Kidney Week

Abstract: TH-OR103

Precision Medicine in Renal Failure: Role of Lanosterol Synthase Gene and Endogenous Ouabain in AKI

Session Information

• Predicting AKI
  November 02, 2017 | Location: Room 282, Morial Convention Center
  Abstract Time: 05:30 PM - 05:42 PM

Category: Acute Kidney Injury

• 003 AKI: Clinical and Translational

Authors

• Simonini, Marco, San Raffaele Scientific Institute, Milan, MILANO, Italy

Marco Simonini, MD

• Lanzani, Chiara, San Raffaele Scientific Institute, Milan, MILANO, Italy

Chiara Lanzani,

• Bignami, Elena, San Raffaele Scientific Institute, Milan, MILANO, Italy

Elena Bignami,

• Casamassima, Nunzia, San Raffaele Scientific Institute, Milan, MILANO, Italy

Nunzia Casamassima,

• Citterio, Lorena, Università Vita-Salute - Ospedale San Raffaele, Milano, Italy

Lorena Citterio,

• Iatrino, Rossella, Vita-Salute San Raffaele University, Milan, Italy

Rossella Iatrino,

• Meroni, Roberta, Ospedale San Raffaele, Milano, Italy

Roberta Meroni,

• Zagato, Laura, Ospedale San Raffaele, Milano, Italy

Laura Zagato,

• Fontana, Simone, Università Vita Salute San Raffaele, Milan, Italy

Simone Fontana,

• Delli carpini, Simona, San Raffaele Hospital, Milano, Italy

Simona Delli carpini,

• Messaggio, Elisabetta, Università San Raffaele, Milano, Italy

Elisabetta Messaggio,

• Brioni, Elena, ospedale San Raffaele, Milan, Italy

Elena Brioni,

• Hamlyn, John, University of Maryland, Baltimore, Baltimore, Maryland, United States

John Hamlyn,

• Manunta, Paolo, HSR-Nefrologia, Milano, Italy

Paolo Manunta,

Background

A key question in renal failure concerns the mechanism(s) that underlie the decline in renal function. Endogenous Ouabain (EO) has been proposed as predictive biomarker for acute kidney injury (AKI), and effector of glomerular damage in salt-sensitive hypertensive rats. Lanosterol Synthase (LSS) is a key enzyme in the EO biosynthesis. This work explores the association of LSS genotypes and kidney EO with renal damage and its progression.

Methods

Three different conditions were investigated: 1. Renal EO: we analyzed EO contents of the cortex and medulla of healthy kidneys derived from nephrectomised patients genotyped for LSS genetic variants. 2. Essential Hypertension: 338 naïve hypertensive (f 162, m 176, age 44.5±0.42 years) were enrolled for a prospective follow-up study, in which BP was maintained in similar range and changes in renal function were followed. 3. AKI: 1097 individuals undergoing elective cardiovascular surgery were enrolled for a prospective, observational study, investigating the genetic predisposition to AKI.

Results

Among LSS genotypes, individuals with LSS AA variant had higher renal cortical content of EO (2.14±0.29 ng/g), than their LSS CC (1.25±0.08 ng/g; p=0.0009) counterparts. The follow-up study revealed a genotype-dependent decline in renal function over time. LSS AA exhibited greater eGFR decay than LSS CC (AA -2.02±1.22 vs CC 2.24±0.76 ml/1.73m2/yr; p=0.027), despite similar blood pressure values. Likewise, the incidence of AKI following cardiovascular surgery was greater among LSS AA individuals, and proportional to the number of A alleles (AA 30.7% vs AC 26.0% vs CC 17.4%; p=0.001).

Conclusion

Our findings support the view that LSS drives a common mechanism of renal damage in hypertension and AKI and this appears to be mediated in part by EO. LSS-based risk stratification can be used for the timely preoperative recognition and improved management of acute kidney failure.