism among our renal transplant recipients between 1985 and 2001. Primary event was defined as doubling of baseline serum-creatinine level. RESULTS: Over a median period of 79 months, 130 patients with 132 kidney grafts were assessed. Baseline clinical variables were comparable among three genotype groups. There was no association between primary event and PAI-1 genotype among the entire cohort. However, among subjects with prior acute rejection episodes, those homozygous for 4G had significantly higher risk of serum creatinine doubling than the other two genotypes (relative risk 2.45, 95% confidence interval 1.19-5.04). PAI-1 genotype does not predict primary events in patients without rejection (relative risk 0.57, 95% confidence interval 0.07-4.17). CONCLUSIONS: PAI-1 4G/5G-promoter polymorphism modulates the risk of renal transplant outcomes after acute rejection(s). Recipients homozygous for PAI-1 4G allele have a higher risk of progressive renal damage after acute rejection episode(s). PAI-1 promoter polymorphisms are potentially important determinants of renal response to rejection.     

Interleukin-4 gene intron-3 polymorphism is associated with transitional cell carcinoma of the urinary bladder

OBJECTIVE: To evaluate whether polymorphism of the interleukin-4 gene exon 3, and of the interleukin-1beta gene exon 5 and promoter region, are associated with transitional cell carcinoma (TCC) of the urinary bladder, as cytokines are hypothesized to be important in cancer formation. PATIENTS, SUBJECTS AND METHODS: The study included 138 patients with TCC of urinary bladder and 105 healthy controls living in the same area. Each genetic polymorphism was typed using polymerase chain reaction-based restriction analysis. Genotype distribution and allelic frequencies between patients and controls were compared. RESULTS: There were significant differences in genotype and allelic distribution of intron 3 RP1/RP2 polymorphism (P < 0.001), but no significant difference in genotype distribution or allelic frequencies of the interleukin-1beta gene polymorphism between patients with bladder cancer and controls. CONCLUSION: The interleukin-4 gene intron 3 polymorphism is associated with bladder cancer and is a potential genetic marker in screening for the possible causes of bladder cancer.     

Pamidronate used to attenuate post-renal transplant bone loss is not associated with renal dysfunction.

BACKGROUND: Pamidronate is a second-generation bisphosphonate that has been used to attenuate post-renal transplant bone loss, but its effect on the function of the renal allograft is unclear. Therefore, we evaluated the long-term renal function in 57 subjects who had participated in a prospective, randomized clinical trial using pamidronate to attenuate bone loss in the renal transplant recipient. METHODS: Thirty subjects (PAM) received intravenous pamidronate, 60 mg at baseline post-transplant and 30 mg in months 1, 2, 3 and 6 post-transplant, while 27 subjects (CON) did not receive pamidronate. We followed renal function, need for renal replacement therapy following transplant rejection, and mortality for 3 years following the start of the original study. RESULTS: PAM did not have increased incidence of renal dysfunction or mortality compared with CON at any time point during the 3 years of follow-up. The incidence of proteinuria was also not different between the two groups. CONCLUSIONS: The prophylactic use of pamidronate in the above doses to attenuate bone loss in renal transplant recipients is not associated with higher incidence of renal dysfunction or mortality in a 3 year follow-up study. These findings may support the use of bisphosphonates in the treatment of early renal transplant-related bone loss.     

Vitamin D deficiency is common in kidney transplant recipients,but is not associated with infections after transplantation

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25-OH vitamin D (25-OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri-transplant and 6 months post-transplant. Logistic regression was used to address the associations of 25-OHD and overall infections and bacterial infections, respectively. For the first 6 months post-transplant, 25-OHD peri-transplant, and for the second period (after 6 to 30 months post-transplant), 25-OHD at 6 months post-transplant was considered. Vitamin D deficiency was common peri-transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25-OHD levels increased from 12.0 ng/mL (IQR 5.3-19.5) peri-transplant to 16.5 ng/mL (IQR 10.6-22.6) 6 months post-transplant (P = .005). We did not detect a significant association between 25-OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44-2.51; aOR 0.67, 95%CI 0.31-1.43) or bacterial infections (aOR 0.79, 95%CI 0.32-1.96; aOR 0.79, 95%CI 0.35-1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25-OHD in the longitudinal course was observed. No significant association between 25-OHD and infections was detected.     

De novo malignancy is associated with renal transplant tourism

Despite the objections to transplant tourism raised by the transplant community, many patients continue travel to other countries to receive commercial transplants. To evaluate some long-term complications, we reviewed medical records of 215 Taiwanese patients (touring group) who received commercial cadaveric renal transplants in China and compared them with those of 321 transplant recipients receiving domestic cadaveric renal transplants (domestic group) over the same 20-year period. Ten years after transplant, the graft and patient survival rates of the touring group were 55 and 81.5%, respectively, compared with 60 and 89.3%, respectively, of the domestic group. The difference between the two groups was not statistically significant. The 10-year cumulative cancer incidence of the touring group (21.5%) was significantly higher than that of the domestic group (6.8%). Univariate and multivariate stepwise regression analyses (excluding time on immunosuppression, an uncontrollable factor) indicated that transplant tourism was associated with significantly higher cancer incidence. Older age at transplantation was associated with a significantly increased cancer risk; however, the risk of de novo malignancy significantly decreased with longer graft survival. Thus, renal transplant tourism may be associated with a higher risk of post-transplant malignancy, especially in patients of older age at transplantation.     

Association of complement C3 gene variants with renal transplant outcome of deceased cardiac dead donor kidneys

Local renal complement activation by the donor kidney plays an important role in the pathogenesis of renal injury inherent to kidney transplantation. Contradictory results were reported about the protective effects of the donor C3F allotype on renal allograft outcome. We investigated the influence of the donor C3F allotype on renal transplant outcome, taking all different donor types into account. C3 allotypes of 1265 donor-recipient pairs were determined and divided into four genotypic groups according to the C3F allotype of the donor and the recipient. The four genotypic groups were analyzed for association with primary nonfunction (PNF), delayed graft function, acute rejection, death-censored graft survival and patient survival. Considering all donor types, multivariable analysis found no association of the donor C3F allotype with renal allograft outcome. Also, for living and deceased brain-dead donors, no association with allograft outcome was found. Post hoc subgroup analysis within deceased cardiac dead (DCD) donors revealed an independent protective association of donor C3F allotype with PNF. This study shows that the donor C3F allotype is not associated with renal allograft outcome after kidney transplantation. Subgroup analysis within DCD donors revealed an independent protective association of the donor C3F allotype with PNF, which is preliminary and warrants further validation.     

Glutathione S-transferase M1 gene but not insulin-like growth factor-2 gene or epidermal growth factor gene is associated with prostate cancer

Prostate cancer is the most common urologic malignancy involving multiple factors. There is evidence that suggests that detoxification enzymes and growth factors may play a role in the formation of prostate cancer. Our aim was to investigate whether polymorphisms of glutathione S-transferase M1 (GST M1), insulin-like growth factor-2 (IGF-2), and epidermal growth factor (EGFR) genes could be used as genetic markers for risk of prostate cancer. In this study, we compared the frequency of the polymorphisms of GST M1, IGF-2, and EGFR genes among 96 patients with prostate cancer and 121 healthy male volunteers from the same geographic area (age, older than 60 years). There was significant difference in the GST M1 genotype between the prostate cancer group and the control group (P=0.042). The GST M1 null genotype was significantly higher in the cancer group (59.4%) than in the control group (45.5%). However, our study did not reveal a significant association between prostate cancer and the distribution of the IGF-2 or EGFR genotypes. This study suggests that the GST M1 gene, but not the IGF-2 or the EGFR genes, may be a risk factor of developing prostate cancer in Taiwan.     

Oral cyclosporine but not tacrolimus reduces renal transplant blood flow

BACKGROUND: Calcineurin inhibitors are important immunosuppressive agents, but cause nephrotoxicity. METHODS: Instantaneous intra-renal transplant hemodynamics were assessed in 22 patients using quantitative cineloop color Doppler imaging after dosing with microemulsion cyclosporine (CSA) or tacrolimus (TAC). RESULTS: CSA dosing resulted in renal hypoperfusion, with a mean relative reduction of 43%+/-20% (range 22-76%) in maximal fractional area (MFA) of color pixels to nadir, compared to baseline. The mean effect occurred 1.1+/-0.9 hr (median 1 hr) after CSA dosing and was abrogated by calcium channel blockers (P <0.05). The main renal artery velocities, resistive index and small vessel perfusion were unchanged, suggestive of medium-sized arteries mediated vasoconstriction. In contrast, TAC did not alter renal vascularity (2.3+/-4.0% absolute reduction of MFA color pixels vs. 10.7+/-6.5% with CSA, P <0.01). CONCLUSION: CSA, but not TAC, induces phasic hypoperfusion of variable severity within small to medium sized intra-renal arteries soon after dosing, mitigated by calcium channel blockade.     

Endoglin gene insertion polymorphism not associated with aneurysmal subarachnoid hemorrhage

OBJECT: Data concerning an association between the ENG gene intronic insertion polymorphism and intracrahial aneurysms (IAs) remain inconsistent. In this study the authors investigated whether this polymorphism is associated with a subarachnoid hemorrhage (SAH) caused by a ruptured IA in a Polish population. METHODS: One hundred nineteen patients with aneurysmal SAH and 119 sex-matched healthy volunteers were studied. The insertion ENG gene polymorphism in intron 7 was identified using polymerase chain reaction-single-strand chain polymorphism method. The distribution of the insertion allele did not differ between the SAH (13%) and control (16%) cases (p = 0.36). The homozygous insertion/insertion genotype frequencies in these cases were 3.4 and 0.8%, respectively (p = 0.18). CONCLUSIONS: The authors failed to find an association between the intronic insertion polymorphism of the ENG gene and aneurysmal SAH in a Polish population.     

Human kallikrein-2 gene polymorphism is associated with the occurrence of prostate cancer

PURPOSE: Human glandular kallikrein, which is encoded by the human kallikrein-2 (KLK2) gene, is significantly associated with the occurrence of prostate cancer (PCa). We tested the association between a functional C748T polymorphism of the KLK2 gene and the occurrence of PCa. MATERIALS AND METHODS: Peripheral venous blood samples were obtained from 254 patients with PCa and 168 controls with benign prostatic hyperplasia. All control subjects had normal serum prostate specific antigen and proved to be free from malignancy on pathological examination of resected prostatic tissues. Serum prostate specific antigen, testosterone, Gleason score, clinical and pathological stage, tumor and prostate volume of the patients were investigated. The KLK2 gene polymorphism was determined by the polymerase chain reaction based restriction fragment length polymorphism method. RESULTS: The PCa group had a younger mean age +/- SEM (73.0 +/- 0.5 vs 74.7 +/- 0.5 years, p = 0.010) and higher C allele frequency (82.1% vs 74.7%, p = 0.010) than the control group. The frequency of the CC, CT and TT genotypes was 65.7%, 32.7% and 1.6% in patients with PCa, and 56.0%, 37.5% and 6.5%, respectively, in controls (p = 0.010). C allele carriers (CC and CT genotypes) were at significantly higher risk for PCa than TT homozygous subjects (p = 0.002). CC homozygous subjects were at significantly higher risk for PCa than T allele carriers (CT and TT genotypes) (p = 0.043). The PCa subgroup of patients with pathologically proved, localized PCa also had a higher frequency of the C allele (87.5% vs 74.7%, p = 0.026) and CC genotypes (78.7% vs 56.0%, p = 0.019) than controls. CONCLUSIONS: Our results suggest that the C allele of the functional C748T polymorphism of KLK2 may increase the risk of PCa.     

Transforming growth factor-beta1 gene polymorphism in renal transplant recipients

BACKGROUND: Cytokine transforming growth factor (TGF) is involved in regulation of tissue repair after injury. More recently, TGF-beta1 codon 10 gene polymorphism has been shown to be associated with circulating TGF-beta levels. We tested whether TGF-beta1 genotype polymorphism was predictive of renal allograft function decline. PATIENTS AND METHODS: The study population consisted of 129 consecutive cadaveric or living related renal transplant recipients at our center between 1985 and 2001. The recipient TGF-beta1 genotype polymorphism was determined from peripheral blood leucocytes DNA. The primary endpoint was rate of glomerular filtration rate decline between the first year and the third year of transplant. RESULTS: Baseline glomerular filtration rate as estimated by MDRD study equation at 1 year measured 50+/-17 mL/min/1.73 m2. At the end of the 3-year follow-up period, 52 patients (40%) experienced biopsy-confirmed acute rejections. Frequency and severity of allograft rejection did not differ with TGF-beta genotypes. However, the decline in glomerular filtration rate was significantly greater in Leu/Leu (TT) than Leu/Pro (CT) recipients, 6.3+/-16.9 mL/min/1.73 m2 versus 0.1+/-10.2 mL/min/1.73 m2, p=0.04. CONCLUSION: Our results demonstrate that recipient TGF-beta1 codon 10 Leu/Leu homozygosity is a potential risk factor of kidney allograft function decline.