Kuo Cheng Lu

Role of circulating cytokines and chemokines in exertional heatstroke

ObjectiveThe interplay between inflammatory and anti-inflammatory cytokines, as well as chemokines, has not been well explored in exertional heatstroke. DesignProspective, observational study. PatientsSeventeen military recruits who developed exertional heatstroke and 17 exertional controls who did not develop exertional heatstroke during the same training exercises. SettingUniversity teaching hospital. Measurements and Main ResultsThe severity of exertional heatstroke was evaluated using a Simplified Acute Physiology Score. Plasma cytokines and chemokines were determined using enzyme-linked immunosorbent assay kits. Body temperatures were 41.2 ± 1.2°C and 37.6 ± 0.8°C in exertional heatstroke and exertional controls, respectively. Significantly, plasma cytokines including interleukin (IL)-1&bgr; (3.1 ± 1.6 vs. 1.2 ± 0.8 pg/mL; p < .05), tumor necrosis factor alpha (4.9 ± 4.1 vs. 1.2 ± 2.4 pg/mL; p < .05), IL-6 (15.8 ± 3.2 vs. 1.2 ± 1.2 pg/mL; p < .01), interferon gamma (7.3 ± 4.9 vs. 2.4 ± 4.1 pg/mL; p < .01), IL-2 receptor (1568 ± 643 vs. 610 ± 214 pg/mL; p < .01), IL-4 (2.5 ± 1.2 vs. 1.2 ± 0.8 pg/mL; p < .05), and IL-10 (12.9 ± 9.4 vs. 2.5 ± 4.9 pg/mL; p < .01) and serum chemokines IL-8 (84.2 ± 79.9 vs. 10.4 ± 3.2 pg/mL; p < .01), monocyte chemoattractant protein 1 (959 ± 589 vs. 158 ± 217 pg/mL; p < .01), and RANTES (12464 ± 10505 vs. 5570 ± 2894 pg/mL; p < .01) were elevated in exertional heatstroke compared with exertional controls. Among cytokines, IL-6, interferon gamma, and IL-2 receptor were positively correlated with Simplified Acute Physiology Score (r = .573, p < .01; r = .625, p < .01; and r = .56, p < .05, respectively). Among chemokines, only serum monocyte chemoattractant protein 1 was positively correlated with Simplified Acute Physiology Score (r = .78, p < .001). There was no correlation between either cytokines or chemokines and body temperature. ConclusionsProinflammatory cytokines IL-1&bgr;, tumor necrosis factor alpha, IL-6; T helper 1 cytokines INF-&ggr; and IL-2 receptor; and chemokines IL-8, monocyte chemoattractant protein 1, and RANTES are increased in patients with exertional heatstroke. T helper 2 cytokines may play a role as anti-inflammatory cytokines. IL-6, interferon gamma, IL-2 receptor, and monocyte chemoattractant protein 1 may serve as prognostic indicators of disease severity in exertional heatstroke.

Aberrant cytokines/chemokines production correlate with proteinuria in patients with overt diabetic nephropathy

BACKGROUND Diabetic nephropathy (DN) occurs in 20% to 30% of all patients with type 2 diabetes mellitus (DM) and is the most common cause of end-stage renal disease. However, the definite pathogenesis, especially the role of immune response, is still unclear. METHODS We studied the production and expression of Th1 (IFN-gamma, IL-2R), Th2 (IL-4, IL-10), proinflammatory cytokines (IL-1beta, and TNF-alpha), and chemokines (MCP-1, and RANTES) in patients with DN. The correlation among cytokines, chemokines, and clinical parameters were examined. RESULTS A patient with DN presented with longer disease duration, heavy proteinuria, and impaired renal function. Our results demonstrated increased proinflammatory cytokines, Th1 cytokines and chemokines, but not Th2 cytokines, in the plasma and urine of patients with DN as compared to patients with DM without overt nephropathy. Enhanced cytokine/chemokine activation in DN was also demonstrated by positive immunohistochemical staining of kidney tissue. We found a positive correlation between daily protein loss and plasma IFN-gamma and IL-2R, and urinary MCP-1, as well as a negative correlation between creatinine clearance and plasma TNF-alpha and urinary MCP-1. CONCLUSIONS There were aberrant cytokines/chemokines production correlated with the degree of proteinuria in patient with overt DN and gross proteinuria. Inflammation may be important in the pathogenesis of DN.

Glycated albumin in diabetic patients with chronic kidney disease

Chronic hyperglycemia results in a non-enzymatic glycation of proteins, and produces Amadori products, such as glycated albumin (GA), glycosylated hemoglobin (HbA1c), and fructosamine. In current clinical practice, long-term glycemic control is assessed by quarterly measurements of HbA1c. Since the degree of hemoglobin glycosylation depends not only on the level of glycemic control, but also on the lifespan of red blood cells, patients with hemoglobin disorders or anemia of any cause may have erroneous HbA1c levels, and consequently receive insufficient treatment. Patients with chronic kidney disease (CKD) often suffer from various types of anemia, and consequently, they are frequently treated with iron and/or erythropoietin therapy or frequent blood transfusion. Thus, serum GA is a potentially useful glycemic index in diabetic patients with CKD, since it is not influenced by anemia and associated treatments. GA may also reflect the status of blood glucose more rapidly (2-3 weeks) than HbA1c (2-3 months), and is beneficial in those with wide variations in blood glucose or at higher risk for hypoglycemia. If clinical investigations support its utility, it may be applicable as a screening tool for all patients with diabetes during routine health examinations. Serum GA levels are also associated with AGE-related fluorescence and the number of glycation sites, and it may influence the structural and functional changes inalbumin. Since end-stage renal disease is an extreme microvascular complication of diabetic nephropathy, CKD patients with diabetes should be carefully managed to prevent disease progression. In this review, the clinical aspects of GA were discussed, including a comparison of GA with other glycated proteins, the utility and limitations of GA as a glycemic index, its influence on the therapeutic effects of hypoglycemic agents, its correlations with vascular complications, and its potential role in pathogenesis, specifically in diabetic patients with CKD.

Role of T Cells in Type 2 Diabetic Nephropathy

Type 2 diabetic nephropathy (DN) is the most common cause of end-stage renal disease and is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Macrophage has been well recognized to play an important role in type 2 DN, leukocyte infiltration, and participated in process of DN, as was proposed recently. Th1, Th2, Th17, T reg, and cytotoxic T cells are involved in the development and progression of DN. The purpose of this review is to assemble current information concerning the role of T cells in the development and progression of type 2 DN. Specific emphasis is placed on the potential interaction and contribution of the T cells to renal damage. The therapeutic strategies involving T cells in the treatment of type 2 DN are also reviewed. Improving knowledge of the recognition of T cells as significant pathogenic mediators in DN reinforces the possibility of new potential therapeutic targets translated into future clinical treatments.

HO-1 induction ameliorates experimental murine membranous nephropathy: anti-oxidative, anti-apoptotic and immunomodulatory effects

BACKGROUND Therapeutic agents for membranous nephropathy (MN) remain ill-defined. Haeme oxygenase (HO)-1 is considered to play a protective role in various disorders. Here, we assessed the efficacy of HO-1 induction therapy for MN. METHODS MN was induced in BALB/c mice with intravenous injections of cationic bovine serum albumin. Three groups of mice were administered 100 micromol/kg Cobalt protoporphyrin (CoPP, a potent HO-1 inducer), Tin protoporphyrin (SnPP, a potent HO-1 inhibitor) or phosphate-buffered saline via intra-peritoneal injections once a week starting from the induction of MN. Disease severity was verified by serum and urine metabolic profiles and by renal histopathology. Cytokine profiles, immunoglobulin production, the expression of oxidative stress markers (thiobarbituric acid reactive substances, TBARS) and apoptosis, as measured by TUNEL, were also determined. RESULTS Mice treated with CoPP displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, accompanied by attenuated immune-complex deposition. The production of immunoglobulins in MN mice treated with CoPP was significantly reduced compared with that of mice in the other two groups. TBARS in the serum and kidneys, as well as apoptosis, were also significantly reduced in CoPP-treated mice. Cytokine mRNA expression in the renal cortex indicated that CoPP not only decreased the expression of proinflammatory cytokines, but also increased the expression of anti-inflammatory cytokines (interleukin-10). CONCLUSIONS HO-1 induction therapy may ameliorate experimental MN via multiple pathways, including anti-oxidative, anti-apoptotic and immunomodulatory effects. HO-1 inducing regimens should be considered as a potential therapeutic intervention in MN in the future.

Role of homocysteine in end-stage renal disease

Patients on dialysis have a substantially higher mortality rate compared with the general population. Dialysis is usually associated with an increased plasma level of homocysteine (Hcy). Hcy is viewed as a nontraditional marker of the prognosis of cardiovascular disease (CVD) in the general population and in patients with chronic kidney disease. The effects of Hcy-lowering therapy in patients with end-stage renal disease (ESRD) remain controversial. We searched multiple databases including PubMed, MEDLINE, and OVID, and conducted a systematic review of the literature. Possible therapeutic measures were also surveyed. Our review shows that effective normalization of plasma Hcy level may decrease CVD-related morbidity and mortality in nondiabetic ESRD patients. Hyperglycemia in association with diabetes mellitus makes ESRD patients resistant to Hcy-lowering therapy. Folic acid fortification may attenuate the beneficial effects of Hcy-lowering therapy. Supraphysiological doses of folic acid and vitamin B supplementation might be needed in ESRD patients with diabetes or high Hcy levels. The response to Hcy-lowering therapy may be influenced by differences within and between populations in sex, genotype, nutrition, and mandatory fortification. Treatment resistance found mainly in diabetic ESRD patients but not in nondiabetic ESRD patients that may need other therapeutic approaches.

Gene polymorphisms of angiotensin-converting enzyme and angiotensin II Type 1 receptor among chronic kidney disease patients in a Chinese population

Chronic kidney disease (CKD) is highly prevalent in Taiwan and an increasing number of patients are affected, with a high risk of progression to end-stage renal disease and huge medical expenses. It has been predicted that the presence of hypertension increases with decreasing renal function due to a decrease in sodium excretion and activation of the renin–angiotensin system (RAS). The aim of this study was to investigate the influence of genetic variants of the RAS gene on CKD. We performed a case control association study and genotyped 135 CKD patients and 270 healthy controls among Han Chinese in Taiwan. All subjects were genotyped for angiotensinogen (AGT-M235T, T174M, A-20C), angiotensin-I converting enzyme (ACE-A2350G) and angiotensin II type 1 receptor (AGTR1-A1166C, C573T, C-521T) polymorphisms of RAS genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significant associations were observed in ACE-A2350G and AGTR1-C573T polymorphism between CKD patients and controls. In regard to ACE-A2350G, compared with the AA genotype the GG genotype protected against CKD (adjusted odds ratio [OR] = 0.34; p = 0.01). In regard to AGTR1-C573T, the CT genotype was a risk for CKD compared with the CC genotype (adjusted OR = 1.82; p = 0.03). We conclude that ACE-A2350G and AGTR1-C573T polymorphisms are likely candidate determinants of CKD.

Angiotensin-converting enzyme insertion/deletion polymorphism contributes high risk for chronic kidney disease in Asian male with hypertension--a meta-regression analysis of 98 observational studies.

Background Associations between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and chronic kidney disease (CKD) have been extensively studied, with most studies reporting that individuals with the D allele have a higher risk. Although some factors, such as ethnicity, may moderate the association between ACE I/D polymorphisms and CKD risk, gender-dependent effects on the CKD risk remain controversial. Objectives This study investigated the gender-dependent effects of ACE I/D polymorphisms on CKD risk. Data sources PubMed, the Cochrane library, and EMBASE were searched for studies published before January 2013. Study eligibility criteria, participants, and interventions Cross-sectional surveys and case–control studies analyzing ACE I/D polymorphisms and CKD were included. They were required to match the following criteria: age >18 years, absence of rare diseases, and Asian or Caucasian ethnicity. Study appraisal and synthesis methods The effect of carrying the D allele on CKD risk was assessed by meta-analysis and meta-regression using random-effects models. Results Ethnicity [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.08–1.42] and hypertension (OR: 1.55; 95% CI: 1.04–2.32) had significant moderate effects on the association between ACE I/D polymorphisms and CKD risk, but they were not significant in the diabetic nephropathy subgroup. Males had higher OR for the association between ACE I/D polymorphisms and CKD risk than females in Asians but not Caucasians, regardless of adjustment for hypertension (p<0.05). In subgroup analyses, this result was significant in the nondiabetic nephropathy group. Compared with the I allele, the D allele had the highest risk (OR: 3.75; 95% CI: 1.84–7.65) for CKD in hypertensive Asian males. Conclusions and implications of key findings The ACE I/D polymorphisms may incur the highest risk for increasing CKD in hypertensive Asian males.

Vitamin D and immune function in chronic kidney disease

The common causes of death in chronic kidney disease (CKD) patients are cardiovascular events and infectious disease. These patients are also predisposed to the development of vitamin D deficiency, which leads to an increased risk of immune dysfunction. Many extra-renal cells possess the capability to produce local active 1,25(OH)2D in an intracrine or paracrine fashion, even without kidney function. Vitamin D affects both the innate and adaptive immune systems. In innate immunity, vitamin D promotes production of cathelicidin and β-defensin 2 and enhances the capacity for autophagy via toll-like receptor activation as well as affects complement concentrations. In adaptive immunity, vitamin D suppresses the maturation of dendritic cells and weakens antigen presentation. Vitamin D also increases T helper (Th) 2 cytokine production and the efficiency of Treg lymphocytes but suppresses the secretion of Th1 and Th17 cytokines. In addition, vitamin D can decrease autoimmune disease activity. Vitamin D has been shown to play an important role in maintaining normal immune function and crosstalk between the innate and adaptive immune systems. Vitamin D deficiency may also contribute to deterioration of immune function and infectious disorders in CKD patients. However, it needs more evidence to support the requirements for vitamin D supplementation.

Pleiotropic effects of vitamin D in chronic kidney disease.

Low 25(OH)D levels are common in chronic kidney disease (CKD) patients and are implicated in all-cause mortality and morbidity risks. Furthermore, the progression of CKD is accompanied by a gradual decline in 25(OH)D production. Vitamin D deficiency in CKD causes skeletal disorders, such as osteoblast or osteoclast cell defects, bone turnover imbalance, and deterioration of bone quality, and nonskeletal disorders, such as metabolic syndrome, hypertension, immune dysfunction, hyperlipidemia, diabetes, and anemia. Extra-renal organs possess the enzymatic machinery for converting 25(OH)D to 1,25(OH)2D, which may play considerable biological roles beyond the traditional roles of vitamin D. Pharmacological 1,25(OH)2D dose causes hypercalcemia and hyperphosphatemia as well as adynamic bone disorder, which intensifies vascular calcification. Conversely, native vitamin D supplementation reduces the risk of hypercalcemia and hyperphosphatemia, which may play a role in managing bone and cardio-renal health and ultimately reducing mortality in CKD patients. Nevertheless, the combination of native vitamin D and active vitamin D can enhance therapy benefits of secondary hyperparathyroidism because of extra-renal 1α-hydroxylase activity in parathyroid gland. This article emphasizes the role of native vitamin D replacements in CKD, reviews vitamin D biology, and summarizes the present literature regarding native vitamin D replacement in the CKD population.