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Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study

BMJ 2017; 356 doi: (Published 09 March 2017) Cite this as: BMJ 2017;356:j791
  1. Morten Schmidt, research fellow1 2 3,
  2. Kathryn E Mansfield, research fellow1,
  3. Krishnan Bhaskaran, senior lecturer1,
  4. Dorothea Nitsch, senior lecturer1,
  5. Henrik Toft Sørensen, professor2,
  6. Liam Smeeth, professor1,
  7. Laurie A Tomlinson, lecturer1
  1. 1Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  2. 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
  3. 3Department of Internal Medicine, Regional Hospital of Randers, Randers, Denmark
  1. Correspondence to: M Schmidt{at}
  • Accepted 27 January 2017


Objective To examine long term cardiorenal outcomes associated with increased concentrations of creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment.

Design Population based cohort study using electronic health records from the Clinical Practice Research Datalink and Hospital Episode Statistics.

Setting UK primary care, 1997-2014.

Participants Patients starting treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers (n=122 363).

Main outcome measures Poisson regression was used to compare rates of end stage renal disease, myocardial infarction, heart failure, and death among patients with creatinine increases of 30% or more after starting treatment against those without such increases, and for each 10% increase in creatinine. Analyses were adjusted for age, sex, calendar period, socioeconomic status, lifestyle factors, chronic kidney disease, diabetes, cardiovascular comorbidities, and use of other antihypertensive drugs and non-steroidal anti-inflammatory drugs.

Results Among the 2078 (1.7%) patients with creatinine increases of 30% or more, a higher proportion were female, were elderly, had cardiorenal comorbidity, and used non-steroidal anti-inflammatory drugs, loop diuretics, or potassium sparing diuretics. Creatinine increases of 30% or more were associated with an increased adjusted incidence rate ratio for all outcomes, compared with increases of less than 30%: 3.43 (95% confidence interval 2.40 to 4.91) for end stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure, and 1.84 (1.65 to 2.05) for death. The detailed categorisation of increases in creatinine concentrations (<10%, 10-19%, 20-29%, 30-39%, and ≥40%) showed a graduated relation for all outcomes (all P values for trends <0.001). Notably, creatinine increases of less than 30% were also associated with increased incidence rate ratios for all outcomes, including death (1.15 (1.09 to 1.22) for increases of 10-19% and 1.35 (1.23 to 1.49) for increases of 20-29%, using <10% as reference). Results were consistent across calendar periods, across subgroups of patients, and among continuing users.

Conclusions Increases in creatinine after the start of angiotensin converting enzyme inhibitor/angiotensin receptor blocker treatment were associated with adverse cardiorenal outcomes in a graduated relation, even below the guideline recommended threshold of a 30% increase for stopping treatment.


  • Contributors: LAT had the idea for the study and acquired data permissions. MS, KEM, and LAT designed the study. MS and KEM managed the data and established the cohort. MS, KEM, and LAT reviewed the literature. MS did the analyses. All authors participated in the discussion and interpretation of the results. MS organised the writing and wrote the initial drafts. All authors critically revised the manuscript for intellectual content and approved the final version. MS is the guarantor.

  • Funding: MS was supported by Aarhus University Hospital, the A.P. Møller Foundation for the Advancement of Medical Science, Snedkermester Sophus Jacobsen and Hustru Astrid Jacobsens Fond, and Christian og Ottilia Brorsons Rejselegat for yngre videnskabsmænd og –kvinder. HTS was supported by the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. KB holds a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 107731/Z/15/Z). LAT and KEM are funded by a Wellcome Trust intermediate clinical fellowship (101143/Z/13/Z). None of these funding sources had a role in the design, conduct, analysis, or reporting of the study.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: LAT and LS were supported by Wellcome Trust and MS by grants from A.P. Møller Foundation for the Advancement of Medical Science, Snedkermester Sophus Jacobsen and Hustru Astrid Jacobsens Fond, Christian og Ottilia Brorsons Rejseleg at for yngre videnskabsmænd og –kvinder; the Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to (and administered by) Aarhus University, but none of these studies has any relation to the present study; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study protocol was approved by the London School of Hygiene and Tropical Medicine Ethics Committee (No 6536) and the Independent Scientific Advisory Committee (ISAC) for Medicines and Healthcare Products Regulatory Agency (No 16_025) and made available to the journal reviewers.

  • Transparency declaration: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Data sharing: No additional data available.

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