#2436 Genetic variability in rosuvastatin metabolism explains rhabdomyolysis and consequent acute renal failure
Authors: Mlinšek Gregor , Blagus Tanja , Vrečko Marija Malgaj , Rigler Andreja Ales , Dolžan Vita 
Published: May 2024

Abstract

Background and Aims
Low density lipoprotein cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Rosuvastatin is one of the most frequently prescribed statins and also one of the most frequent causes of rhabdomyolysis with consequent acute renal failure (ARF). Risk factors for statin induced rhabdomyolysis, i.e. the type of statin and its dose, patient's age, kidney and liver function, gender and concurrent treatment with cytochrome P450 (CYP) inhibitors, should be considered at the time of statin prescription. Single nucleotide polymorphisms (SNPs) in genes coding the transport proteins (SLCO1B1, ABCG2) and CYP2C9, catalysing rosuvastatin oxidation, may lead to decreased protein function leading to accumulation of plasma rosuvastatin which increases the risk of rhabdomyolysis.
Herewith we present a case of a female patient admitted to our department due to rhabdomyolysis and ARF with the aim of alerting against uncritical high dose rosuvastatin prescribing and of pointing out the role of genetic variability in drug metabolizing enzymes and transporters (DMET) in rosuvastatin side effects.

Method
a 79-years old Caucasian woman admitted to our department due to rhabdomyolysis and ARF was genotyped for polymorphisms in DMET genes coding for CYP2C9 (rs1799853, rs1057910, rs28371686, rs28371685), SLCO1B1 (rs4149056, rs2306283) and ABCG2 (rs2231142) using competitive allele specific polymerase chain reaction (KASPar).

Results
Presented patient suffered from an acute myocardial infarction in October 2023. She was treated with percutaneous coronary intervention, antiaggregation therapy and hypolipidemic therapy (rosuvastatin 40 mg/ezetimibe 10 mg). Her creatinine was 55 μM (eGFR 61 ml/min) at the time of statin prescription. Several months later she was admitted septic with myoglobin &gt;50.000 μg/L and creatinine approximately 1600 μM. Infection was treated with piperacillin/tazobactam. Myoglobin was removed with Theranova dialyzer. The patient was dismissed home two weeks later with creatinine 230 μM.
As potential patient's risk factors for rhabdomyolysis we considered high dose of rosuvastatin, patient's higher age and slower rosuvastatin disposition due to SNPs in DMET. Sepsis may have been an additional contributory factor.
Genotyping revealed polymorphisms in all three genes involved in rosuvastatin metabolism and transport: CYP2C9, SLCO1B1 and ABCG2 (Table 1). Two genotypes resulted in the phenotypes with slower rosuvastatin metabolism, probably leading to gradual accumulation of plasma rosuvastatin, which may have manifested in rhabdomyolysis that contributed to ARF. Heterozygous CYP2C9*2 and *3 carriers have, in comparison to the wild type carriers, approximately 30% and 80% slower rosuvastatin metabolism, respectively. Heterozygous ABCG2 c.421C&gt;A carrier state may also contribute slightly to rosuvastatin accumulation. Furthermore, the potential interaction with inflammation should not be overlooked, as inflammation may have a major effect on drug metabolism and transport through downregulation of CYP enzymes as well as drug transporters.
If genotypes of the respective DMET genes were known in advance, high dose rosuvastatin could have been avoided despite relatively good kidney function at the time of rosuvastatin prescription.

Conclusion
Statins should be prescribed with caution and their dose adapted to the risk factors that should always be checked for at the time of statin prescription.
We recommend periodical surveillance of serum creatinine, eGFR, urine protein to creatinine ratio, liver tests, creatine kinase and myoglobin in patients treated with high dose statins.
Furthermore, SLCO1B1, ABCG2 and CYP2C9 genotyping before rosuvastatin prescription would enable insight into its metabolism. Genotype information could lead to more cautious statin prescribing, especially in the presence of other factors, such as infection or concomitant drug treatment that may modify the activity of DMET.
In the case of chronic kidney disease drug dosing should be appropriately adjusted in accordance with drug's Summary of product characteristics and KDIGO guidelines.