Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ‘’cancer pandemic’’. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors (AU)

Intestinal microbiota and diabetic kidney diseases: the Role of microbiota and derived metabolites inmodulation of renal inflammation and disease progression.

Diabetic kidney disease (DKD) represents a growing public health burden and is the leading cause of end-stage kidney diseases. In recent years, host-gut microbiota interactions have emerged as an integral part for host homeostasis. In the context of nephropathies, mounting evidence supports a bidirectional microbiota-kidney crosstalk, which becomes particularly manifest during progressive kidney dysfunction. Indeed, in chronic kidney disease (CKD), the "healthy" microbiota structure is disrupted and intestinal microbes produce large quantities of uremic solutes responsible for renal damage; on the other hand, the uremic state, fueled by reduced renal clearance, causes shifts in microbial metabolism and composition, hence creating a vicious cycle in which dysbiosis and renal dysfunction are progressively worsened. In this review, we will summarize the evidence from clinical/experimental studies concerning the occurrence of gut dysbiosis in diabetic and non-diabetic CKD, discuss the functional consequences of dysbiosis for CKD progression and debate putative therapeutic interventions targeting the intestinal microbiome.

Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics.

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ''cancer pandemic''. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors.

Serum uric acid as a surrogate marker of favorable response to bevacizumab treatment in patients with metastatic colon cancer

Bevacizumab is a monoclonal antibody which is a vascular endothelial growth factor inhibitor. It obscures vascularization of tumor tissue and damages intratumoral microcirculation. The damaged intratumoral microcirculation leads to tissue hypoxia and results in increase of uric acid level. The main aim of our study was to investigate the relationship between uric acid change and response to bevacizumab therapy. This study included a total of 158 patients with metastatic colorectal cancer who had received bevacizumab therapy. The number of male patients was 100 (63.3 %) while female patients number was 58 (37.7 %). The median age was 61 (29-83). There was relationship between increase of uric acid level of third month uric acid level and stable disease (p < 0.001). There was a significant overall survival increased in the group with increased uric acid level (p < 0.001). The decline of CEA level was related to uric acid level (p < 0.022). In conclusion, this study is the first showing significant increases of serum uric acid in patients with metastatic colorectal cancer who favorably responded to chemotherapy with bevacizumab. But further studies are justified to test whether monitoring uric acid levels might predict clinical outcomes of patients with metastatic colorectal cancer (AU)

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Serum uric acid as a surrogate marker of favorable response to bevacizumab treatment in patients with metastatic colon cancer.

Bevacizumab is a monoclonal antibody which is a vascular endothelial growth factor inhibitor. It obscures vascularization of tumor tissue and damages intratumoral microcirculation. The damaged intratumoral microcirculation leads to tissue hypoxia and results in increase of uric acid level. The main aim of our study was to investigate the relationship between uric acid change and response to bevacizumab therapy. This study included a total of 158 patients with metastatic colorectal cancer who had received bevacizumab therapy. The number of male patients was 100 (63.3 %) while female patients number was 58 (37.7 %). The median age was 61 (29-83). There was relationship between increase of uric acid level of third month uric acid level and stable disease (p < 0.001). There was a significant overall survival increased in the group with increased uric acid level (p < 0.001). The decline of CEA level was related to uric acid level (p < 0.022). In conclusion, this study is the first showing significant increases of serum uric acid in patients with metastatic colorectal cancer who favorably responded to chemotherapy with bevacizumab. But further studies are justified to test whether monitoring uric acid levels might predict clinical outcomes of patients with metastatic colorectal cancer.

Peri-aortic fat tissue and malnutrition-inflammation-atherosclerosis/calcification syndrome in end-stage renal disease patients.

PURPOSE: Thoracic peri-aortic fat tissue (PFT) is considered as a metabolically active organ in atherosclerosis. Malnutrition, inflammation and atherosclerosis/calcification (MIAC) are the most commonly encountered risk factors of cardiovascular disease in end-stage renal disease (ESRD) patients. Calcification of the aorta was found to be an important cardiovascular risk marker predicting future events, morbidity and mortality in this population. We aimed to investigate the relationship between PFT, MIAC syndrome and thoracic aortic calcification (TAC) in ESRD patients. METHODS: Seventy-nine ESRD patients receiving hemodialysis (HD) or peritoneal dialysis (PD) and 20 control subjects were enrolled in this cross-sectional study. PFT and TAC were assessed using a 64-MDCT scanner. Patients with serum albumin <3.5 g/dL were defined as patients with malnutrition; those with serum C-reactive protein level >10 mg/L had inflammation, and those with coronary artery calcification score (CACS) >10 had atherosclerosis/calcification. RESULTS: TAC and PFT were significantly higher in ESRD patients compared with control subjects. There was a statistically significant relationship between PFT and TAC in ESRD patients (r = 0.458, p < 0.0001). PFT was found to be significantly increased when the MIAC components increased. PFT was positively associated with age, BMI, uric acid, hemoglobin and CAC. The multivariate analysis revealed that age and uric acid were independent predictors of increased PFT. Twenty-four (30.4 %) patients had none, 30 (37.9 %) had one component, 17 (21.5 %) had two components, and 8 (10.2 %) had all MIAC components. PFT was highest among patients having all three components (28.6 cm(3)) and lowest among those who do not have the MIAC syndrome (8.54 cm(3)). TAC was highest among patients having all three components (179.2 HU) and lowest among those who do not have the MIAC syndrome (0 HU). CONCLUSIONS: We found a relationship between PFT and MIAC syndrome in ESRD patients.

Ocular pulse amplitude and retrobulbar blood flow change in dipper and non-dipper individuals.

PURPOSE: To evaluate ocular pulse amplitude (OPA), IOP values, and hemodynamic changes in the ophthalmic artery, central retinal artery, and short posterior ciliary artery in dipper and non-dipper patients. METHODS: A total of 59 right eye measurements of healthy subjects with normotensive were included to the study. Ambulatory blood pressure (BP) monitoring measurement (ABPM), Doppler imaging, and OPA measurements were performed in the same day. The patients in which systolic BP decreased during the nocturnal time by 10% of the diurnal BP or more were called dippers. A patient whose nocturnal systolic BP fell by <10% or even rose was defined as non-dipper. Color Doppler imaging was used for blood flow velocity assessment of ophthalmic, central retinal, and posterior ciliary arteries. For each artery, peak systolic and end-diastolic velocities (PSV and EDV, respectively), resistive index (RI), and pulsalite index (PI) were automatically calculated by the machine. Mean IOP and OPA values were calculated after three consecutive measurements. RESULTS: The mean OPA in non-dipper patients was significantly lower compared with that of dipper patients (P=0.011). There was no significant difference in IOP levels between groups. There was no significant difference in the PSV, EDV, RI, and PI in the ophthalmic, posterior ciliary, and central retinal arteries between the groups. CONCLUSION: Our study demonstrated that OPA level in non-dippers is lower than dippers. This may give additional information about the effect of BP changes on OPA values.

Chronic kidney disease after hematopoietic cell transplantation: a systematic review.

Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD); however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9317 adults and children underwent HCT and 7317 (79%) survived to at least 100 days, permitting inclusion of 5337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in mL/min/1.73 m(2)) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (DeltaeGFR = -40.0 versus -18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common; however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.

Effect of peritoneal dialysis solution type on serum lipid levels in end-stage renal disease.

Among the different cardiovascular risk factors, lipid abnormalities dominate the high mortality in chronic ambulatory peritoneal dialysis patients. So far, no data comparing the effect of standard glucose-containing, amino acid-containing, and icodextrin-containing peritoneal dialysis solutions on serum lipid concentrations in a chronic ambulatory peritoneal dialysis population are available. To determine the effect of peritoneal dialysis solutions on parameters of lipid metabolism, 67 subjects who had continued their usual dialysis for the last six months were enrolled in the study. Group A consisted of 18 patients who were receiving only glucose-based peritoneal dialysis solutions, group B consisted of 18 patients who were receiving glucose and amino acid-based peritoneal dialysis solutions, and group C consisted of 31 patients who were receiving glucose and icodextrin-based peritoneal dialysis solutions. Serum lipid parameters including total cholesterol, low-density lipoprotein, high-density lipoprotein, triglyceride, and lipoprotein (a) were determined in all groups. No significant difference in serum lipid parameters was found between groups A, B, and C. These results demonstrate the lack of the effect of amino acid or icodextrin-based peritoneal solutions on dyslipidemia of CAPD patients.

Effects of immunosuppressive drugs on serum lipid levels in renal transplant recipients.

BACKGROUND: Hyperlipidemia is an important metabolic disorder that is common among renal transplant recipients. This study investigated the possible effects of transplantation and immunosuppressive drugs on lipid profiles in this patient group. METHODS: We retrospectively evaluated the records of 179 patients who underwent renal transplantation between 1996 and 2000, recording lipid profile findings-total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), and triglyceride (TG)-before and at least 6 months after transplantation. We also recorded patient demographics, underlying renal disorder, and immunosuppressive drug regimens. RESULTS: Sixty-nine (38.5%) patients were women and 110 men (61.5%). The mean age (+/- SD) of the 179 recipients was 35.7 +/- 11.8 years (range, 11 to 62 years). The respective pre- versus posttransplantation lipid profile findings were: TC, 171.6 +/- 42.4 mg/dL versus 204.7 +/- 45.3 mg/dL, P < .001; LDLc, 114.5 +/- 34.5 mg/dL versus 142.2 +/- 39.7 mg/dL, P < .001; HDLc, 46.7 +/- 13.6 mg/dL versus 42.5 +/- 12.3 mg/dL, P = .001; TG, 142.9 +/- 55.7 mg/dL versus 178.8 +/- 71.8 mg/dL, P < .001. Increased lipid levels were found to be independent of patient age, sex, donor type, and immunosuppressive drug regimen. CONCLUSION: The results suggested that antihyperlipidemic drugs should be administered routinely to renal transplant recipients irrespective of the immunosuppressive drug regimen or graft source.

Relationship of posttransplantation erythrocytosis to hypercalcemia in renal transplant recipients.

Experimental studies have demonstrated that calcium is an essential molecule in modulation of erythropoiesis. The aim of this study was to investigate the role of serum calcium levels on the development of posttransplantation erythrocytosis (PTE) among renal transplant recipients. We enrolled 155 patients (36 females/119 males; mean age, 34.9 +/- 9.7 years) with normal graft function who underwent renal transplantation between 1999 and 2002. All of the demographic features and various laboratory parameters were retrospectively analyzed as possible factors associated with erythrocytosis. PTE appeared in 43 (27.7%) patients during the follow-up period. Sixty-three (40.6%) patients developed hypercalcemia (corrected serum calcium level > or =10.2 mg/dL). Serum calcium levels tended to increase in patients with PTE, but significantly decreased in patients without PTE (10.6 +/- 0.6 vs 9.8 +/- 0.5 mg/dL; P < .0001). Similarly, hypercalcemia was more common among patients with PTE compared with patients without PTE (74.4% vs 27.7%; P < .0001). Hypercalcemic patients had a significantly higher frequency of PTE than normocalcemic patients (50.7% vs 11.9%; P < .0001). There were no differences in other laboratory and demographic data between the patients with and without PTE (P > .05). These findings suggest that hypercalcemia may lead to increased PTE in renal transplant recipients.

Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients.

Although hyperuricemia is a well-known adverse effect of cyclosporine (CsA) treatment, there are contradictory data regarding the effect of tacrolimus on uric acid levels. The aim of this study was to examine the influences of CsA and tacrolimus-based treatment regimens on serum uric acid levels in 155 renal transplant recipients with normal allograft function who underwent renal transplantation between 1999 and 2002. Serum uric acid levels were recorded at 1, 6, 12, 18, and 24 months follow-up. The patients were treated with CsA-based (n = 73), tacrolimus-based (n = 47), or conversion from CsA-based to tacrolimus-based (n = 35) immunosuppressive regimens. Serum uric acid levels for patients in the CsA and tacrolimus groups were 6.3 +/- 1.6 versus 7.9 +/- 1.9 mg/dL and 6.5 +/- 1.8 versus 8.0 +/- 1.8 mg/dL at the study outset and 24 months, respectively. Both of the treatment regimens showed progressively increasing serum uric acid levels (P < .001). Serum uric acid levels of patients with treatment conversion from CsA to tacrolimus were 8.6 +/- 2.8 mg/dL before conversion and 8.1 +/- 1.9 mg/dL after conversion. There was no alteration in serum uric acid levels after the change of treatment (P > .05). These findings indicate that, compared with CsA, tacrolimus offers no advantage for serum uric acid levels in renal transplant recipients.

Acute pancreatitis due to ramipril therapy.

Few data exist about the incidence of drug induced acute pancreatitis in the general population. Drugs are related to the aetiology of pancreatitis in about 1.4%-2% of cases. Although angiotensin converting enzymes are generally well tolerated, acute pancreatitis has been reported in a few subjects treated with captopril, enalapril, and lisinopril. A 85 year old man with a long standing history of hypertension, who was treated with ramipril 5 mg once daily, presented with acute pancreatitis. Other causes of the disease were ruled out. After cessation of ramipril his condition improved and amylase level decreased. This was his third episode of acute pancreatitis since ramipril was started in 2000. To the authors' knowledge ramipril induced pancreatitis has not previously been reported.

Causes of anemia in renal transplant recipients.

Iron-deficiency anemia is one of the major problems encountered in renal transplant recipients. The aim of this retrospective study was to reevaluate the causes of anemia among 100 anemic kidney recipients. Patients with serum creatinine levels greater than 2 mg/dL were excluded from the study. Female patients were considered to be anemic if the hemoglobin was <12 g/dL for males, <13 g/dL. Complete blood count, serum creatinine, serum iron, iron-binding capacity, ferritin, transferrin saturation, erythrocyte folate, and serum vitamin B(12) levels were measured in all patients. Mean hemoglobin value was 10.2 +/- 1.4 g/dL for female and 9.9 +/- 1.3 for male patients, mean corpuscular volume (MCV) 91.3 +/- 4.9 fL. We observed normocytic anemia in 60, macrocytic anemia in 30, and microcytic anemia in 10 patients. A low level of serum folate was observed in 9 (15%) and of vitamin B(12) in 5 (8.8%) of 60 patients with normocytic anemia. Folate deficiency was found in 18 (60%) and vitamin B(12) deficiency in 12 (40%) of 30 patients with macrocytic anemia. All patients with microcytic anemia had iron deficiency. Splenomegaly was seen significantly more often in patients with macrocytic than normocytic anemia (P =.008). Folate and vitamin B(12) deficiency were the major causes of nutritional anemia; oral or parenteral supplementation with these vitamins is likely to cure the anemia in the majority of cases.