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BACKGROUND AND OBJECTIVES: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates. RESULTS: In patients with normoalbuminuria (n=2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8-6.4) years (event rate, 3.5; 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2; 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3; 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles. CONCLUSIONS: TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629.
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Diabetes Mellitus Tipo 2/etiología , Nefropatías Diabéticas/etiología , Receptor Celular 1 del Virus de la Hepatitis A/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Insuficiencia Renal Crónica/etiología , Anciano , Canagliflozina/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Nefropatías Diabéticas/complicaciones , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Insuficiencia Renal Crónica/complicaciones , Índice de Severidad de la Enfermedad , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
INTRODUCTION: There is considerable controversy on the accuracy of Kidney Injury Molecule-1 (KIM-1) in prediction of acute kidney injury (AKI) in children. Therefore, the present study intends to provide a systematic review and meta-analysis of the value of this biomarker in predicting AKI in children. METHODS: An extensive search was performed on the Medline, Embase, Scopus and Web of Science databases by the end of 2019. Cohort and case-control studies on children were included. Urinary KIM-1 levels were compared between AKI and non-AKI groups. Findings were reported as an overall standardized mean difference (SMD) with a 95% confidence interval (CI). Also, the overall area under the receiver operating characteristic (ROC) curve (AUC) of KIM-1 in predicting AKI in children was calculated. RESULTS: Data from 13 articles were included. Urinary KIM-1 levels in children with stage 1 AKI were higher than the non-AKI group only when assessed within the first 12 hours after admission (SMD = 0.95; 95% CI: 0.07 to 1.84; p = 0.034). However, urinary KIM-1 levels in children with stage 2-3 AKI were significantly higher than non-AKI children (p <0.01) at all times. The AUC of urinary KIM-1 in predicting AKI in children was 0.69 (95% CI: 0.62 to 0.77). CONCLUSION: Based on the available evidence, KIM-1 seems to have moderate value in predicting AKI in children. Since previous meta-analyses have provided other urinary and serum biomarkers that have better discriminatory accuracy than KIM-1, so it had better not to use KIM-1 in predicting AKI in children.
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BACKGROUND AND OBJECTIVES: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. RESULTS: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT. CONCLUSIONS: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.
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Albuminuria/orina , Quimiocina CCL2/orina , Proteína 1 Similar a Quitinasa-3/orina , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Interleucina-18/orina , Túbulos Renales/metabolismo , Insuficiencia Renal Crónica/orina , Anciano , Anciano de 80 o más Años , Albuminuria/diagnóstico , Albuminuria/etiología , Albuminuria/fisiopatología , Biomarcadores/orina , Progresión de la Enfermedad , Femenino , Humanos , Hipertensión/complicaciones , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Medición de Riesgo , Factores de Riesgo , UrinálisisRESUMEN
BACKGROUND AND OBJECTIVES: In early-phase studies of individuals with hypertensive CKD and normal serum total CO2, sodium bicarbonate reduced urinary TGF-ß1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO2 is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15-89 ml/min per 1.73 m2, urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO2 of 22-28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n=35) or placebo (n=39) for 6 months. The primary outcome was change in urinary TGF-ß1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6. RESULTS: Key baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m2, and serum total CO2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF-ß1/creatinine (difference in change, 13%, 95% CI, -10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, -10% to 28%; change within the placebo group, -4%, 95% CI, -19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, -10%, 95% CI, -38% to 31%), fibronectin-to-creatinine (8%, 95% CI, -15% to 37%), NGAL-to-creatinine (-33%, 95% CI, -56% to 4%), or UACR (1%, 95% CI, -25% to 36%) was observed. CONCLUSIONS: In nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF-ß1, KIM-1, fibronectin, NGAL, or UACR over 6 months.
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Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Bicarbonato de Sodio/uso terapéutico , Factor de Crecimiento Transformador beta1/orina , Anciano , Anciano de 80 o más Años , Biomarcadores/orina , Creatinina/orina , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/orina , Método Doble Ciego , Femenino , Fibronectinas/orina , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Lipocalina 2/orina , Masculino , Persona de Mediana Edad , Bicarbonato de Sodio/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Utah , VeteranosRESUMEN
Background: Individuals with type 2 diabetes (T2D) or the apolipoprotein L1 high-risk (APOL1-HR) genotypes are at increased risk of rapid kidney function decline (RKFD) and kidney failure. We hypothesized that a prognostic test using machine learning integrating blood biomarkers and longitudinal electronic health record (EHR) data would improve risk stratification. Methods: We selected two cohorts from the Mount Sinai BioMe Biobank: T2D (n=871) and African ancestry with APOL1-HR (n=498). We measured plasma tumor necrosis factor receptors (TNFR) 1 and 2 and kidney injury molecule-1 (KIM-1) and used random forest algorithms to integrate biomarker and EHR data to generate a risk score for a composite outcome: RKFD (eGFR decline of ≥5 ml/min per year), or 40% sustained eGFR decline, or kidney failure. We compared performance to a validated clinical model and applied thresholds to assess the utility of the prognostic test (KidneyIntelX) to accurately stratify patients into risk categories. Results: Overall, 23% of those with T2D and 18% of those with APOL1-HR experienced the composite kidney end point over a median follow-up of 4.6 and 5.9 years, respectively. The area under the receiver operator characteristic curve (AUC) of KidneyIntelX was 0.77 (95% CI, 0.75 to 0.79) in T2D, and 0.80 (95% CI, 0.77 to 0.83) in APOL1-HR, outperforming the clinical models (AUC, 0.66 [95% CI, 0.65 to 0.67] and 0.72 [95% CI, 0.71 to 0.73], respectively; P<0.001). The positive predictive values for KidneyIntelX were 62% and 62% versus 46% and 39% for the clinical models (P<0.01) in high-risk (top 15%) stratum for T2D and APOL1-HR, respectively. The negative predictive values for KidneyIntelX were 92% in T2D and 96% for APOL1-HR versus 85% and 93% for the clinical model, respectively (P=0.76 and 0.93, respectively), in low-risk stratum (bottom 50%). Conclusions: In patients with T2D or APOL1-HR, a prognostic test (KidneyIntelX) integrating biomarker levels with longitudinal EHR data significantly improved prediction of a composite kidney end point of RKFD, 40% decline in eGFR, or kidney failure over validated clinical models.
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Diabetes Mellitus Tipo 2 , Registros Electrónicos de Salud , Apolipoproteína L1/genética , Biomarcadores , Diabetes Mellitus Tipo 2/diagnóstico , Tasa de Filtración Glomerular/genética , Humanos , Riñón , Aprendizaje Automático , PronósticoRESUMEN
BACKGROUND AND OBJECTIVES: Tenofovir disoproxil fumarate (tenofovir) is associated with elevated concentrations of biomarkers of kidney damage and dysfunction in individuals with HIV. The relationship of these kidney biomarkers with longitudinal kidney function decline is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated associations of 14 urinary biomarkers of kidney injury with changes in eGFR among 198 men and women with HIV who initiated tenofovir between 2009 and 2015 in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Urinary biomarkers included albumin-to-creatinine ratio, α-1-microglobulin, ß-2-microglobulin, cystatin C, kidney injury molecule-1 (KIM-1), IL-18, neutrophil gelatinase-associated lipocalin (NGAL), clusterin, osteopontin, uromodulin, monocyte chemoattractant protein-1, EGF, trefoil factor 3, and chitinase 3-like protein 1. We used multivariable linear mixed-effect models controlling for demographics, traditional kidney disease risk factors, and HIV-related risk factors to evaluate associations of baseline biomarkers with first-year changes in eGFR, and associations of year 1 and first-year change in biomarkers with changes in eGFR from year 1 to year 3. We used the least absolute shrinkage and selection operator method to identify a parsimonious set of biomarkers jointly associated with changes in eGFR. RESULTS: Median eGFR before tenofovir initiation was 103 (interquartile range, 88-116) ml/min per 1.73 m2. During the first year of tenofovir use, eGFR decreased on average by 9.2 (95% confidence interval, 6.5 to 11.9) ml/min per 1.73 m2 and was stable afterward (decrease of 0.62; 95% confidence interval, -0.85 to 2.1 ml/min per 1.73 m2 per year). After multivariable adjustment, higher baseline ß-2-microglobulin, KIM-1, and clusterin were associated with larger first-year eGFR declines, whereas higher baseline uromodulin was associated with a smaller eGFR decline. First-year increase in urinary cystatin C and higher year 1 IL-18 were associated with larger annual eGFR declines from year 1 to year 3. The parsimonious models identified higher pre-tenofovir clusterin and KIM-1, lower pre-tenofovir uromodulin, and higher year 1 IL-18 as jointly associated with larger eGFR declines. CONCLUSIONS: Urinary biomarkers of kidney injury measured before and after tenofovir initiation are associated with subsequent changes in eGFR in individuals with HIV. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_28_CJASNPodcast_18_9_S.mp3.
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Fármacos Anti-VIH/efectos adversos , Tasa de Filtración Glomerular , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/fisiopatología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/fisiopatología , Tenofovir/efectos adversos , Adulto , Fármacos Anti-VIH/uso terapéutico , Biomarcadores/orina , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/orina , Humanos , Enfermedades Renales/orina , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tenofovir/uso terapéuticoRESUMEN
Little is known about the association of the TIMD4 (T-cell immunoglobulin and mucin domain 4 gene)-HAVCR1 (hepatitis A virus cellular receptor 1) variants and lipid metabolism, the risk of coronary heart disease (CHD) and ischemic stroke (IS). The present study aimed to determine the TIMD4-HAVCR1 variants, their haplotypes and gene-environment interactions on serum lipid levels, the risk of CHD and IS, and the lipid-lowering efficacy of atorvastatin in a southern Chinese Han population. Genotypes of three variants in 622 controls, 579 CHD, and 546 IS patients were determined by the Snapshot technology. Atorvastatin calcium tablet (20 mg/day) was given in 724 hyperlipidemic patients for 8 weeks after genotyping. The rs12522248 genotypic and allelic frequencies were different between controls and patients, and were associated with the risk of CHD and IS. The rs1501908G-rs12522248T-rs2036402T haplotype was associated with an increased risk of CHD; the G-C-T haplotype was associated with lower risk of CHD; and the C-C-C haplotype was associated with an increased risk of IS. Variants and their haplotypes in controls were associated with triglyceride (rs1501908), low-density lipoprotein cholesterol (LDL-C, rs1501908, G-T-T), high-density lipoprotein cholesterol (HDL-C, rs12522248, C-C-C) and the ratio of total cholesterol (TC) to HDL-C (C-C-C). Interactions of rs1501908- and rs2036402-alcohol (HDL-C); rs1501908- and rs12522248-high body mass index (hBMI, ≥24 kg/m2; TC); and TIMD4-HAVCR1 variants-atorvastatin on several lipid parameters were detected. Interactions of rs12522248TC/CC-hBMI, G-T-T-, and C-C-C-smoking on the risk of CHD; and C-C-C-smoking, C-C-C-, and G-C-T-hBMI on the risk of IS were also observed. These findings suggest that the TIMD4-HAVCR1 variants may be the genetic risk factors for CHD and IS.