The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant alpha-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 versus wild type 0.65 ± 0.16 mg/dL, p<0.05), and in urinary neutrophil gelatinase-associated lipocalin (NGAL, 278.92 ± 176.24 versus wild type 49.11 ± 22.79 ng/mL, p<0.05), but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a two-fold upregulation of the Ren1 gene, marked over-expression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice versus 2.01 ± 0.58 mg/dL in wild type, p<0.05), urine NGAL (9198.79 ± 3799.52 in transgenic mice versus 3252.94 ± 2420.36 ng/mL in wild type, p<0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice versus 2.6 ± 0.5 in wild type, p<0.05), tubule cast score (3.2 ± 0.4 in transgenic mice versus 2.5 ± 0.5 in wild type, p<0.05), and Tunel-positive nuclei (10.1 ± 2.1 in the transgenic group versus 5.7 ± 1.6 per 100 cells counted in wild type, p<0.01). Our findings indicate functional renal impairment, urinary biomarker elevations, and induction of renin gene and protein expression in the kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury.