Urine Markers of Kidney Tubule Cell Injury and Kidney Function Decline in SPRINT Trial Participants with CKD
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Authors: Malhotra, Rakesh; Katz, Ronit; Jotwani, Vasantha; Ambrosius, Walter T.; Raphael, Kalani L.; Haley, William; Rastogi, Anjay; Cheung, Alfred K.; Freedman, Barry, I; Punzi, Henry; Rocco, Michael, V; Ix, Joachim H.; Shlipak, Michael G.
Abstract
Background and objectiveseGFR 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, & measurementsAmong 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m(2)) 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.ResultsMean 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 m(2). 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 m(2) 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.ConclusionsUrine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.
Identification of HAVCR1 gene haplotypes associated with mRNA expression levels and susceptibility to autoimmune diseases
HUMAN GENETICS
Authors: Raul Garcia-Lozano, Jose; Abad, Cristina; Escalera, Ana; Torres, Belen; Fernandez, Olga; Garcia, Alicia; Sanchez-Roman, Julio; Sabio, Jose-Mario; Ortego-Centeno, Norberto; Raya-Alvarez, Enrique; Nunez-Roldan, Antonio; Martin, Javier; Francisca Gonzalez-Escribano, Maria
Abstract
Human HAVCR1 gene maps on 5q33.2, a region linked with susceptibility to allergic and autoimmune diseases. The aims of the present study were to define the haplotypes of HAVCR1 gene taking into account both HapMap Project SNP haplotypes and exon 4 variants, to investigate a possible relationship between these haplotypes and mRNA expression levels, and to assess whether HAVCR1 gene is involved in susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Genotyping of three ins/del variants in the exon 4 was performed by fragment length analysis. Five tag SNPs genotypes and mRNA levels were determined using TaqMan assays. We defined four major haplotypes in our population: the two major haplotypes (named haplotypes A and B) bear both the 5383_5397del variant and the two most common SNP sets found in the CEU population. Quantification analysis revealed that genotype B/B had the highest median of mRNA expression levels (vs. BX + XX, p < 0.0001). Additionally, frequency of the genotype BB was significantly higher in RA patients than in controls (12.3 vs. 5.9% in controls, p = 0.0046, p (c) = 0.014, OR = 2.23, 95% CI 1.23-4.10). Our results support a relationship between HAVCR1 haplotypes and mRNA expression levels, and suggest an association of this gene with autoimmune diseases.