A simple and efficient method of generating HCMV pp65-specific T cells using overlapping peptides.

The methods for expansion of human cytomegalovirus (HCMV)-specific T lymphocytes are limited due to the complex culture process, long culture duration, and human leukocyte antigen (HLA) restriction. Here, we report that in vitro stimulation with pp65 kDa phosphoprotein (pp65)-derived overlapping synthetic peptides rapidly generates large numbers of HCMV-specific cytotoxic T lymphocytes from peripheral blood mononuclear cells (PBMCs) regardless of HLA type. Treatment of PBMCs from healthy volunteers expressing HLA-A*02:01 or HLA-A*24:02 with 138 pp65 overlapping peptides (OLP) resulted in an expansion of HCMV pp65 NLVPMVATV (NLV) pentamer-specific CD8+ T lymphocytes that expressed interferon (IFN)-γ, but the pp65 NLV peptide did not generate HCMV-specific CD8+ T lymphocytes in PBMCs obtained from an HLA-A*24:02 donor due to HLA restriction. The OLP-induced T lymphocytes specific for HCMV derived from PBMCs of HLA-A*02:01- and HLA-A*24:02-expressing donors showed effective cytolytic responses against target cells loaded with OLP or the NLV epitope, but pp65 NLV peptide-induced T lymphocytes did not. Phenotypic analyses demonstrated that OLP increased the frequency of CD3+ CD8+ cells, but not CD3+ CD4+, CD14+, or CD56+ cells, in donor PBMCs. Thus, this study provides evidence that in vitro stimulation with OLP efficiently generates sufficient numbers of HCMV pp65-specific cytotoxic T lymphocytes for adoptive cell therapy. Keywords: human cytomegalovirus; cytotoxic T lymphocyte; overlapping peptides; pp65; cytotoxicity.

Gaussian Process Regression (GPR) Representation in Predictive Model Markup Language (PMML).

This paper describes Gaussian process regression (GPR) models presented in predictive model markup language (PMML). PMML is an extensible-markup-language (XML) -based standard language used to represent data-mining and predictive analytic models, as well as pre- and post-processed data. The previous PMML version, PMML 4.2, did not provide capabilities for representing probabilistic (stochastic) machine-learning algorithms that are widely used for constructing predictive models taking the associated uncertainties into consideration. The newly released PMML version 4.3, which includes the GPR model, provides new features: confidence bounds and distribution for the predictive estimations. Both features are needed to establish the foundation for uncertainty quantification analysis. Among various probabilistic machine-learning algorithms, GPR has been widely used for approximating a target function because of its capability of representing complex input and output relationships without predefining a set of basis functions, and predicting a target output with uncertainty quantification. GPR is being employed to various manufacturing data-analytics applications, which necessitates representing this model in a standardized form for easy and rapid employment. In this paper, we present a GPR model and its representation in PMML. Furthermore, we demonstrate a prototype using a real data set in the manufacturing domain.

Combination of Echinocandins and Trimethoprim/Sulfamethoxazole for the Treatment of Pneumocystis jiroveci Pneumonia After Heart Transplantation.

BACKGROUND: The echinocandins have shown anti-Pneumocystis jiroveci activity in nonhuman animal models; however, the corresponding human clinical experience has been rarely reported. We report a clinical picture of P jiroveci pneumonia (PJP) and determine the effects of concomitant therapy with echinocandins and trimethoprim (TMP)-sulfamethoxazole (SMZ). METHODS: We investigated a retrospective case series of heart transplantation (HT) recipients with PJP from July 1988 to December 2015. Recipient charts were reviewed for their demographic characteristics, underlying conditions, concomitant infections, PJP prophylaxis, TMP-SMZ dosages, adverse events, echinocandin use, oxygenation, and outcomes. RESULTS: Eleven of 451 HT recipients developed PJP after a median duration of 2.8 years after transplantation. All 11 were treated with TMP-SMZ; 5 of them were treated with echinocandins added to the standard TMP-SMZ regimen. The longest interval between transplantation and PJP development was 16.3 years. The mortality rate was 33.3% in recipients receiving TMP-SMZ alone, whereas it was 20% in those receiving echinocandins as well. The most common side effects of TMP-SMZ include nausea and vomiting, metabolic acidosis, and hyperkalemia. Five recipients developed acute psychosis after a median duration of 6 days of TMP-SMZ therapy. The incidence of psychosis increased from 25% in recipients receiving TMP at ≤15 mg/kg/d to 100% in those receiving TMP at >15 mg/kg/d. CONCLUSIONS: Echinocandins along with the standard TMP-SMZ regimen may effectively alleviate PJP developed after HT. The ideal prophylaxis duration is lifelong owing to the late onset of PJP. The typically intolerable adverse effects of TMP-SMZ therapy for PJP may necessitate dosage adjustments in some cases.

Risk factors and outcome for colistin-resistant Acinetobacter nosocomialis bacteraemia in patients without previous colistin exposure.

The clinical characteristics of patients with colistin-resistant Acinetobacter baumannii bacteraemia have been documented, but those of patients with bacteraemia caused by other Acinetobacter species remain unknown. Previous exposure to colistin has been shown to be associated with the emergence of colistin resistance, but may be not the only predisposing factor. In the current study, we highlight the risk and outcome of patients without previous exposure to colistin who acquired colistin-resistant Acinetobacter nosocomialis (ColRAN) bacteraemia. This 11-year single-centre retrospective study analysed 58 patients with ColRAN bacteraemia and 213 patients with colistin-susceptible A. nosocomialis (ColSAN) bacteraemia. Antimicrobial susceptibilities were determined with an agar dilution method. The clonal relationship of ColRAN isolates was determined with pulsed-field gel electrophoresis. A conjugation mating-out assay was conducted to delineate the potential transfer of colistin resistance genes. Multivariable analysis was performed to evaluate the risk factors for ColRAN bacteraemia. Chronic obstructive pulmonary disease (COPD) was independently associated with ColRAN bacteraemia (OR 3.04; 95% CI 1.45-6.37; p 0.003). Patients with ColRAN bacteraemia had higher APACHE II scores, but the two groups showed no significant differences in 14-day mortality (10.3% vs. 10.3%) or 28-day mortality (15.5% vs. 15.0%). ColRAN isolates had greater resistance than ColSAN isolates to all antimicrobial agents except for ciprofloxacin (0% vs. 6.6%). There were 16 different ColRAN pulsotypes, and two major clones were found. Colistin resistance did not transfer to colistin-susceptible A. baumannii or A. nosocomialis. These results show that COPD is an independent risk factor for acquisition of ColRAN bacteraemia. The mortality rates were similar between patients with ColRAN and ColSAN bacteraemia.

Monotherapy with tacrolimus for heart and liver transplant: a case report.

BACKGROUND: Multiple-organ transplantation cases are rare, partly due to the shortage of donor organs. However, recent reports of outcomes of multiple-organ transplantations show encouraging survival rates for recipients as compared to single-organ transplant recipients. CASE REPORT: A 33-year-old female who was a known hepatitis B carrier and who had been diagnosed with peripartum dilated cardiomyopathy was experiencing end-stage heart failure. The patient received orthotopic heart transplantation. After heart transplantation, the recipient received prednisolone, cyclosporine, and mycophenolate mofetil for immunosuppressive therapy. Seventy-one days later, the recipient began to develop progressive jaundice, ascites, and hepatoencephalopathy and was re-admitted to the hospital. Fulminant hepatitis was diagnosed. She was referred for emergency cadaveric liver transplantation 110 days after the heart transplantation because of her critical condition. After transplantation, she was improved and her condition maintained by a single immunosuppressive therapy, tacrolimus, with mean dose of 0.06 mg/kg/d. CONCLUSION: We presented a case that was complicated by fulminant hepatitis after heart transplantation and successfully rescued by liver transplantation.

The impact of number of drugs prescribed on the risk of potentially inappropriate medication among outpatient older adults with chronic diseases.

BACKGROUND: Older patients with chronic diseases often take multiple prescription drugs, increasing their risk of adverse health events. However, polypharmacy remains ill-defined. AIM: To investigate the impact of number of drugs prescribed on potentially inappropriate medication (PIM) and the associated risk factors in older outpatients with chronic diseases. DESIGN: Retrospective cross-sectional study. METHODS: We retrospectively assessed 780 older patients (mean, 75.5 ± 7.1 years) with long-term (≥ 28 days) prescriptions for chronic diseases at the geriatric clinics of a university hospital from January to June 2012 using the Screening Tool of Older Person's potentially inappropriate Prescriptions (STOPP). Clinical information for each patient was analyzed. Logistic regression and receiver operating characteristic curve (ROC) analyses were performed; number needed to harm (NNH) was also estimated. RESULTS: According to STOPP criteria, 302 patients (39%) had at least one PIM. Multivariate analysis revealed that PIM risk was associated with the number of medications prescribed (P < 0.001) and the presence of cardiovascular (P < 0.001) or gastrointestinal disease (P = 0.003). The estimated area under the ROC for the number of medications needed to predict PIM risk was 0.680 (P < 0.001) with the optimal cut-off value of five medications. After adjusting covariates, patients prescribed ≥ 5 drugs [adjusted odds ratio (OR) = 5.4; adjusted NNH = 4.25; P < 0.001] and those prescribed 4 drugs (adjusted OR = 3.5; adjusted NNH = 6.88; P = 0.003) had significantly higher PIM risk than those prescribed ≤ 2 drugs. CONCLUSIONS: The number of prescribed medications can be an index of PIM risk in older patients with chronic diseases. Clinicians should suspect high PIM risk in older outpatients with ≥ 5 prescriptions.

Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study.

BACKGROUND: In addition to lung cancers, tuberculosis infections have been associated with increased risk of non-pulmonary malignancies in case reports. Our population-based study employed standardized incidence ratios (SIRs) to systemically survey non-pulmonary cancer risks after tuberculosis infections. METHODS: Data of patients who had newly diagnosed tuberculosis, were aged 20 years or older, and had no prior cancer or tuberculosis were sampled from the Taiwan National Health Insurance database between 2000 and 2010. SIRs compared cancer incidence in patients with tuberculosis infections to the general population. SIRs of specific cancers were further analyzed with respect to gender and time after tuberculosis infections. RESULTS: After a follow-up period of 28 866 person-years, 530 tuberculosis cases developed cancers compared with 256 cases in the general populations (2.07, 95% confidence interval (CI), 1.90-2.26). The SIR of non-pulmonary malignancies was also increased (1.71, 95% CI, 1.54-1.90). For males, SIRs were increased within 1 year after tuberculosis diagnosis for the following cancers: head and neck, esophageal, colorectal, liver, lung, melanomas, and Hodgkin's disease. SIRs were increased for liver, biliary, lung, and bladder cancers beyond the first year after tuberculosis diagnosis. For females, SIRs were increased for leukemia, esophageal, and lung cancers within the first year, and only for leukemia beyond 1 year post diagnosis. CONCLUSION: Having found increased risks of several cancers that differ with gender and time after tuberculosis diagnosis, physicians may consider these factors in patients following tuberculosis diagnosis.

Clinical outcomes of tigecycline alone or in combination with other antimicrobial agents for the treatment of patients with healthcare-associated multidrug-resistant Acinetobacter baumannii infections.

Tigecycline (TG) has been shown to be active in vitro against Acinetobacter baumannii, although data on the clinical efficacy of TG alone or in combination for the treatment of infections due to multidrug-resistant A. baumannii (MDRAB) remain limited. The purpose of this study was to investigate the clinical outcomes of patients with healthcare-associated infections (HAIs) caused by MDRAB who were treated with imipenem/cilastatin and sulbactam, and TG alone or in combination with other antibiotics. A total of 386 patients with HAIs caused by MDRAB were retrospectively analyzed and grouped into TG and non-TG groups, depending on whether they received TG treatment. Of the 266 patients in the TG group, 108 were treated with TG alone and 158 were treated with TG in combination with ceftazidime, ceftriaxone, piperacillin/tazobactam, or a carbapenem. All 120 patients in the non-TG group were treated with imipenem/cilastatin and sulbactam. The primary outcome measure was 30-day mortality after TG treatment and the secondary outcome was clinical outcome. There were no significant differences in survival rates between the two groups. However, the rate of unfavorable outcome was significantly lower (p < 0.05) among patients in the TG group than among patients in the non-TG group. The most significant predictor of unfavorable outcome was sepsis, whereas TG treatment and microbial eradication were the most significant predictors of favorable outcomes. Our study represents the largest study of patients with MDRAB infection treated with TG and expands our understanding of the role of TG therapy alone or in combination with other agents for the treatment of HAI caused by MDRAB.

Bacteremic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis: a single or two distinct clinical entities?

The phenotypically indistinguishable Acinetobacter baumannii and Acinetobacter nosocomialis have become leading pathogens causing nosocomial pneumonia in critically ill patients. A. baumannii and A. nosocomialis nosocomial pneumonias were grouped as a single clinical entity previously. This study aimed to determine whether they are the same or a different clinical entity. A total of 121 patients with A. baumannii and 131 with A. nosocomialis bacteremic nosocomial pneumonia were included during an 8-year period. Despite the similar Charlson co-morbidity scores at admission, patients with A. baumannii pneumonia were more likely to have abnormal haematological findings, lobar pneumonia, significantly higher Acute Physiology and Chronic Health Evaluation II scores and higher frequency of shock at the onset of bacteraemia than those with A. nosocomialis pneumoni. A. baumannii isolates were resistant to more classes of antimicrobials, except colistin, and therefore the patients with A. baumannii pneumonia were more likely to receive inappropriate antimicrobial therapy. The 14-day mortality was significantly higher in patients with A. baumannii pneumonia (34.7% vs. 15.3%, p 0.001). A. baumannii was an independent risk factor for mortality (OR, 2.03; 95% CI, 1.05-3.90; p 0.035) in the overall cohort after adjustment for other risk factors for death, including inappropriate antimicrobial therapy. The results demonstrated the difference in clinical presentation, microbial characteristics and outcomes between A. baumannii and A. nosocomialis nosocomial pneumonia, and supported that they are two distinct clinical entities.

Assessment of follow-up sonography and clinical improvement among infants with congenital muscular torticollis.

BACKGROUND AND PURPOSE: Infants grow rapidly, which causes the SCM to thicken physiologically. Therefore some cases of physiologically-thickened SCM can be confused with a poor response to physical therapy. There have been only a few quantitative ultrasonographic studies on the clinical outcome of rehabilitation for CMT. Our aim was to evaluate whether a new sonographic assessment method that uses the muscular thickness ratio of the SCM can help quantify the outcome of rehabilitation therapy for patients with CMT. MATERIALS AND METHODS: We evaluated 48 patients (male/female, 17:31; mean age, 3.9 months) who were diagnosed with CMT and who underwent initial and follow-up sonography. The ratio of the thickness of the involved SCM to the thickness of the intact SCM (SCM thickness ratio) was calculated. A scoring system based on the range of motion of the neck was used to assess clinical improvement. The correlations between clinical improvement and the thickness of the involved muscle, the difference in involved muscle thickness, the SCM thickness ratio, and the difference in the SCM thickness ratio were evaluated with Spearman rank correlations. RESULTS: Follow-up Cheng scores were higher than initial scores; this difference indicates clinical resolution (follow-up, 4.90; initial, 3.38). The SCM thickness ratio at follow-up was lower than that at the initial evaluation (follow-up, 1.29-1.34; initial, 1.65-1.77). Intra- and interobserver agreements were excellent. Most variables were moderately correlated with clinical improvement (correlation coefficients, 0.36-0.509). R1 showed the highest correlation with clinical improvement (0.481 and 0.509), followed by the initial maximal thickness of the SCM (0.434 and 0.488). ΔP (P1-P2) and ΔR showed similar correlation coefficients with clinical improvement. CONCLUSIONS: Measurement of the SCM thickness ratio appears to overcome the problem of a false-positive diagnosis of clinical aggravation of CMT resulting from physiologic growth. R1 and ΔR are accurate objective measurements, which can be used in the management of CMT.

Efficacy of double filtration plasmapheresis in removing xenoantibodies and prolonging xenograft survival in an ex vivo swine perfusion model.

INTRODUCTION: In xenotransplantation, antibodies mediate humoral rejection, resulting in organ dysfunction. Removal of xenoantibodies is likely a first step for successful transplantation. Double filtration plasmapheresis (DFPP) selectively removes large molecular weight pathogenic substances, such as immunoglobulins (Ig), without other plasma proteins. The antibodies fractions removed and the changes in blood biochemistry are unanswered questions after DFPP in addressed this ex vivo swine heart perfusion model. MATERIALS AND METHODS: Twelve swine hearts were perfused with human blood in a modified Langendorff's apparatus. The perfusate containing human blood was divided into 2 groups: controls (N = 6) and DFPP-treated group (N = 4). Blood counts, biochemistry data, and immunological profiles were compared at 3 time points: before and after DFPP and after heart perfusion. RESULT: Perfusion times of control and DFPP groups were 5.43 ± 1.81 vs 9.25 ± 3.00 hours, respectively. Only the values of albumin and total protein showed difference. The immunologic profile revealved complete removal of IgM and most IgG, IgA, C3, and C4, namely, 79.95%, 88.58%, 83.15%, and 87.97%, respectively. CONCLUSION: DFPP showed excellent efficacy to remove xenoantiboidies and prolong xenograft survival in an ex vivo perfusion model.

Successful treatment with continuous enteral protease inhibitor in a patient with severe septic shock.

OBJECTIVE: The mortality rate among patients with septic shock is high despite current therapy. We present a case of Fournier's gangrene and septic shock at 4 years post-heart transplantation that was reversed by "continuous enteral feeding" of the digestive enzyme inhibitor, gabexate mesilate. Recently, powerful pancreatic digestive proteases in the lumen of the intestine have been identified as initiators of the systemic inflammatory response. Intraluminal inhibitions of the proteases significantly attenuates intestinal damage, system inflammation, and multiorgan failure in experimental forms of shock but it has not been tested in man. METHODS AND RESULTS: Gabexate mesilate, a synthetic digestive protease inhibitor, was continuously administered in two liters of crystalloid solution to a patient by enteral feeding during septic shock. The condition and markers for shock due to sepsis reversed in a few days. CONCLUSION: This case suggested that "enteral" digestive protease inhibition may decrease and even reverse the sequelae of shock and sepsis.

Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study.

Repeated isolation of multidrug-resistant Acinetobacter baumannii (MDRAB) from respiratory secretions poses a great challenge for infection control. We conducted a retrospective case-control study to evaluate the efficacy and adverse effect of inhaled colistin methanesulfonate (CMS) in the eradication of MDRAB from the respiratory tract. Patients who were admitted to Taipei Veterans General Hospital between February 2009 and June 2010, had at least two sets of monomicrobial culture of MDRAB from respiratory secretions, and remained in hospital for at least 14 days after the first isolation of MDRAB (index day) were included. Patients who received intravenous CMS were excluded. Patients who received CMS inhalation for ≥ 3 days were selected as cases whereas the controls were matched for age and Acute Physiology and Chronic Health Evaluation II score. Thirty-nine cases and controls were identified. The duration of CMS inhalation was 10.9 ± 3.6 days. The use of inhaled CMS was the only independent factor associated with the eradication of MDRAB within 14 days after the index day (OR 266.33; 95% CI 11.26-6302.18, p <0.001), and shortened the duration of MDRAB recovery from the respiratory tract by 13.3 ± 1.45 days. The adverse effects were similar for both groups. The increase of colistin minimal inhibitory concentrations in the last isolate compared with the index isolate from the same patient did not differ between the two groups. In conclusion, our study demonstrated that inhaled CMS enhanced the eradication of MDRAB from the respiratory tract without significant clinical adverse effect or impact on colistin resistance.

Clinical characteristics and outcomes of bacteremia due to different genomic species of Acinetobacter baumannii complex in patients with solid tumors.

PURPOSE: Acinetobacter baumannii, Acinetobacter genomic species 3 (AGS 3), and Acinetobacter genomic species sensu Tjernberg and Ursing (AGS 13TU) are phenotypically indistinguishable and are often reported together as the A. baumannii complex (ABC). Few studies have investigated the difference in outcome caused by these different species, and all involved heterogeneous groups of patients. This study aimed to delineate whether there are differences in the clinical characteristics and outcome among patients with solid tumors and bacteremia caused by A. baumannii or two other non-baumannii ABC species (AGS 3 plus AGS 13TU). METHODS: Patients with solid tumors and ABC bacteremia over a period of 5 years in a medical center were identified. The patient data were retrospectively reviewed and analyzed. RESULTS: We identified 103 patients with ABC bacteremia during the study period. Bacteremia was due to A. baumannii in 30 patients, AGS 3 in 24 patients, and AGS 13TU in 49 patients. Among the 103 patients with ABC bacteremia, recent stay in the intensive care unit (ICU) (p = 0.008) was independently associated with the acquisition of A. baumannii bacteremia. Multivariate analysis revealed that bacteremia caused by A. baumannii (hazard ratio [HR] 2.990, 95% confidence interval [CI], 1.021-8.752, p = 0.046) and Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥21 (HR 4.623, 95% CI 1.348-15.859, p = 0.015) were independent factors associated with 14-day mortality. CONCLUSIONS: Infection with A. baumannii and a high APACHE II score (≥21) might be associated with poor outcome in patients with solid tumors and ABC bacteremia.

Effects of the surface characteristics of nano-crystalline and micro-particle calcium phosphate/chitosan composite films on the behavior of human mesenchymal stem cells in vitro.

Calcium phosphate (CaP) compounds, the main inorganic constituent of mammalian bone tissues, are believed to support bone precursor cell growth and osteogenic differentiation. Chitosan, a deacetylated derivative of chitin, is a versatile biopolymer to offer broad possibilities for cell-based tissue engineering. In the present study, different scales of CaP crystals on chitosan membranes were prepared for culture of human mesenchymal stem cells (hMSCs) in vitro. A series of aqueous CaP suspensions with different concentrations were mixed with chitosan solution and chitosan/calcium phosphate (C/CaP) films were fabricated by the solvent-casting method. With different weight ratios of CaP in chitosan solution, the various surface characteristics of nano-amorphous (C/CaP 0.1), nano-crystalline (C/CaP 0.5) and micro-particle (C/CaP 2) CaP compounds were examined by scanning electron microscopy and electron dispersion spectroscopy. X-ray diffraction on micro-particles of CaP indicated the formation of crystalline hydroxyapatite. The behavior of hMSCs, including proliferation, cell spreading and osteogenic differentiation, was studied on the C/CaP films. In basal culture medium, the incorporation of CaP into chitosan films could promote the proliferation of hMSCs. The C/CaP 0.5 film with connected CaP nano-crystals had better cellular viability. The fluorescence microscope images at 14 days of culture revealed extensive networks of F-actin filaments of hMSCs on chitosan, C/CaP 0.1 and C/CaP 0.5 films. The cellular morphology on C/CaP 2 film with discrete CaP micro-particles was partly restrained. In osteogenic medium, the alkaline phosphatase (ALP) activity of hMSCs increased and showed the process of osteogenic differentiation. The ALP levels on C/CaP 2 film were higher than those on C/CaP 0.1 and C/CaP 0.5 films. These results demonstrated that the crystallinity and topography of CaP on chitosan membranes could modulate the behaviors of cultured hMSCs in vitro.

Prediction models for the risk of new-onset hypertension in ethnic Chinese in Taiwan.

Prediction model for hypertension risk in Chinese is still lacking. We aimed to propose prediction models for new-onset hypertension for ethnic Chinese based on a prospective cohort design on community, which recruited 2506 individuals (50.8% women) who were not hypertensive at the baseline (1990-91). Total 1029 cases of new-onset hypertension developed during a median of 6.15 (interquartile range, 4.04-9.02) years of follow-up. In the clinical model, gender (2 points), age (8 points), body mass index (10 points), systolic blood pressure (19 points) and diastolic blood pressure (7 points) were assigned. The biochemical measures, including white blood count (3 points), fasting glucose (1 point), uric acid (3 points), additional to above clinical variables, were constructed. The areas under the receiver operative characteristic curves (AUCs) were 0.732 (95% confidence interval (CI), 0.712-0.752) for the point-based clinical model and 0.735 (95% CI, 0.715-0.755) for the point-based biochemical model. The coefficient-based models had a good performance (AUC, 0.737-0.741). The point-based clinical model had a similar net reclassification improvement as the coefficient-based clinical model (P=0.30), and had a higher improvement than the point-based biochemical model (P=0.015). We concluded that the point-based clinical model could be considered as the first step to identify high-risk populations for hypertension among Chinese.

The A1166C polymorphism of angiotensin II Type 1 receptor as a predictor of renal function decline over 4 years follow-up in an apparently healthy Chinese population.

AIM: The angiotensin II Type 1 receptor (AT1R) A1166C (rs5186) genez polymorphism is equivocally associated with the patients' susceptibility to chronic kidney disease or end-stage renal disease. We conducted a prospective study to investigate the influence of AT1R A1166C gene polymorphism on the quantitative changes of renal function. METHOD: Of 1500 people screened, 112 non-diabetic normotensive elderly Chinese were recruited and received biochemistry examination at the baseline, at the second and fourth year follow-up. Serum creatinine and calculated renal parameters, using Cockroft-Gault (CG) formula, Modification of Diet in Renal Disease (MDRD) Study and abbreviated MDRD (abMDRD) equation, were used to evaluate renal function and their progression. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULT: Age was 71.9 +/- 3.7 years (range 60 - 81). Serum creatinine, CG creatinine clearance (CrCl), MDRD and abMDRD glomerular filtration rate (GFR) were significantly decreased at the 2 and 4-year follow-up (all p < 0.001). The magnitude of 4-year decline of above four renal parameters was significantly higher in subjects carrying the AT1R AA genotype than C-allele carriers (p = 0.014, 0.033, 0.008 and 0.014 for creatinine, CG CrCl, MDRD and abMDRD GFR, respectively). This association was still significant in multivariate analyses (p = 0.019, 0.045, 0.035 and 0.018, respectively). CONCLUSION: This longitudinal study showed that the aging process was associated with decline of renal function in the healthy elderly. The AT1R A1166C gene polymorphism might modulate these changes in the Chinese. This provides further knowledge essential in the assessment of renal disease and determination of renal function in the older subjects.