Pathophysiological Interactions between Chronic Kidney Disease and Cardiac Remodelling
Authors: Liu Shan , Kompa Andrew R , Wang Bing H , Krum Henry 
Published: November 2023

Purpose

In the setting of chronic kidney disease, cardiovascular disease is the most common cause of death. However, the underlying pathophysiological interactions between two organs are not fully understood. Therefore, we investigated the pathophysiological changes that occur when myocardial infarction (MI) follows a kidney injury (5/6 nephrectomy ‐ STNx).

Methods

STNx or Sham surgery was induced in male Sprague Dawley rats initially with each group randomised to receive MI or Sham surgery (left anterior descending coronary artery ligation) 4 weeks later. Animals were followed for a further 8 weeks. The animals (n=36) were randomized into four groups: Sham‐operated STNx+Sham‐operated MI (Control), Sham‐operated STNx+MI (MI), STNx+Sham‐operated MI (STNx) and STNx+MI. Echocardiography, glomerular filtration rate and blood pressure were assessed prior to MI or Sham surgery and at the end of the study. On the completion, hemodynamic measurements were obtained and tissues collected for analysis.

Results

Survival rate was 100%, 77.8%, 60.9% and 39.8% in Control, MI, STNx and STNx+MI animals, respectively. Despite no deterioration in renal function was observed post‐MI, increased renal interstitial fibrosis (p<0.05) and kidney injury molecule‐1 (KIM‐1) protein levels (p<0.001) were observed in STNx+MI vs STNx animals. Trend towards decreases in delta left ventricular ejection fraction (p=0.085) and delta fractional shortening (p=0.074) were found in STNx+MI vs MI animals. Heart weight/body weight ratio was greater in STNx+MI vs STNx animals (p<0.05), despite no difference in blood pressure was observed. Tau logistic, the time constant of active relaxation, was significantly prolonged in STNx+MI vs MI animals at week 12. The rate of rise and fall of pressure in the left ventricle, dP/dtmax and dP/dtmin were significantly reduced in STNx+MI vs Control animals. Left ventricular end diastolic pressure (LVEDP) and slope of end diastolic pressure‐volume relationship (EDPVR) were significantly increased in MI, STNx and STNx+MI animals compared to Control animals. STNx+MI animals demonstrated greater cardiomyocyte cross‐sectional area and increased cardiac interstitial fibrosis compared to either STNx (p<0.01 and p<0.05 respectively) or MI (p<0.001 and p<0.01 respectively) animals. These changes were associated with significant increases in collagen I gene expression in the LV comparing STNx+MI to either STNx or MI animals (p<0.05). Phosphorylated p38 MAPK (p<0.05) and phosphorylated p44/42 MAPK (p<0.01) protein expression was increased in the LV in STNx+MI vs STNx animals. TGF‐β1 (p<0.01), collagen IV (p<0.01), IL‐6 (p<0.05) gene expression and TGF‐β protein expression (p<0.001) were increased in the kidney in STNx+MI vs MI animals.

Conclusions

This study demonstrated the existence of more pronounced kidney and heart impairment in a model of combined chronic kidney disease and chronic heart failure. Such enhanced impairment may be separate from systemic hemodynamic changes. MI accelerated STNx‐induced renal fibrosis and KIM‐1 protein levels as well as cardiac hypertrophy and fibrosis, and all of these were blood pressure independent. This study established a potential useful model in pathophysiological and mechanistic assessing of cardiorenal syndrome.