Association between IGF-1 and chronic kidney disease among US adults

Background  

Insulin-like growth factor (IGF-1) has been associated with cardiovascular disease, hypertension and diabetes in previous studies. However, the association between IGF-1 and chronic kidney disease (CKD) has not been previously studied. Therefore, we examined the association between serum IGF-1 and CKD in a representative sample of US adults.     

常染色体显性遗传性多囊肾病患者与血管紧张素转换酶基因多态性的关系

目的 研究人常染色体显性遗传性多囊肾病（ADPKD）与血管紧张素转换酶（ACE）基因多态性的关系。 方法 用PCR方法对103例ADPKD患者及16个ADPKD家系（患者35例,非患病直系亲属30人）进行ACE基因多态性分析。收集患者及家系成员的临床资料,以发病年龄、肝囊肿、高血压、尿路感染、尿路结石、血尿等为主要参数,用统计学方法研究该病ACE基因多态性与ADPKD的关系。 结果 DD型患者的发病年龄比DI型患者早7.2岁[（31.90±11.41）岁比（39.10±10.08）岁];DD型患者的发病年龄比Ⅱ型患者[（46.15±14.74）岁]早14.25岁;DI型患者的发病年龄比Ⅱ型患者早7.05岁,各型间的差异均有统计学意义（均P ＜ 0.05）。3组间高血压、血尿差异有统计学意义。11个家系检查结果显示,ACE基因多态性在ADPKD家系中具有遗传连锁关系,但无统计学意义;家系中患病与非患病者ACE基因型频率差异无统计学意义;家系中患病与非患病者男女之间ACE基因型频率差异无统计学意义;家系中肾功能不全组与肾功能正常组之间DD型及D等位基因频率差异有统计学意义（P ＜ 0.05）。 结论 DD型患者的发病年龄较早,Ⅱ型患者的发病年龄较晚,DI型居中。DI型患者血尿的发生率较高,Ⅱ型患者血尿的发生率较低。DI型患者高血压的发生率较高。ACE基因多态性在ADPKD家系中不提供基因诊断信息; ACE基因多态性与人ADPKD的发病无显著相关性;ACE基因多态性与性别无明显关系。DD型基因型是ADPKD发生肾功能不全的易感因素。     

Association of glutathione S-transferase M1 and T1 gene polymorphism with oxidative stress in diabetic and nondiabetic chronic kidney disease

Background and Objective: Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that work as one of the endogenous antioxidants in our body. This study was designed to look into the association of GST polymorphism with oxidative stress in both diabetic and nondiabetic chronic kidney disease (CKD). Design and Methods: Three groups of patients (50 in each): diabetics without CKD (DM), diabetic CKD (DM-CKD), and nondiabetic CKD (NDM-CKD) and 50 age- and sex-matched healthy controls were recruited. Genotyping was done for GSTM1 and GSTT1 genes using a multiplex polymerase chain reaction. Serum GST and malondialdehyde (MDA) as a marker of oxidative stress were measured spectrophotometrically. Results: Based on genotyping, subjects were categorized as GSTM1+/GSTT1+, GSTM1?/GSTT1+, GSTM1+/GSTT1?, and GSTM1?/GSTT1?. Serum GST levels were lower among subjects with deletion in one/both GST genes, whereas MDA levels were found to be correspondingly raised. A negative correlation for MDA versus GST levels was observed among genotypes with one/both gene deletions. Presence of GSTM1+/GSTT1? and GSTM1?/GSTT1? was significantly higher among patients with CKD in both diabetics and nondiabetics. Interpretations and Conclusions: GSTM1 and GSTT1 deletions singly or together were associated with lower GST levels and higher oxidative stress in both diabetic and nondiabetic CKD. Interestingly, GSTT1 deletion appears to be associated with both diabetic and nondiabetic CKD irrespective of the GSTM1 status.     

No association of the -2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathy.

BACKGROUND: The clinical course of IgA nephropathy is highly variable, ranging from complete remission to progression with end-stage renal disease. Although the mechanisms involved in disease progression are not characterized in detail, loss of renal function is positively correlated with mononuclear cell infiltration. In general, chemokines play an important role in the directional recruitment of inflammatory cells. Recently, a polymorphism in the distal 5' regulatory region of the chemokine monocyte chemoattractant protein-1 (MCP-1), which affects gene expression, has been described (A/G at position -2518). The aim of our study was to evaluate a possible association of this polymorphism with disease progression in patients with IgA nephropathy, as well as susceptibility to this form of glomerulonephritis. METHODS: Blood samples from 207 patients with biopsy proven IgA nephropathy and 140 ethnically, age and sex-matched healthy controls were collected and genomic DNA was extracted. MCP-1 -2518 genotype was assessed by PCR, followed by restriction fragment length polymorphism analysis. Genotype distribution between the two groups was compared by chi(2) test. Cumulative renal survival was assessed by Kaplan-Meier plot and log-rank analysis. RESULTS: 111 (53.6%) patients had the MCP-1 -2518 wild-type A/A, 83 (40.1%) were heterozygous for the G allele and 13 (6.3%) patients showed homozygosity. The allelic distribution was not significantly different in the control group of 140 healthy blood donors (P = 0.71). Renal survival analysis of patients did not reveal statistically significant differences in cumulative survival (P = 0.32), median survival time and 5 year survival rate between the wild-type group and carriers of the G allele. Furthermore, the number of infiltrating CD68-positive monocytes/macrophages into the kidneys of patients with IgA nephropathy was not statistically different between the groups. CONCLUSION: Our data indicate that no association exists between the -2518 A/G polymorphism and susceptibility to IgA nephropathy or its clinical course.     

Association of sequence polymorphism in the mitochondrial D-loop with chronic kidney disease

Background: The mitochondrial displacement loop (D-loop) is known to accumulate mutations and single nucleotide polymorphisms (SNPs) at a higher frequency than other regions of mitochondrial DNA (mtDNA). Methods: This is a case–control study. We sequenced SNPs in the D-loop of mtDNA and investigated their association with the risk of chronic kidney disease (CKD). Results: A total of 144 SNPs referring to the positions of the Revised Cambridge Reference Sequence (rCRS) for mitochondrial genome were identified in a case–control study. The minor alleles of nucleotides 73G, 146C, 150T, 194T, 195C and 310C were associated with an increased risk for CKD patients. Conclusion: Analysis of genetic polymorphisms in the mitochondrial D-loop can help identify the people who are at a high risk of developing chronic kidney disease. These SNPs can be considered as potential predictors for CKD.     

The relationship between albuminuria, MCP-1/CCL2, and interstitial macrophages in chronic kidney disease

Glomerular-derived proteins may activate tubular cells to express the macrophage-directed chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Macrophages at interstitial sites have a central role in directing renal scarring. We have prospectively assessed the relationship between albuminuria, urinary MCP-1/CCL2, interstitial macrophage infiltration, in situ damage, and clinical outcomes in a large group of patients with chronic kidney disease. We studied 215 patients and quantified albumin-creatinine ratio (ACR), urinary MCP-1/CCL2, interstitial macrophage numbers, and in situ damage. ACR correlated with urinary MCP-1/CCL2 (correlation 0.499; P<0.001), interstitial macrophage numbers (correlation 0.481; P<0.001), and index of chronic damage (correlation 0.363; P<0.001). Macrophage numbers closely correlated with in situ damage (correlation 0.755; P<0.001). By multivariate analysis ACR, urinary MCP-1/CCL2, and interstitial macrophage numbers were interdependent. By Kaplan-Meier survival analysis albuminuria, urinary MCP-1/CCL2, interstitial macrophages, and chronic damage predict the outcome. ACR, macrophage numbers, chronic damage, and creatinine independently predicted renal survival. The association of ACR with other variables was strongest in patients with less advanced disease states. There is a close association between albuminuria, urinary MCP-1/CCL2, and interstitial macrophage infiltration with in situ damage and clinical outcomes. These findings support the hypothesis that albuminuria triggers tubular MCP-1/CCL2 expression with subsequent macrophage infiltration. These processes may represent the dominant pathway for the progression of renal injury before the establishment of advanced renal scarring.     

MCP-1 gene activation marks acute kidney injury

Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but whether this can be used as a biomarker of acute kidney injury (AKI) is unknown. We obtained kidney and urine samples from mice with intrarenal (maleate), prerenal (endotoxemia), or postrenal (ureteral obstruction) injury. We also studied the independent effects of uremia without concomitant kidney injury by performing bilateral ureteral transection in mice. Additionally, we obtained urine samples from APACHE II-matched critically ill patients with or without advancing azotemia (n = 10 in each group). We assayed selected samples for MCP-1, MCP-1 mRNA, and for an activating histone mark (H3K4m3) at urinary fragments of the MCP-1 gene and contrasted the results with those obtained for neutrophil gelatinase-associated lipocalin (NGAL), a comparator "AKI biomarker" gene. Maleate increased urinary MCP-1 protein and mRNA more than the corresponding increases in NGAL. Endotoxemia and ureteral obstruction also increased NGAL and MCP-1 gene expression. Uremia, in the absence of renal injury, induced the NGAL gene, but not MCP-1, suggesting the possibility of better specificity of MCP-1 for AKI. Clinical assessments supported the utility of MCP-1 as a biomarker (e.g., nonoverlapping concentrations of urinary MCP-1 in patients with and without AKI). Elevated levels of urinary MCP-1 mRNA and levels of H3K4m3 at the MCP-1 gene supported MCP-1 gene activation in patients with renal injury. In conclusion, these data suggest that MCP-1 has potential as a biomarker of AKI and provide "proof of concept" that urinary histone assessments provide mechanistic insight among patients with kidney disease.     

Association between cytomegalovirus disease and chronic rejection in kidney transplant recipients

BACKGROUND: It has long been suggested that cytomegalovirus (CMV) disease plays a role in the pathogenesis of chronic rejection (CR). However, its role has been difficult to prove, given the strong association between acute rejection and CMV, and the even stronger association between acute rejection and CR. To try to isolate the relative contribution of CMV infection in the pathogenesis of CR, we used multivariate techniques to examine risk factors for CR, including CMV disease. METHODS: Our study population consisted of adult recipients of a first kidney graft who underwent transplantation at a single center between 1/1/85 and 6/30/97 (n = 1339). RESULTS: Multivariate analysis using time to CR as the dependent variable demonstrated acute rejection to be the strongest risk factor (relative risk [RR] = 17.8, P = 0.0001), followed by older donor age (RR = 1.46, P = 0.01). The presence of CMV disease showed a trend toward increased risk for CR (RR = 1.30, P = 0.10), although the association was not as strong as with the other two variables. Comparing only those recipients with acute rejection and CMV disease versus those with acute rejection but no CMV disease, the relative risk of developing CR was 1.37 times higher in the former group. Recipients with acute rejection and CMV developed CR sooner and with a higher incidence versus those with acute rejection but no CMV (P = 0.002). It is interesting, however, that CMV disease was only a risk factor for CR in the presence of acute rejection. Recipients with no acute rejection and CMV disease did not have a higher incidence of CR versus those with no acute rejection and no CMV (P = NS). CONCLUSION: CMV disease seems to play some role in the pathogenesis of CR but only in the presence of acute rejection. Reasons may include (i) the inability to adequately treat acute rejection due to the presence of CMV disease or (ii) the increased virulence of latent CMV virus in recipients being treated for acute rejection. Our data may suggest a role for more aggressive prophylaxis against CMV disease, especially at the time of treatment for acute rejection.     

Association between the CX3CR1 gene V249I polymorphism and delayed kidney allograft function

BackgroundFractalkine is a member of the chemokine family that acts as an adhesion molecule and as an extracellular chemoattractant promoting cellular migration. In this study, we analysed the association between the CX3CR1 gene V249I (rs3732379) SNP and renal allograft function.MethodsThe study enrolled 270 Caucasian kidney allograft recipients. The following parameters were recorded in each case: the recipient's age and gender, delayed graft function (DGF) defined as the need for dialysis in the first 7 days after transplantation, occurrence and number of episodes of acute rejection (AR), and chronic allograft dysfunction (CAD).ResultsDelayed graft function was diagnosed in 39.2% of individuals with the CC genotype, 22.7% with CT and 23.5% of those with the TT genotype. The differences were statistically significant (CC vs. TT + CT: OR = 2.17; 95% CI = 1.28–3.70, p = 0.0042). In multivariate analysis the CC genotype was an independent and significant predictor of higher risk of DGF. The distribution of genotypes and alleles of the CX3CR1 gene polymorphism among patients with and without AR as well as CAD did not differ significantly.ConclusionsThe results of this study suggest that the CX3CR1 gene V249I (rs3732379) SNP CC genotype is associated with increased risk of DGF.     

CYP2D6基因多态性对慢性肾脏疾病合并高血压患者使用美托洛尔疗效的影响

目的 探讨CYP2D6基因多态性对慢性肾脏疾病合并高血压患者使用美托洛尔疗效的影响.方法 使用PCR荧光法检测95例患者CYP2D6基因型,并分为A组(基因型为*1/*1、*2/*2、*1/*2)、B组(基因型为*1/* 10、*2/* 10)、C组(基因型为*10/* 10).3组患者治疗前血压、心率、性别、年龄、体质指数(BMI)、血脂、空腹血糖差异无统计学意义.使用相同剂量美托洛尔,比较3组患者治疗1个月后收缩压、舒张压、心率的变化.结果 A组与C组治疗后收缩压、舒张压、心率变化的差异无统计学意义,A组与B组、C组与B组治疗后收缩压、舒张压、心率变化的差异差异均有统计学意义.结论 CYP2D6基因多态性对慢性肾脏疾病合并高血压患者使用美托洛尔的疗效有影响.     

MCP1 2518 A/G polymorphism affects progression of childhood focal segmental glomerulosclerosis

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is a highly specific chemokine for monocytes and plays roles in pathogenesis of various renal diseases. The aim of this study is to investigate the effect of MCP1 2518 A/G polymorphism on the incidence and clinical course of focal segmental glomerulosclerosis (FSGS) in children. MCP1 2518 A/G genotype was identified by PCR-RFLP in 60 biopsy-proven FSGS patients, 76 steroid sensitive nephrotic syndrome (SSNS) patients, and 96 healthy children. MCP-1 levels in urine and serum were measured by ELISA in all patients and the correlations of genotype with MCP-1 levels and clinical outcome were evaluated. The genotype frequencies for MCP1 were similar in all groups. The percentage of patients who develop chronic renal failure was higher in patients with AA allele compared to GA or GG alleles (46% vs. 35% respectively, p?<?0.01, Odds ratio: 1.59). Serum MCP-1 levels were similar in all groups, whereas urinary MCP-1 levels of the patients with FSGS (1680?pg/mg creatinine) were significantly higher than that of patients with SSNS (365?pg/mg creatinine, p?<?0.05) and healthy controls (348?pg/mg creatinine; p?<?0.05). Urinary MCP-1 levels were correlated with the degree of proteinuria in FSGS group (r?=?0.529, p?=?0.016). Our results suggest that the AA genotype might be a risk factor for the progression of renal disease in FSGS and MCP1 genotyping may help the physicians to predict prognosis in these patients.     

Association between serum magnesium and anemia in patients with chronic kidney disease

International Urology and Nephrology - An inverse association was shown between serum magnesium levels and anemia in the general population. However, limited information is available about the...     

Association between cumulative exposure to blood pressure and new-onset chronic kidney disease

Objective To investigate the association between cumulative exposure blood to pressure (cum BP) and new-onset chronic kidney disease (CKD). Methods In this prospective cohort study, 101 510 employees of Kailuan Group receiving annual health examination during 2006 to 2007 were observed. The participants received the second, third, and fourth annual health examinations during 2008 to 2009, 2010 to 2011, and 2012 to 2013 year respectively. Their urinary and serum creatinine were tested, and participants with incomplete SBP, DBP data and CKD were excluded. Further excluding those who somehow failed to take annual health examination, with incomplete data, or new-onset CKD 27 809 participants were selected in the analysis. According to cum BP exposure quintile grouping: Q1＜3.70 scores; Q2: 3.70-6.16 scores; Q3: 6.17-8.45 scores; Q4: 8.46-10.95 scores; Q5≥10.96 scores. Multivariate Logistic regression was used to analyze the association between cum BP level and new-onset CKD by cum BP exposure quintile grouping. Results The rise of cum BP exposure level caused the increased incidence of CKD. The incidences of CKD in the five quintile groups were 2.59%, 3.11%, 4.19%, 5.81%, and 7.73% respectively (P＜0.01). Compared with Q1 group, multivariate logistic regression analysis showed that after the adjustment of age, gender, education, income, smoking, drinking, BMI, FBG, TC, TG, LDL, HDL, UA and CRP, the incidences of CKD gradually increased in the Q2, Q3, Q4, and Q5 cum BP quintile groups, and OR(95%CI) values were 1.08(0.86-1.35), 1.26(1.01-1.58), 1.57(1.27-1.95), 1.78(1.43-2.21) respectively (P for trend＜0.01). Similar results were obtained in different genders. For each single point increase of cum BP exposure level, the incidence of CKD increased 6% in the general population (P for trend＜0.01), increased 8% in male (P for trend＜0.01), and 3% in female (P for trend=0.12). Conclusion As the cumulative exposure to blood pressure increases, the risk of CKD incidence rises, especially in men.     

Association between prehypertension and chronic kidney disease in the Japanese general population

The increased prevalence of chronic kidney disease (CKD) is a consequence of the accumulation of risk factors, one of which is hypertension. Here we assessed the prevalence of CKD according to blood pressure among 232,025 patients in a Japanese nationwide database with a focus on the prevalence and risk factors of CKD in prehypertension. Patients were stratified by blood pressure and included 75,474 with optimal blood pressure (less than 120/80 mm Hg); 59,194 with prehypertension and a normal blood pressure (120-129/80-84 mm Hg) or 46,547 patients with high-normal blood pressure (130-139/85-89 mm Hg); and 50,810 with hypertension (over 140/90 mm Hg without anti-hypertensive drugs). CKD was defined as an estimated glomerular filtration rate of stage 3 or lower or having proteinuria greater than 1+ by a dipstick method. The prevalence of CKD among patients with optimal blood pressure, prehypertension having normal or high-normal blood pressure, and hypertension was 13.9, 15.6, 18.1, and 20.7% in men, and 10.9, 11.6, 12.9, and 15.0% in women, with a significant difference between genders at each strata of blood pressure. In men, but not in women, whose blood pressure was high-normal, the CKD risk was significantly greater (odds ratio 1.11) than those with optimal blood pressure. Obesity (body mass index over 25) was significantly associated with an increased risk of CKD in both men and women (odds ratio 1.43 and 1.26, respectively), and there was an additive effect of obesity and pre-hypertension on CKD risk in men compared with men with optimal blood pressure. Thus, the prevalence of CKD increased with the severity of blood pressure. Prehypertension with high-normal blood pressure, particularly in conjunction with obesity, was found to be an independent risk factor of CKD in men.