Purpose: While renal donation is safe and widely employed for the treatment of endstage chronic kidney disease, recent experimental and human studies suggest complex cardiovascular adaptation that may impact long-term cardiovascular homeostasis. Indeed, in a large animal model of acute uninephrectomy (UNX) we observed reduced CO and increased SVR. Here we define chronic cardiovascular, renal and humoral adaptation in a large animal model 12 weeks after UNX with the goal of understanding integrative adaptations so as to advance possible cardiorenal protective strategies in the setting of mild renal insufficiency and UNX commonly associated with renal donation. Methods: Dogs were assigned to UNX (n=6) or sham operation (n=6). Echocardiography was performed at baseline and after 12 weeks. At 12 weeks cardiovascular, renal and humoral functions were assessed invasively. Fibrosis was assessed by Picrosirius red staining, and microarray analyses were performed on tissue from the left atrium (LA) and left ventricle (LV). Data are presented as mean±SD, * indicates p<0.05. Results: UNX dogs had compensatory increased left kidney (LK) weight at 12 weeks (80±10 vs. 59±5g, *) as well as increased LK GFR (59±11 vs. 41±6 mL/min, *). The groups were equal regarding MAP, PAP, PCWP, CO and SVR, and diastolic and systolic functions were unaltered in both groups 12 weeks after surgery. Plasma ANP, BNP and aldosterone were not different after 12 weeks, however plasma cGMP was higher in the UNX dogs (6.2±1.2 vs. 4.6±1.0 pmol/mL, *). LK urinary cGMP excretion was increased in the UNX dogs (1132±325 vs. 667±121 pmol/min, *) and there was a trend for increased renal generation of cGMP (UNX 777±345 vs. sham 475±112 pmol/min, p=0.07). Left atrial fibrosis was higher in the UNX group (13.7±5.1 vs. 7.7±2.3%, *). The UNX group had > 2 fold significant changes in the expression of 10 genes in the LA and 7 genes in the LV, associated with cardiac remodeling. Conclusion: UNX in a large animal is characterized by compensatory renal hypertrophy and preserved cardiovascular homeostasis after 12 weeks. Importantly however, the cardiorenal protective cGMP system is activated which may reflect triggering of endogenous vasodilating pathways mediating the preserved cardiovascular and renal function. Furthermore, our model is characterized by subclinical atrial fibrosis and altered remodeling-related gene expressions in the LA and LV. These studies provide insights into the complex responses to UNX and possible cGMP therapeutic strategies for cardioprotection in the setting of reduced renal mass.