The research of Maria V. Irazabal Mira, M.D., is focused on understanding the pathogenesis and molecular mechanisms of renal injury in autosomal dominant polycystic kidney disease (ADPKD), with the purpose of identifying early disease biomarkers for risk stratification, prediction of disease progression and new pathways for therapeutic interventions. Identification of disease-specific early biomarkers are of great interest to Dr. Irazabal, as current markers focus on later stages where anatomical damage is already present or remains unchanged until late stages of the disease.

Dr. Irazabal's research involves preclinical studies as well as translational mechanistic studies in humans. An area of particular interest is the presence of increased reactive oxygen species (ROS), renal mitochondrial abnormalities and energetic dysregulations that present early in the disease and precede renal function decline, therefore appearing to have some causal relation to the disease.

Focus areas

• Predictive models in ADPKD. Dr. Irazabal has been working on the development of statistical models to determine if there is a predictable linkage between renal size (or other biomarkers) and decline in renal function. Her previous work resulted in the development of a novel imaging classification of ADPKD. This classification can be used to select the most appropriate patients for clinical trials and identify patients with progressive disease likely to benefit from an effective therapy. Importantly, this classification has been validated in several different ADPKD patient cohorts, and several countries have already adopted this classification for selecting which patients with ADPKD to treat.
• Reactive oxygen species (ROS). Increased ROS is associated with ADPKD early in the disease, but the underlying mechanisms are not yet understood. Dr. Irazabal is conducting mechanistic studies in rodents to determine the underlying mechanisms that contribute to increased ROS, the organism response in the context of ADPKD, and how this may contribute to cystogenesis. Strategies to decrease ROS production from early stages in ADPKD is also being explored by Dr. Irazabal in preclinical models.

• Mitochondrial morphology and function. Mitochondria play an important role in cellular bioenergetics and maintenance of cellular redox status, and mitochondria dysfunction has been implicated in several renal diseases including PKD. Importantly, in PKD, mitochondrial dysfunction is present from early stages of the disease. Dr. Irazabal's research is focused on understanding the molecular mechanisms that lead to early mitochondrial dysfunction in PKD. Her research involves studying mitochondrial structure, dynamics and function.

  In addition, Dr. Irazabal is developing several methodologies at Mayo Clinic's Translational Polycystic Kidney Disease (PKD) Center to identify early markers of mitochondrial dysfunction in ADPKD, to determine whether these may be useful real-time biomarkers to assess disease severity and progression in patients with ADPKD.

• Energetic dysregulations. Preclinical studies have shown that PKD cells undergo metabolic reprogramming, however, the principal contributors to this energetic dysregulation in PKD remain unclear. Dr. Irazabal is leading several metabolomics studies in preclinical models and patients with ADPKD aiming to uncover abnormal metabolic pathways for new therapeutic strategies and early disease biomarkers in ADPKD.

Significance to patient care

Through preclinical studies and translational studies in humans, Dr. Irazabal aims to identify novel, early and real-time biomarkers to determine disease severity, predict disease progression and uncover dysregulations in metabolic pathways that could be targeted for therapeutic intervention to delay disease progression of ADPKD.