Development Of eGFR Research Articles

Timing of Initiation of Xanthine Oxidase Inhibitors Based on Serum Uric Acid Level Does Not Predict Renoprognosis in Patients with Preserved Kidney Function.

Background: Despite recent evidence of remaining possibility that early initiation of xanthine oxidase inhibitors (XOIs) is beneficial in renoprognosis for patients with stage 2 or less chronic kidney disease (CKD), no evidence is available regarding the difference in renoprognosis based on serum uric acid (sUA) levels at the initiation of XOIs among patients with preserved kidney function. Methods: New XOI initiators were divided into quartiles based on baseline sUA. Primary outcome was the composite incidence of a significant estimated glomerular filtration rate (eGFR) decline (≥40% decline in eGFR from baseline or development of eGFR <30 mL/1.73 m2/min) or all-cause death within 5 years. Results: After excluding inapplicable patients, 1170 XOI initiators were analyzed (mean ± standard deviation age: 68 ± 14.3 years; sUA: 10.6 ± 1.15 mg/dL). On overall median [interquartile range (IQR)] follow-up of 824 (342, 1576) days, incidence rate of the primary outcome was 287 per 1000 person-years for 5 years. Although the nonadjusted model showed a dose-response association between baseline sUA level and the outcome, the adjusted model showed no significant association. Adjusted hazard ratios (95% confidence interval) of the second, third, and fourth quartiles of baseline sUA with the composite outcome within 5 years compared to the first quartile were 1.00 (0.78, 1.29), 1.00 (0.80, 1.30), and 1.02 (0.80, 1.32), respectively. Conclusions: Early initiation of XOIs did not predict a significant benefit on renoprognosis even among the population with preserved kidney function. The validity of initiating XOIs with the aim of improving renoprognosis based on sUA is questionable.

Relationship of serum lipid parameters with kidney function decline accompanied by systemic arterial stiffness: a retrospective cohort study.

Dyslipidemia is associated with kidney function decline (KFD), although the non-linear relationship of lipid parameters to KFD has not been fully elucidated. We aimed to determine the detailed relationship of baseline lipid parameters with KFD, considering the mediation of arterial stiffness. A total of 27 864 urban residents with estimated glomerular filtration rate (eGFR) ≥60mL/min/1.73 m2 at baseline, who participated in a median of three (range two to eight) consecutive annual health examinations were studied. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI). KFD was defined as development of eGFR <60mL/min/1.73 m2. During the study period, 1837 participants (6.6%) developed KFD. Receiver operating characteristic analysis determined that the cutoff values independently associated with KFD are 123mg/dL for low-density lipoprotein cholesterol (LDL-C) [area under the curve (95% confidence interval) 0.570 (0.557-0.583)], 65mg/dL for high-density lipoprotein cholesterol (HDL-C) [0.552 (0.539-0.566)], 82mg/dL for triglycerides (TG) [0.606 (0.593-0.618)] and 1.28 for TG/HDL-C ratio [0.600 (0.587-0.612)]. These cut-offs were independently associated with KFD in Cox analysis. Regarding the contribution of each lipid parameter to KFD, a linear relationship was observed for both TG and TG/HDL-C, and a U-shaped relationship for HDL-C. A adjusted mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed (mediating rate: 2.9% in TG, 2.5% in TG/HDL-C ratio). Regarding the association to KFD, a linear relationship was observed for both TG and TG/HDL-C, and a U-shaped relationship for HDL-C. A mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed after adjustment for confounders. TG and TG/HDL-C ratio related linearly to KFD and this was partially mediated by CAVI. A U-shaped relationship was observed between HDL-C and KFD risk. LDL-C showed no significant association. Further study should investigate whether intensive TG-lowering treatment prevents KFD via decreasing CAVI.

Persisting prediabetic conditions and glomerular filtration rate – A longitudinal study

The aim was to explore differences in the development of eGFR in persisting prediabetic conditions. This prospective study including 1327 individuals showed that eGFR decreased more in individuals with persisting IGT than in individuals with persisting IFG. Repeating OGTT and monitoring eGFR might improve the risk estimation in prediabetes.

Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling

IntroductionSodium–glucose cotransporter 2 (SGLT2) inhibitors are now recommended in guidelines for persons with type 2 diabetes mellitus (T2DM) and at risk of advanced kidney disease as part of the glucose-lowering...

Plasma Biomarkers as Risk Factors for Incident CKD

IntroductionEarlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation.MethodsWe evaluated the association of novel plasma biomarkers with incident CKD using a case-cohort design in participants without diabetes and with baseline estimated glomerular filtration rate (eGFR) ≥ 60 ml/min per 1.73 m2 in the Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohorts. Incident CKD was defined as development of eGFR < 60 ml/min per 1.73 m2 and ≥40% decline in eGFR from baseline. We measured plasma markers of inflammation/fibrosis—soluble tumor necrosis factor receptors (TNFRs) 1 and 2 (TNFR-1 and TNFR-2), monocyte chemotactic protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble urokinase-type plasminogen activator receptor (suPAR)—and tubular injury (kidney injury molecule 1 [KIM-1]). Cox regression models weighted for the case-cohort design were used to estimate hazard ratios (HRs) of incident CKD after adjustment for CKD risk factors, eGFR, and albuminuria.ResultsIn MESA (median follow-up of 9.2 years), there were 497 individuals in the random subcohort and 163 incident CKD cases. In REGARDS (median follow-up of 9.4 years), there were 497 individuals in the random subcohort and 497 incident CKD cases. Each 2-fold higher plasma KIM-1 (adjusted HR 1.38 [95% CI 1.05–1.81]), suPAR (1.96 [1.10–3.49]), TNFR-1 (1.65 [1.04–2.62]), TNFR-2 (2.02 [1.21–3.38]), and YKL-40 (1.38 [1.09–1.75]) concentrations were associated with incident CKD in MESA. In REGARDS, TNFR-1 (1.99 [1.43–2.76]) and TNFR-2 (1.76 [1.22–2.54]) were associated with incident CKD.ConclusionPlasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS.

POS-285 EPIDEMIOLOGYICAL FEATURES OF CHRONIC KIDNEY DISEASE IN CENTRAL CHINA

Chronic kidney disease (CKD) has been a global public health issue in the past decades and affects more than 10% population worldwide. But there are still limited studies to explore the epidemiological features of CKD in China. From July 2016 to June 2018, a total of 29100 participants were randomly enrolled from 3 urban communities and 4 rural districts of Henan province. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min.1.73m2 or urinary albumin to creatinine ratio ≥ 30 mg/g (albuminuria). Diabetic subjects with systolic blood pressure > 140mmHg, albuminuria or an eGFR less than 60 mL/min/1.73 m2 were classified as having DKD. Participants completed a questionnaire assessing lifestyle and relevant medical history, and blood and urine specimens were taken. Serum creatinine, uric acid, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein and urinary albumin were assessed. The age- and sex-adjusted prevalences of CKD and DKD were calculated, and risk factors associated with the presence of reduced eGFR, albuminuria, DKD, severity of albuminuria and progression of reduced renal function were analyzed by binary and ordinal logistic regression. A two-sample mendelian randomization (MR) analysis was employed to calculate the causal effects between risk factors and CKD. The exposure included alcohol consumption, physical activities, BMI, diabetes, hypertension and dyslipidemia, the outcome was eGFR < 60 and albuminuria, respectively. There were 23869 rural participants were recruited. Totally, 4347 participants were suffering from CKD, in which 962 subjects were DKD patients.The overall adjusted prevalence of CKD was 16.4% (15.9–16.8%) and that of DKD was 2.9% (2.7–3.1%). In all participants with diabetes,the prevalence of reduced eGFR was 6.3% and that of albuminuria was 45.3%. The overall prevalence of CKD in participants with diabetes was 48.0% (95% CI = 43.1–52.9%). A total of 5231 urban participants were recruited. The overall adjusted prevalence of CKD was 16.8% (15.8–17.8%) and that of DKD was 3.5% (3.0–4.0%). Decreased renal function was detected in 132 participants (2.9%), whereas albuminuria was found in 858 participants (14.9%). In all participants with diabetes,the prevalence of reduced eGFR was 6.3% and that of albuminuria was 45.3%. The overall prevalence of CKD in participants with diabetes was 48.0%. Results of the binary and ordinal logistic regression indicated that the factors independently associated with a higher risk of reduced eGFR and albuminuria were older age, male gender, smoking, alcohol consumption, overweight,obesity, diabetes, hypertension, dyslipidemia and hyperuricemia. MR analysis showed that increased BMI and hypertension had casual effects on development of eGFR < 60 (β = 0.15 and 1.38) and albuminuria (β = 0.08 and 0.46). The results of our current study demonstrate that the prevalences of CKD and DKD are still high in Chinese rural and urban population and they are going to be a major social-economic burden in China. High prevalent hypertension and diabetes are primary risk factors for them. Increased BMI and hypertension have causal effects on development of CKD. Specific strategies and interventions aimed at reducingthe burden of CKD and DKD are urgently needed.

Abstract 2333: Mutational landscape of multiple primary lung cancers and its correlation with environmental factors

Abstract Background: Multiple primary lung cancers (MPLC) are reported to occur in 0.2-20 % of all primary lung cancer cases. MPLC are considered to harbor various genetic profiling patterns among the tumors even within the same individuals, though they developed from the same occupational and environmental exposure. In this study, we performed paired mutational analyses to clarify genetic mutations in MPLC and its relationship with environmental factors. Materials and methods: We obtained 38 surgical specimens from 17 patients who were pathologically diagnosed as MPLC and underwent surgery at Osaka City University Hospital between October 2007 and March 2019. In addition to the clinicopathological features, the patients' age, sex, smoking history, body mass index, radiologic features and surgical procedures were reviewed. Four of the 17 MPLC patients had metachronous lesions, whereas 13 patients only had synchronous lesions. For genetic profiling of MPLC patients, the extracted DNAs were deep-sequenced on Ion S5 sequencer (Thermo Fisher) for somatic mutations in 409 cancer-associated genes (Ion AmpliSeq Comprehensive Cancer Panel). The study was approved by institutional review board of Osaka City University Hospital and written informed consent was obtained from all of the patients. For statistically analyses, we assumed genetic mutations occurred by chance and calculated the frequency of concomitant mutations in multiple tumors within the same individuals based on a previous study (JME study; Kawaguchi T et al, J Clin Oncol 2016). Comparing the assumed frequency of mutations with the actual data, statistically analyses whether mutations would occur concomitantly or randomly were performed using an exact test. Results: Deep sequencing was successfully performed in all of the specimens with the mean coverage of 823. Results from comprehensive genetic analyses suggested that the mutation profiles differed among the tumors within the same individuals, whereas EGFR, KRAS, TP53, and PARP1 mutations were concomitantly detected in multiple tumors within the same individuals. In this study, the frequency of EGFR mutations was significantly higher in never or light -smokers and females. The occurrence of concomitant EGFR or KRAS mutations in multiple tumors within the same individuals was significantly more frequent than expected by chance (EGFR, P = .0023; KRAS, P = .0049), suggesting environmental factors play more role in EGFR and KRAS mutations than the other mutations including TP53 which occurred more randomly in individual tumors. Concomitant EGFR or KRAS mutations were particularly prominent in never or light-smokers and males. Conclusions: Results from our MPLC study confirmed that the development of EGFR or KRAS-mutated tumors were strongly related to environmental factors such as sex and smoking history, and suggested that the other mutations may occur randomly. Citation Format: Motohiro Izumi, Jun Oyanagi, Kenji Sawa, Mitsuru Fukui, Koichi Ogawa, Yoshiya Matsumoto, Yoko Tani, Tomohiro Suzumura, Tetsuya Watanabe, Hiroyasu Kaneda, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Tomoya Kawaguchi, Yasuhiro Koh. Mutational landscape of multiple primary lung cancers and its correlation with environmental factors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2333.

Delayed remnant kidney function recovery is less observed in living donors who receive an analgesic, intrathecal morphine block in laparoscopic nephrectomy for kidney transplantation: a propensity score-matched analysis

BackgroundThis study analyzed remnant kidney function recovery in living donors after laparoscopic nephrectomy to establish a risk stratification model for delayed recovery and further investigated clinically modifiable factors.Patients and methodsThis retrospective study included 366 adult living donors who underwent elective donation surgery between January 2017 and November 2019 at our hospital. ITMB was included as an analgesic component in the living donor strategy for early postoperative pain relief from November 2018 to November 2019 (n = 116). Kidney function was quantified based on the estimated glomerular filtration rate (eGFR), and delayed functional recovery of remnant kidney was defined as eGFR < 60 mL/min/1.73 m2 on postoperative day (POD) 1 (n = 240).ResultsMultivariable analyses revealed that lower risk for development of eGFR < 60 mL/min/1.73 m2 on POD 1 was associated with ITMB, female sex, younger age, and higher amount of hourly fluid infusion (area under the receiver operating characteristic curve = 0.783; 95% confidence interval = 0.734–0.832; p < 0.001). Propensity score (PS)-matching analyses showed that prevalence rates of eGFR < 60 mL/min/1.73 m2 on PODs 1 and 7 were higher in the non-ITMB group than in the ITMB group. ITMB adjusted for PS was significantly associated with lower risk for development of eGFR < 60 mL/min/1.73 m2 on POD 1 in PS-matched living donors. No living donors exhibited severe remnant kidney dysfunction and/or required renal replacement therapy at POD 7.ConclusionsWe found an association between the analgesic impact of ITMB and better functional recovery of remnant kidney in living kidney donors. In addition, we propose a stratification model that predicts delayed functional recovery of remnant kidney in living donors: male sex, older age, non-ITMB, and lower hourly fluid infusion rate.

Abstract MP17: Sedentary Behavior and Longitudinal Changes in Kidney Function in US Hispanics/Latinos: Findings From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

Introduction: Sedentary behavior increases cardiovascular risk due to detrimental effects on blood pressure, vascular function, and glucose metabolism. U.S. Hispanics/Latinos have a high prevalence of sedentary behavior and a large burden of chronic kidney disease (CKD). Therefore, we evaluated the association between sedentary behavior and changes in kidney function over time. Hypothesis: We assessed the hypothesis that higher sedentary time will be associated with increase in proteinuria, decrease in estimated glomerular filtration rate (eGFR), and incident CKD. Methods: We used data from the HCHS/SOL, a community-based cohort of self-identified Hispanic/Latino adults (18-74 years) from diverse backgrounds in the U.S. This study includes 11181 adults who underwent one-week accelerometry at Visit 1 (baseline, 2008-2011) and completed Visit 2 (2014-2017). Linear regression was used to assess the association of sedentary time with change in eGFR and urine albumin- to-creatinine ratio (ACR), and Poisson regression with robust variance was used to estimate the association with rate of incident CKD (defined as the composite of either the development of eGFR &lt;60ml/min/1.73m 2 and a decline in eGFR ≥1 ml/min per year, or ACR ≥30 mg/g), adjusted for covariates and time elapsed between visits. Results: At baseline, mean age was 42.2 years, 51.4% women, mean sedentary time was 11.8 hours, mean eGFR was 106.1mL/min, and median ACR 6.7mg/g. After a median follow-up of 5.9 years, the average decline in eGFR was 0.8ml/min/year and the average change in ACR was 0.3mg/g/year. In fully adjusted models, individuals with higher sedentary time experienced a greater decline eGFR from Visit 1 to Visit 2 (Table 1). Sedentary time was not significantly associated with change in ACR or incident CKD. Conclusion: Sedentary behavior may be associated with a decline in kidney function in U.S. Hispanics/Latinos, which may have important implications for prevention of kidney disease and associated cardiovascular risk in this population.

Association of De Ritis Ratio and Neutrophil Lymphocyte Ratio with renal functional decline and all-cause mortality in renal cell carcinoma.

741 Background: We sought to investigate utility of pre-operative neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and De Ritis Ratio as predictors of all-cause mortality (ACM) and renal functional decline renal cell carcinoma (RCC). Methods: Multi-institutional retrospective analysis of patients undergoing surgery for RCC. Multivariable analysis (MVA) was conducted to elucidate independent risk factors for ACM, de novo estimated glomerular filtration rate (eGFR)&lt;45 ml/min/1.73m2 and eGFR&lt;30 ml/min/1.73m2. Kaplan-Meier analysis (KMA) was used to investigate ACM, and de novo CKD. Results: 2928 patients were analyzed [1850 Male/1078 Female, median follow up 30.5 months, median tumor size 4.5 cm, 1741 partial nephrectomy (PN)/1187 radical nephrectomy (RN)]. 690 patients had NLR ≥ 3, while 208 patients had NLR ≥ 6; 110 patients had PLR ≥ 3; and 474 patients had De Ritis Ratio ≥ 3. MVA for risk factors associated with worsened ACM showed male sex (OR 1.6, p=0.02), HTN (OR 2.1, p=0.001), increasing tumor size (OR 1.12, p&lt;0.001), clear cell RCC (OR 2.0, p=0.001), RN (OR 1.6, p=0.048), NLR≥ 6 (OR=2.4, p=0.001), Di Ritis Ratio≥3 (OR 2.4, p&lt;0.001), and de novo eGFR&lt;45 (OR=1.6, p=0.015) to be independent risk factors. MVA for factors associated with development of eGFR&lt;45 included increasing age (OR 1.03, p&lt;0.001), male (OR 1.5, p=0.01), HTN (OR 2.3, p&lt;0.001), clear cell RCC (OR 2.2, p&lt;0.001), RN (OR 6.8, p=0.03), NLR≥6 (OR 2.0, p=0.002), and Di Ritis Ratio≥3 (OR 2.3, p&lt;0.001) to be independently associated. Variables associated with development of eGFR&lt;30 included age (OR 1.05, p&lt;0.001), DM (OR=3.01, p&lt;0.001), black race (OR 1.9, p=0.005), Di Ritis Ratio≥3 (OR 2.0, p=0.001), and NLR≥6 (OR 2.1, p=0.002). PLR was not associated with OS, de novo eGFR&lt;45, or de novo eGFR&lt;30. On KMA, NLR≥6 was associated with worse OS (p&lt;0.001). Di Ritis ratio ≥1.5 was associated with worse OS p&lt;0.001 and Di Ritis ratio (≥3) was associated decreased freedom from of de novo eGFR&lt;45 (p=0.026). Conclusions: Elevated NLR and De Ritis Ratio were associated with functional decline and worsened OS, while PLR was not predictive. These markers may be helpful in identifying high-risk patients.

Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Classes of Glucose-Lowering Medications on Renal Outcome in Type 2 Diabetes

ObjectiveTo assess whether sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy is associated with a favorable renal prognosis for patients with type 2 diabetes melllitus (T2DM) outside the clinical trials setting. Participants and MethodsThis retrospective study analyzed routinely collected health care records of ∼160 medical institutions in Japan from April 1, 2014, to December 31, 2017/2018 (varying at the institutional level). Adults with T2DM but without end-stage renal disease who initiated either SGLT2i or other classes of glucose-lowering medications (o-GLM) were matched using propensity score. The primary outcome was the time course of estimated glomerular filtration rate (eGFR) displayed in spline curve. The composite of renal worsening (>40% decline in eGFR) and the development of eGFR<30 mL/1.73 m2 per minute was evaluated as a secondary outcome. Two sensitivity analyses were conducted to determine the robustness of results. ResultsWe compared a matched cohort of 1433 SGLT2i users and 2739 o-GLM users (mean age: 61 years). The eGFR declined over time in both groups during the observation period (median: 17 months; maximum: 54 months), with a slower eGFR slope observed in SGLT2i users. This slower decline was consistently observed across different SGLT2i agents and different baseline eGFR groups. The cumulative incidence of composite renal endpoints was lower in the SGLT2i group with a hazard ratio of 0.70 (95% CI, 0.50-0.98; P=.039). Those findings were consistent in sensitivity analyses limited to the period adherent to the initial drug regimen and with a different approach for propensity score calculation. ConclusionIn a matched cohort of T2DM patients, SGLT2i use was associated with preserved renal function relative to o-GLM use over 2 to 4 years.

Development and validation of a novel scoring index (C-reactive protein, age, race, and tumor size) to predict renal functional decline post partial nephrectomy.

597 Background: Functional decline is a sequelae of extirpative renal surgery with potential for significant morbidity. We utilized pre-operative patient demographics, C-reactive protein, and tumor size to design and validate a novel scoring index to predict functional decline post partial nephrectomy. Methods: A multi-institutional dataset was utilized for analysis of patients with pre-operative estimated glomerular filtration rate (eGFR) &gt; 60mL/min/1.73m2 by CKD-EPI equation. Multivariable analysis (MVA) was carried out for potential variables associated with development of post-operative chronic kidney disease (CKD) stage IIIB at last follow-up (eGFR &lt; 45 mL/min/1.73m2). Significant variables were included in the predictive model and assigned an index score based on odds ratio. Receiver-operating-characteristic (ROC) analysis was employed to evaluate predictive validity, and bootstrapping technique was utilized to validate the model. Results: 924 patients were analyzed. 826 patients had post-operative eGFR &gt; 45, while 111 patients had eGFR. Factors on MVA independently associated with increased risk of development of eGFR &lt; 45 included age 65+ (OR = 2.6, p &lt; 0.001), African-American race (OR = 2.3, p = 0.006), C-reactive protein level &gt; 0.5mg/dL (OR = 5.3, p &lt; 0.001), and tumor size &gt; 4 cm (OR = 1.458, p = 0.189). For CART (C-reactive protein, Age, Race, Tumor size) score, the following values were assigned: age ( &lt; 65 = 1, age &gt; 65 = 3), race (non-African-American = 1, African-American = 2), tumor size ( &lt; 4 = 1, &gt; 4cm = 2), and CRP ( &lt; 0.5mg/dL = 1, &gt; 0.5mg/dL = 4). Analysis demonstrated 2.6% (12/469) of patients with a low (4-6) score had de novo eGFR &lt; 45 postoperatively, while 35% (41/117) of patients with a high (10-11) score had de novo eGFR &lt; 45. ROC analysis revealed AUC of 0.778, and ROC bootstrapping validation of 95 randomly selected patients revealed an AUC of 0.808. Conclusions: CART score represents a novel composite score that significantly predicts development of eGFR &lt; 45 after surgery. This scoring system may assist in patient counseling and clinical decision making, as well as an impetus to improve outcomes in at-risk patient subgroups.

Congenital solitary kidney size at birth could predict reduced eGFR levels later in life.

To evaluate the impact of congenital solitary functioning kidney (CSFK) length, measured early in life, on the eGFR levels during the follow-up. We retrospectively selected 162 CSFK patients undergoing, within 60 days of life, renal length (RL) measurement by ultrasound. We divided the population in: Group 1 = RL ≥ 2 standard deviation score (SDS). Group 2 = RL < 2 SDS and showing RL ≥ 2 SDS during the follow-up. Group 3 = RL < 2 SDS and showing RL < 2 SDS during the follow-up. development of eGFR below the range of normality. The median follow-up period of the overall population was 6.2 years (range 2-21.5 years). The cumulative proportion of patients free of primary outcome at 15 years of age was 96.4% in group 1, 64.6% in group 2, and 45.6% in group 3 (p = 0.03). The RL > 2 SDS within 60 days of life was a significant protective factor (hazard ratio = 0.13; 95% C.I. 0.02-0.97) against development of primary outcome. RL ≥ 2 SDS within 60 days of life could identify a population of CSFK with reduced risk of presenting reduced eGFR levels later in life.

Proenkephalin and risk of developing chronic kidney disease: the Prevention of Renal and Vascular End-stage Disease study

Background: Proenkephalin (pro-ENK) was recently found to be associated with low estimated glomerular filtration rate (eGFR). The association of pro-ENK with urinary albumin excretion (UAE), another marker for chronic kidney disease (CKD), has not been investigated. We examined the association of pro-ENK with eGFR and UAE as markers of CKD.Methods: We included 4375 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. CKDeGFR was defined as development of eGFR <60 ml/min/1.73 m2 and CKDUAE as albuminuria >30 mg/24 h.Results: Baseline median pro-ENK was 52.2 (IQR: 44.9–60.5) pmol/L. After a median follow-up of 8.4 (IQR: 7.9–8.9) years, 183 subjects developed CKDeGFR and 371 developed CKDUAE. The association of pro-ENK with CKDeGFR was modified by sex (Pinteraction < 0.1), in such a way that after adjustment, the association only remained significant in men (adjusted hazard ratio per SD increase in 10log-transformed pro-ENK, 1.65; 95% CI: 1.15–2.36) and not in women (0.83; 0.58–1.20). No significant association was observed between pro-ENK and CKDUAE risk (0.83; 0.58–1.20).Conclusions: High pro-ENK is associated with increased risk of CKDeGFR in men, but not in women. No association of pro-ENK with CKDUAE was observed. These results should be interpreted with caution, since residual confounding and potential overfitting of models could have influenced the results.

Relation of uric acid level to rapid kidney function decline and development of kidney disease: The Jackson Heart Study.

Whether elevated uric acid (UA) is an independent risk factor for chronic kidney disease (CKD) is not well established. The authors evaluated the relationship of UA with rapid kidney function decline (RKFD) and incident CKD among 3702 African Americans (AAs) in the Jackson Heart Study with serum UA levels measured at baseline exam (2000-2004). RKFD was defined as ≥ 30% eGFR loss and incident CKD as development of eGFR < 60mL/min/1.73m2 with a ≥ 25% decline in eGFR between baseline and exam 3 (2009-2013). RKFD and CKD were found in 11.4% and 7.5% of the participants, respectively. In a fully adjusted model, the odds of RKFD (OR, 1.8; 95% CI, 1.25-2.49) and incident CKD (OR, 2.00; 95% CI, 1.31-3.06) were significantly higher among participants in the top UA quartile vs bottom quartile. In the JHS, elevated UA was significantly associated with RKFD and incident CKD.

Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety

Background: To observe effectiveness and renal safety of long-term low-dose cyclosporine in idiopathic membranous nephropathy (IMN).Methods: Sixty-eight patients were enrolled in this prospective cohort study. Renal endpoint was defined as a decrease in eGFR ≥50% from baseline and a development of eGFR ≤60 ml/min/1.73m2.Results: A cyclosporine dose of 2.0 ± 0.5 mg/kg/d and a prednisone of 0.3 ± 0.2 mg/kg/d were prescribed. The duration of cyclosporine treatment was 27 (3–80) months. The overall remission rate was 91% with a relapse rate of 42%. Fourteen patients had cyclosporine-related acute renal injury (CsA-ARI) within the first three months, and 16 patients had cyclosporine related chronic renal injury (CsA-CRI) within the first year. At the end of follow-up (50 ± 18 months), 16 patients (24%) reached renal endpoint. Presence of intimal fibrosis of small artery and higher time-averaged proteinuria were identified as independent risk factors for renal endpoint. RAS inhibition treatment decreased the risk of poor renal outcome. Patients in CsA-ARI group had the highest proteinuria at the third month, the highest time-average proteinuria and the highest proportion of cases reaching renal endpoint. Patients with CsA-CRI were of the oldest age and with the lowest baseline eGFR.Conclusions: Low-dose cyclosporine is effective in treating IMN. CsA-ARI and no response in proteinuria during the first three months of cyclosporine treatment had the lowest benefit/risk ratio, and these patients should be switched to non-calcineurin-inhibitor based regimen. Patients of older age, with lower baseline eGFR, or having intimal sclerosis of small artery, are more likely to develop progressive renal dysfunction.

Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA)

Among populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear. Retrospective cohort study. 5,810 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) > 60mL/min/1.73 m(2) using the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation. Serum bicarbonate concentrations. Rapid kidney function decline (eGFR decline > 5% per year) and incident reduced eGFR (eGFR < 60mL/min/1.73 m(2) with minimum rate of eGFR loss of 1 mL/min/1.73 m(2) per year). Average bicarbonate concentration was 23.2 ± 1.8mEq/L. 1,730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%-20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03-1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate level < 21 mEq/L relative to 23-24 mEq/L was 1.35 (95% CI, 1.05-1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83-1.62) for incident reduced eGFR. Cause of metabolic acidosis cannot be determined in this study. Lower serum bicarbonate concentrations are associated independently with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with baseline eGFR > 60 mL/min/1.73 m(2). If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria or may have a causal role in the development of eGFR < 60 mL/min/1.73 m(2).

EGFR and beyond: evolution of molecular classification of lung cancer

Diagnosis and management of lung cancer, the world’s most common cancer, has been transformed over the past decade. This transformation has emerged from the molecular analysis of these cancers and the demonstration of the critical role of molecular diagnosis in understanding lung cancer biology, therapy response, and outcome. The demonstration of the critical treatable mutations in the EGFR gene in a subset of lung adenocarcinomas in 2004 and, subsequently, rearrangements of ALK in 2007, has led to professional guidelines from three organizations—College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and International Association for the Study of Lung Cancer (IASLC)—for standardization of clinical practice around the world to implement these analyses into routine patient care. Even as EGFR and ALK analysis are becoming routine, newer markers with similar potential are being discovered and implemented into clinical trials. This presentation will address the historical development of EGFR and ALK analysis in lung cancer, as well as newer, emerging targets (such as ROS1, RET, and MET), as we evolve from a purely histologic classification of lung cancer towards a classification strategy that incorporates molecular pathology.

Abstract 2734: c-Met antibody LY2875358 (LA480) shows differential antitumor effects in non-small cell lung cancer

Abstract c-Met is a member of the receptor tyrosine kinase family and is the receptor for hepatocyte growth factor (HGF). c-Met is involved in many mechanisms of cancer proliferation and metastasis. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional up-regulation, or by ligand-dependent autocrine or paracrine mechanisms. Lung cancer is the leading cause of cancer death worldwide. Despite the successful development of EGFR- or EML4-ALK-targetd therapies, treatment options remain limited for patients with advanced lung cancer, making the identification of new therapeutic targets essential. c-Met expression was reported in 41-72% non-small cell lung cancer (NSCLC), amplification of c-Met occurs in 5-10 % of patients, and c-Met mutations have been detected in 8-13% of patients. We have developed a bi-valent c-Met antibody LY2875358 (LA480), which blocks ligand-dependent and ligand-independent c-Met activations. It is currently in clinical development. Here, we have demonstrated that LY2875358 alone or in combination with standard-of-care (SOC) affected cell proliferation, migration and signal transduction in NSCLC cells with c-Met gene amplification, mutations and overexpression. In vitro, LY2875358 induces wild type and mutant c-Met internalization and degradation. In vivo, LY2875358 alone shows a marked antitumor activity in Met amplification NSCLC xenograft models. The combination of LY2875358 with SOC chemotherapeutics treatments has better efficacy than either treatment alone, both in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2734. doi:1538-7445.AM2012-2734

Metabolic syndrome and kidney disease: a systematic review and meta-analysis.

Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS AND POPULATION: We searched MEDLINE (1966 to October 2010), SCOPUS, and the Web of Science for prospective cohort confidence interval (CI) studies that reported the development of microalbuminuria or proteinuria and/or CKD in participants with MetS. Risk estimates for eGFR <60 ml/min per 1.73 m(2) were extracted from individual studies and pooled using a random effects model. The results for proteinuria outcomes were not pooled because of the small number of studies. Eleven studies (n = 30,146) were included. MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m(2) (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of MetS increased (trend P value = 0.02). In patients with MetS, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m(2) for individual components of MetS were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fasting glucose 1.14 (1.03, 1.26). Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS. MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m(2) and microalbuminuria or overt proteinuria.