Although guidelines permit up to a 30% acute increase in creatinine following initiation of renin angiotensin system inhibitors (RASi), new evidence published in the Clinical Journal of the American Society of Nephrology associates creatinine rises of 10% or more with increased risks for death, cardiovascular events, and end-stage renal disease (ESRD).

Using data from the Stockholm Creatinine Measurements (SCREAM) project, researchers identified 31,951 patients initiating RASi during 2007 to 2011. Creatinine increases exceeding 10% within 2 months of RASi initiation were consistently associated with greater risks over a median 3.5 years, Edouard L. Fu, MD, a PhD candidate at Leiden University in The Netherlands, and colleagues reported. The risk for all-cause mortality significantly increased by 15%, 22%, and 55% with creatinine rises of 10% to 19%, 20% to 29%, and 30% or more, respectively, compared with a reference creatinine rise of less than 10%. Heart failure risk significantly increased by 14%, 23%, and 41%, respectively. Myocardial infarction risk rose by 5%, 32%, and 29%, respectively, but the increases were not significant. Lastly, ESRD risk increased significantly by 3-, 3-, and 8-fold, respectively. Patients with CKD stages 4 and 5 were previously excluded from study.  

Findings from the current study differ somewhat from results from several trials, such as TRANSCEND, but “the tendencies and effects in these studies are in the direction of the effects that we observed,” Dr Lu’s team observed.

The investigators pointed out that these findings do not necessarily mean RASi should be discontinued after acute creatinine increases. Additional studies are needed to clarify optimal thresholds for discontinuation.

“Because reanalyses of TRANSCEND and ADVANCE found no evidence for modification of the benefit of RASi by level of creatinine increase, we speculate that creatinine increases may therefore be a risk marker of disease rather than directly leading to adverse outcomes,” Dr Lu and his colleagues stated.

“Monitoring creatinine before and after initiation of RASi identifies patients at high risk for subsequent adverse outcomes,” they added.

Among the study’s limitations, the researchers could not determine the persistence of acute creatinine rises and lacked information on blood pressure and proteinuria.

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Fu EL, Trevisan M, Clase CM, et al. Association of acute increases in plasma creatinine after renin-angiotensin blockade with subsequent outcomes. Clin J Am Soc Nephrol. 14:1336–1345, 2019. doi:10.2215/CJN.03060319