Intended for healthcare professionals


Renal function after new treatment with renin-angiotensin system blockers

BMJ 2017; 356 doi: (Published 09 March 2017) Cite this as: BMJ 2017;356:j1122
  1. Marie Valente, senior clinical trial coordinator1,
  2. Sunil Bhandari, consultant nephrologist/honorary clinical professor2
  1. 1Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
  2. 2Department of Renal Medicine, Hull and East Yorkshire Hospital NHS Trust and Hull York Medical School, Kingston upon Hull HU32JZ, UK
  1. Correspondence to: S Bhandari Sunil.bhandari{at}

Even small increases in creatinine concentration could signal a higher risk of poor outcomes

Use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) to block action of the renin-angiotensin-aldosterone system is a mainstay of treatment for hypertension, heart failure, and diabetic and proteinuric nephropathy, as well as post-myocardial infarction therapy.123 However, in some patients, renal function declines sharply when they start treatment with these agents. Current guidelines recommend monitoring renal function before and after starting ACEI or ARB and suspending treatment if creatinine concentration increases by more than 30%.

Schmidt and colleagues (doi:10.1136/bmj.j791) used two powerful UK databases—the Clinical Practice Research Datalink and Hospital Episode Statistics—to carry out a population based cohort study.4 They suggest that a 10-30% rise in serum creatinine after the start of treatment can predict increased risk of adverse renal and cardiac outcomes or death, even after correction for baseline renal function. As renin-angiotensin system blockers are among the most prescribed drugs in the UK, balancing the risks and benefits of their use has become part of everyday clinical decision making. What does this study tell us that can help to optimise use of these important drugs?

The headline result is somewhat unexpected and challenges the published dogma that a rise in creatinine signals that the new treatment is having the desired intrarenal effect. Strong evidence from trials, epidemiological studies, and meta-analyses supports the use of ACEI and ARB in a wide variety of clinical conditions,5 although recent cardiovascular guidelines recommend caution in patients with both heart failure and stage 4 or 5 kidney disease.2 Little good evidence supports decisions about discontinuation, except perhaps in patients with resistant hyperkalaemia. Patients with chronic kidney disease are less likely than others to be treated with these drugs,6 and a trial in advanced chronic kidney disease in ongoing.7 As the authors point out, the basis of current guidelines to stop treatment above a creatinine increase cut-off of 30% may be questionable.

Schmidt and colleagues’ study shares the strengths and limitations of any population based cohort study; confirming a causal relation between drug associated changes in creatinine concentration and later outcomes is not possible, and we are reliant on the quality and completeness of the data available. Their cohort was necessarily limited to patients with follow-up creatinine values (40% of identified cohort), which potentially selected a group thought to be at higher risk. Surrogate markers (coding for transplant, dialysis, or arteriovenous fistula) were used to identify end stage renal disease, presumably owing to poor direct coding. There was no untreated comparator group, and the observed number of events was low, amounting to less than 10 per 100 patient years. Also, some notable baseline differences existed between patients with increases in creatinine concentration above and below 30%. However, the authors corrected for confounding factors as far as possible, and the “dose response” they identified is striking.

The size of the new study allowed exploration of outcomes that trials are rarely powered to investigate, and the generalisability of this real world analysis is a key strength for clinicians with a patient in front of them. The study must be taken as “big data real life analysis,” not a randomised controlled trial, but the findings certainly give pause for thought.

Given the increased risk of worse outcomes associated with even small increases in creatinine concentration, should we consider changing practice? The same group of authors recently reported that monitoring of creatinine and potassium concentrations on starting treatment with ACEI or ARB was done to guideline standards in just 10% of patients. They further reported that treatment continued in 80% of patients whose creatinine concentrations increased by more than 30%.8 So rather than changing guidelines, we should be encouraging much better adherence to existing guidelines. The reasons for poor adherence have not yet been explored; the problem may be lack of awareness or that changes within the creatinine reference range are not acted on, despite the detrimental effect on renal function.

Patients with increases in creatinine concentration after starting treatment with renin-angiotensin system blockers should be treated as a high risk group. They form an important proportion of the studied cohort—16.3% had an increase of 10% or more. Practice and guidelines are increasingly moving towards individualised care. “One size does not fit all in real life clinical management,” and this study gives a useful summary of risks that will allow a more informed and evidence based discussion with patients.5

As the authors suggest, perhaps a raised creatinine should be used as a marker to identify patients who need closer monitoring, further cardiovascular risk assessment and lifestyle advice, and potentially more aggressive treatment of underlying disorders. First and foremost, however, the message from this study is that clinicians need to get their house in order and appropriately monitor patients exposed to renin-angiotensin system blockers, especially in the first three months of treatment.


  • Research, doi: 10.1136/bmj.j791
  • Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.

  • Provenance and peer review: Commissioned; not externally peer reviewed.


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