Renin-angiotensin polymorphisms and QTc interval prolongation in end-stage renal disease

BACKGROUND: Polymorphisms of renin-angiotensin system (RAS) genes in patients with end-stage renal disease (ESRD) on chronic hemodialysis may be associated with QTc interval prolongation, leading to fatal arrhythmias. The objective of this study was to determine (1) the prevalence of QTc prolongation in hemodialysis patients, and (2) the association of a prolonged QTc in these patients with RAS polymorphisms [angiotensin-converting enzyme-insertion/deletion (ACE-I/D), angiotensin type 1 receptor-A1166C (AT1R-A1166C), and angiotensinogen-M235T (AGT-M235T)]. METHODS: Twelve-lead electrocardiograms (ECGs), serum electrolytes (sodium, potassium, and calcium), and ACE and angiotensin II levels were obtained 10 to 12 hours after a hemodialysis session in 43 patients with ESRD on chronic hemodialysis [mean age (+/-SD), 55 +/- 14 years]. Using polymerase chain reaction (PCR), the presence of polymorphisms of the ACE-I/D, AT1R-A1166C, and AGT-M235T genes was determined from the buccal cells. A maximum QT interval in patients with sinus rhythm and normal QRS duration was corrected for heart rate using Hodges' formula. RESULTS: Fifty-eight percent of the patients had QTc interval prolongation (>440 msec). The ACE-DD genotype (P = 0.002) and the C allele of the AT1R-A1166C gene (P = 0.004), but not the AGT-M235T gene, contributed to QTc prolongation. CONCLUSION: Polymorphisms of ACE and AT1R genes additively contribute to QTc prolongation found in a great majority of ESRD patients. Therefore, ESRD patients with both or one of these polymorphisms may be at a higher risk for sudden cardiac death.     

Renin-angiotensin system polymorphisms in Taiwanese primary vesicoureteral reflux

We studied the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms for association with susceptibility to primary vesicoureteral reflux (VUR) and disease progression in 74 Taiwanese children, including 16 with end-stage renal disease (ESRD), and 117 normal controls. Polymerase chain reaction-amplified products containing the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, Alu I/D, the AGT gene C-532T, G-217A, G-152A, A-20C, A-6G, T174M, T235M, and the AT1R gene A-1138T, T-810A, T-713G, C-521T, AG-214CC, A-153G, A1166C polymorphisms were analyzed by restriction enzyme digestion, gel electrophoresis, or single-strand conformation polymorphism analysis. All the polymorphisms examined were in Hardy-Weinberg equilibrium. The strong non-random association within the ACE, AGT, and AT1R genes suggests low levels of intragenic recombination. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of the six ACE polymorphisms among primary VUR patients with or without ESRD was statistically different. The linked ACE T-A-T-A-A-I allele was observed significantly more frequently in VUR children with ESRD (P<0.001). A significant increase of left ventricular mass index was also found in the linked ACE T-A-T-A-A-I allele group compared with the non-ACE T-A-T-A-A-I allele group of patients aged 18 years with renal progression. The AGT A-6G genotype frequencies were significantly different when the analysis was stratified by genotype of the ACE polymorphisms. The data showed that ACE gene polymorphisms were associated with progressive renal deterioration in Taiwanese children with VUR and might act synergistically with the –6 G allele of the AGT gene.Kuo-Pao Liu and Ching-Yuang Lin contributed equally to this work     

Renin-angiotensin system polymorphisms and hemoglobin level in renal allografts: a comparative study between losartan and enalapril

INTRODUCTION: In this study, hemoglobin (Hb) concentrations secondary to enalapril (E) or losartan (L) therapy were evaluated with respect to renin-angiotensin system (RAS) polymorphisms in renal transplant recipients. MATERIALS AND METHODS: After determination of RAS polymorphisms [angiotensin-converting enzyme (DD, non-DD), angiotensinogen (TT, non-TT), and angiotensin receptor type 1 (CC, non-CC)] by polymerase chain reaction, 70 renal transplant recipients were recruited to four groups randomly: first and second groups were treated with E (10 mg/d, 15 patients) and L (50 mg/d, 20 patients) alone, respectively. The third group received E+L (10 mg/d + 50 mg/d, 13 patients) and the fourth group (22 patients) received no medication. The treatment protocol was followed for 16 weeks. Complete blood counts were checked before treatment and every 2 months. P<.05 was considered to indicate statistical significance. RESULTS: Treatment for 4 months decreased the Hb level in the E+L (14.15 +/- 0.94 to 12.06 +/- 0.66 g/dL, P=.000), E (14.00 +/- 0.86 to 13.11 +/- 0.82 g/dL, P=.02), and L (14.12 +/- 0.90 to 12.10 +/- 2.35 g/dL, P=.01) groups, but not in the control group (13.55 +/- 0.70 to 13.36 +/- 0.69 g/dL, P>.05). None of these regimens showed greater Hb reduction than the others (P>.05). None of the RAS polymorphisms predicted the intensity of the reduced Hb according to the type of treatment (P>.05). Any other sets of RAS polymorphisms (alone or together) did not impact on Hb levels pre- or post-intervention (P>.05). CONCLUSION: Our findings suggest that low dosages of E and/or L decrease Hb levels regardless of the RAS polymorphisms.     

Renin-angiotensin system component gene polymorphisms in Japanese maintenance haemodialysis patients

Summary: The renin-angiotension system (RAS) component gene polymorphisms was examined in 216 patients undergoing maintenance haemodialysis (HD) therapy and in 208 control subjects. the RAS polymorphisms selected for analysis were angiotensin I converting enzyme (ACE) I/D, angiotensinogen (Agt) T235/M235, angiotensin II type 1 receptor (AGT1R) A1166/C1166. the control allelic frequencies was ACE I/D (0.63/0.37), Agt T235/M235 (0.16/0.84), and AGT1R A1166/C1166 (0.94/0.06). Recently, relationships between ACE I/D and the progression of renal disease attract great attention in Japanese and Caucasian populations. ACE D allele was expected to be more frequent in HD population. However, no accumulation of ACE D allele or Agt T235 allele, AFT1R C1166 allele in Japanese end-stage renal disease (ESRD) subjects was detected. to explain the paradoxical result of positive association of ACE D allele with progression of renal disease and no bias of ACE genotype in ESRD subjects, further investigation with systematic prospective study regarding the change of ACE genotype distribution around the period of entering dialysis therapy is required.     

Renin-angiotensin system

Renin, a protease that cleaves the prohormone angiotensinogen thereby releasing angiotensin I, plays a major role in regulating blood pressure and electrolyte balance. Although renin is synthesized mainly in the cortical cells of the kidney, the presence of renin or reninlike activity has been recognized in various extrarenal tissues of humans and animals, including such reproductive organs as LH-containing cells of the anterior pituitary, placentral trophoblasts, and Leydig cells of the male gonad. It has also been learned that the renin in these extrarenal tissues generates angiotensins locally, which may interact with angiotensin II receptors in a paracrine or autocrine manner. However, the precise roles of the renin-angiotensin system in extrarenal tissue are not yet understood. We demonstrated the renin-angiotensin system in human testis by measuring the plasma renin activity (PRA), plasma angiotensin II (PAII), and testosterone in the internal spermatic vein (ISV) simultaneously after treatment with hCG, and elucidated the relationship between the renin-angiotensin system and sex steroids from Leydig cells of the male gonad.     

ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5–14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage (P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04–6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.M. Kosti and A. Stankovi contributed equally to this work     

TLR-4 polymorphisms and leukocyte TLR-4 expression in febrile UTI and renal scarring

Background

In this study, we aimed to determine the relation of TLR-4 Asp299Gly and Thr399Ile polymorphisms and monocyte/neutrophil TLR-4 expression to febrile urinary tract infection (UTI) and renal scar development in children.

Methods

The study was performed in children with a history of febrile UTI. Patients with and without renal scarring were classified as group 1 and group 2, respectively, while the control cases in our previous study were used as the control group (group 3). All three groups were compared for the rate of TLR-4 Asp299Gly and Thr399Ile polymorphisms, and for basal and lipopolysaccharide-stimulated monocyte/neutrophil TLR-4 expression levels.

Results

There were 168 patients (86 in group 1, 82 in group 2) and 120 control cases. Monocyte/neutrophil TLR-4 expression levels were similar in groups 1 and 2. However, both groups had lower TLR-4 expression than group 3. The rate of TLR-4 Asp299Gly polymorphism was not different in all groups. TLR-4 Thr399Ile polymorphism was higher in groups 1 and 2 than in group 3 (14.0, 12.2, and 2.0 %, respectively), while group 1 and group 2 were not different. Furthermore, monocyte TLR-4 expression level was lower in those having TLR-4 Thr399Ile polymorphism than in those without this polymorphism.

Conclusions

Patients with febrile UTI had more frequent TLR-4 Thr399Ile polymorphism and lower monocyte/neutrophil TLR-4 expression. These findings indicate that children carrying TLR-4 Thr399Ile polymorphism and/or having low level of monocyte/neutrophil TLR-4 expression have a tendency to develop febrile UTI. However, we could not show the association of TLR-4 polymorphisms and of TLR-4 expression level to renal scarring.     

Outcome of post-infectious renal scarring

In this issue of Pediatric Nephrology, Gebäck et al. from Gothenburg, Sweden, show that after a mean follow-up after childhood urinary tract infection of 41 years, kidney function decreases from a mean of 93 ml/min/1.73m² to 81 ml/min/1.73m². This was found in women with severe bilateral renal scarring. They had experienced their UTI during childhood in the 1950s and 1960s and had been drawn from a population-based cohort of more than 1,000 children. A previous paper on this same group of women had shown a higher systolic blood pressure of 3 mmHg during the day and 5 mmHg during the night compared with a control group. This contrasted with a follow-up study published earlier by the same group on two different cohorts in which no impairment of kidney function or increase in hypertension could be found. The present follow-up time was 13 years longer than that of any previous studies. Data on the long-term outcome of children who have had one or several urine infections is very important, as the fear of long-term complications has been driving the extensive investigations to which these children have traditionally been subjected. Further population-based follow-up data can help us to outline modern guidance on imaging after UTI.     

Renin-angiotensin genes in renal development and the occurrence and progression of renal diseases

The function of angiotensin II has evolved from recognition of its vasoconstrictive functions and regulations of fluid balance to its pivotal role in progressive tissue destruction, particularly renal scarring. This review highlights angiotensin's newest role in normal and abnormal organogenesis as well as the impact on renal damage of subtle variations in genes that control angiotensin's actions including angiotensinogen, angiotensin converting enzyme, and its receptors.     

肾素－血管紧张素系统在骨关节炎发病中的研究

骨关节炎是一种以关节软骨退变为主的慢性疾病，但其具体发病机制目前仍不清楚。肾素－血管紧张素系统在维持人体内部环境的稳定中起着重要作用，近年来也被认为在骨关节炎的发生、发展中发挥重要的调控作用。本文针对肾素－血管紧张素系统信号通路调控骨关节炎及退变的分子机制进行综述。     

Myofibroblast phenotypes expression in experimental renal scarring

Background. Myofibroblasts have been implicated in the pathogenesis of wound healing and tissue fibrosis. A role has also been put forward for these cells in the development of experimental and clinical renal scarring. Subjects and methods. We examined the expression of myofibroblast phenotypes by immunohistochemistry, relying on an avidin-biotin-peroxidase method, during the course of renal scarring in rats submitted to subtotal (5/6) nephrectomy (SNx). We also attempted to identify changes in immunoreactive transforming growth factor-{beta} (TGF-{beta}) and collagen (III and IV) within remnant kidneys in order to determine their association with the expression of the myofibroblasts. Results. In normal sham-operated rats, &agr;-smooth muscle actin (&agr;-SMA) was confined to the media of renal arteries and arterioles. In contrast, in rats with renal ablation we observed the early (day 7) appearance of myofibroblasts expressing &agr;-SMA (A) in the interstitium of remnant kidneys particularly around vessels. Interstitial cells expressing &agr;-SMA increased with time as tubulointerstitial fibrosis progressed. By day 30 some interstitial cells also expressed vimentin (V). Various interstitial myofibroblast phenotypes (A, V, VA) were expressed during the course of experimental renal scarring. Interstitial myofibroblasts appeared to be associated with TGF-{beta} as these cells' cytoplasm stained for both this growth factor and &agr;-SMA. Interstitial fibrosis was also associated with increased interstitial expression of both collage III and IV. Some atrophic tubular cells showed positive immunostaining for vimentin during the late stages of renal scarring (days 90-150). In the glomeruli, a segmental expression of &agr;-SMA was noted from day 21 after SNx onward. Normal glomerulal endothelial cells appeared to express vimentin while epithelial cells expressed both vimentin and desmin (D). The glomerular immunostain for vimentin increased with time but decreased as glomerulosclerosis progressed. In contrast, glomerula desmin and &agr;-SMA immunostain continued to rise with progressive glomerulosclerosis. This was associated with the appearance of type III collagen within scarred glomeruli. Both vimentin and desmin appeared within the walls of the renal arterioles and increased with time from day 7 and 15, respectively. Vimentin was also expressed in the peritubular capillaries of remnant kidneys. By contrast, &agr;-SMA, normally present in the media of arterioles, decreased as arteriolar sclerosis progressed. These changes cannot be exclusively attributed to systemic hypertension as they were absent in a group of age-matched, sham-operated, spontaneously hypertensive rats. Discussion: Myofibroblasts may play a role in the pathogenesis of glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis. Further, the aquisition of new myofibroblastic phenotypes by glomerular and tubular cells may contribute to renal fibrosis.     

Can postpyelonephritic renal scarring be prevented?

Pyelonephritis in childhood may, in the worst cases, lead to long-term cardiovascular morbidity due to tubulointerstitial renal scarring. Renal damage is the end result of an interplay between (1) urinary tract anatomy and function, (2) bacterial virulence factors, and (3) the host innate immune system, which on the one hand manages bacterial clearance, but on the other causes tubulointerstitial inflammation, which underlies the renal scarring. It is unclear how common postpyelonephritic scarring is, and how many of the "scars" in fact represent congenital renal hypoplasia. We do, however, know that some situations have an increased risk for scars, i.e., large renal-uptake defects on initial renal scintigraphy or pyelonephritis in young girls with dilating vesicoureteral reflux. It seems logical that antiinflammatory or antioxidant therapy given concomitantly with antibiotics should lower the risk of postpyelonephritic scarring. Animal studies give some support to this idea, but research on humans has been surprisingly scant. In this issue of Pediatric Nephrology, we publish a study that indicates that antioxidant therapy with vitamin A or E given to children with pyelonephritis may indeed lower the risk for renal scarring. This is a track that needs to be pursued further.