Differentiating uremic vs non-uremic mediators of type 3 cardiorenal syndrome in rats.

Acute kidney injury (AKI) is common in critically ill patients and is associated with significant increases in mortality. Acute kidney injury can lead to cardiac dysfunction (Type 3 reno-cardiac syndrome); however, the biological mechanisms underlying this deleterious inter-organ crosstalk remain unclear. Cardiac dysfunction in AKI can occur secondary to loss of kidney function (uremic causes) such as increased blood urea nitrogen (BUN) or volume overload, but it may also be caused by non-uremic factors, such as inflammatory signaling from the injured kidney parenchyma.  The goal of the current study was to characterize acute changes in cardiac function in rats with ischemic AKI and determine if they were mediated by uremic or non-uremic causes.   

All studies were approved by the Augusta University Institutional Animal Care and Use Committee Studies. Studies were performed in 10–12-week-old male Sprague Dawley rats. Group 1,  ‘Control’ rats (n=6), were anesthetized with isoflurane (1-5%), the right kidney removed, and the left kidney left in place. In group 2, ‘IRI’ rats (n=7), the right kidney was removed and renal ischemia induced by placing clamps on the left renal artery for 45 minutes. In group 3, ‘uremic’ rats (n=7), both the left and right kidneys were removed. Rats were given buprenorphine for analgesia and allowed to recover for 24 hours before cardiac function measurements were performed using a Vevo 3100 ultrasound. At the conclusion of cardiac measurements, animals were sacrificed. Blood was collected via cardiac puncture and the heart, lungs and kidneys excised.

There was no difference in body weight in any of the groups; however, left kidney weights were significantly greater in the IRI group (1.44g) compared to the control group (1.14g, p=0.001). Neither heart nor wet or dry lung weights were significantly different between groups. When compared to control kidneys, ejection fraction (88% IR and 87% uremic vs 79% control, p<0.01) and fractional shortening (59% IR and 58% uremic vs 49% control p<0.01) were significantly greater in both IR and uremic rats. Left ventricular arterial wall thickness (mm IR and 3.5 mm uremic vs 2.9 mm control) was also greater in both IR and uremic rats compared to controls. Cardiac output tended to be greatest in the IR group (72.3 mL/min) compared to the control (49.2 mL/min) and uremic (58.4 mL/min) groups, although this did not reach statistical significance.  Mitral valve early wave peak velocity ((MVE) 872 mm/s IR vs 672 mm/s uremic and 727 mm/s control, p<0.03) and Mitral valve A wave peak velocity ((MVA) 510 mm/s IR vs 377 mm/s uremic and 384 mm/s control, p<0.01) were both significantly greater in rats with IR compared to control or uremic rats. Isovolumetric relaxation time (IVRT) 21.3 ms IR vs 25 ms uremic (p<0.05) and 24.2 ms control (N.S)) was also reduced in IR rats compared to uremic rats. 

Our data identify changes in cardiac function following loss of kidney function in rats. While increases in ejection fraction were common to uremic rats with and without the presence of an injured kidney, diastolic filling was greater, and IVRT shorter, only in uremic rats with an injured kidney present. Our data are consistent with the notion that acute loss of kidney function causes dysregulation of cardiac function in rats. Importantly, our data suggest that the presence of an injured kidney may promote increased stress on the heart independent of the effects of uremia alone.