Activation of different genes would explain the higher severity of acute kidney injury in males than in females

Researchers have generated a female and male pig model of ischemia/reperfusion renal injury and organ regeneration to study sex differences in gene activation and molecular processes.

Acute kidney injury is characterized by a rapid decline in kidney function with a high mortality rate and progression to end-stage renal disease requiring dialysis and transplantation. Ischemia or lack of blood is the most frequent cause of this type of injury, affecting one in five patients in emergency admissions. This type of injury shows gender differences: for every two women, there are three men who progress to chronic and end-stage renal disease. Clinical studies have shown that men have a mortality rate twice as high as that of women and have observed that sex is an independent predictor of mortality. To understand what are the molecular processes of this type of damage and the differences between sexes, the Renal Pathophysiology group of Vall d'Hebron Research Institute (VHIR) has led a study to analyze the biochemical markers, tissue lesions and molecular changes that occur in this process. The results have been published in Scientific Reports.

Previous studies have shown that early intervention can mitigate the severity of acute kidney injury and allow tissue regeneration. Unfortunately, there are no early markers available to prevent the still functioning tissue from progressing to chronic injury, nor therapeutic solutions to restore the damaged kidney. Now, Vall d'Hebron researchers have created a model in male and female pigs with ischemia/reperfusion injury. "We have studied the changes that occur at basal state, during ischemia and seven days after ischemic injury to know the processes that favor kidney regeneration, as well as the molecular mechanisms of the disease for each sex, since classically preclinical studies have been performed preferentially in males", explains Dr. Gerard Cantero, researcher of the Renal Pathophysiology group at VHIR.

The results of the study showed no differences between both sexes in the levels of two renal function markers: blood urea nitrogen (BUN) and serum creatine (SCr). However, as Dr. Luis Castro, a specialist in the Urology Department of the Vall d'Hebron Hospital, explains, "it was observed that females had higher mononuclear cell infiltrates of the immune system at baseline and during regeneration, while males showed more damage in the renal tubules during injury". Analyses of kidney biopsies revealed differences between the timing of kidney injury and repair in each sex and also between males and females at the same study point in relation to the regulation of relevant genes and pathways. "Some of these changes, which were later confirmed in human samples, seem to be related to the production of male sex hormones", says Dr. Anna Meseguer, head of the Renal Pathophysiology group at VHIR.

Overall, this study constitutes an extensive characterization of the differences in gene expression at different times during the process of kidney ischemia/reperfusion and subsequent regeneration and between the two sexes. Specifically, the analysis revealed five temporal and four sexual gene patterns. "The results provide data with great translational value that could help to design specific strategies to promote kidney regeneration in humans, depending on sex", concludes Dr. Stéphane Nemours, first author of the study in the Renal Pathophysiology group at VHIR and current researcher at the Biodonostia Health Research Institute.

The project has been carried out in collaboration with the Urology Department and the Pathological Anatomy Department of the Vall d'Hebron University Hospital and the Laboratory Animal Service (LAS) and the Statistics and Bioinformatics Unit (UEB) of VHIR.

Pigs, a model with great translational value to humans

Pigs represent the most valued standard model for renal transplantation studies involving ischemia/reperfusion. It is the ideal model for translational research because of its similarities to humans at the level of genome, size, metabolism, renal anatomy and biochemical parameters of renal function (SCr and BUN markers).

On a technical level, the size of the kidney allows the collection of samples from the same animal at different times, overcoming the variability and individual disparity that can occur in rodents. Samples obtained from the kidney are also comparable, as the same amount of tissue from the same part of the organ can be obtained for all animals. In addition, data obtained in an experimental model of ischemia/reperfusion allow a clear definition of ischemia-related events compared to other factors that may occur in patients.