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Contributors: A Bansal (UPenn) | P Dedhia (U of

Cincinnati) | A Elebiary (Lahey Clinic) | X Vela (U of El
Salvador) | D Thomson (ECU) | P Jawa (ECU) | S
Sridharan (Lister Hospital, UK) | F Iannuzsella (IRCCS,
Italy) | D Mitema (Johns Hopkins U) | Malvinder Parmar
(Northern Ontario, Canada) | Wisit Cheungpasitporn

I ssue 2

Volume 2

Year 2015


Editor: Tejas Desai | Chief: Cynthia Christiano | Free subscription by emailing



by Wisit Cheungpasitporn (@wisit661)

The long-term protective effects of renin?angiotensin system (RAS)

inhibitors, including angiotensin-converting enzyme inhibitors (ACEis) or
angiotensin II receptor blockers (ARBs), in patients with congestive heart
failure (CHF) and diabetic nephropathy are now well established. Animal
models also suggest renoprotective effects of RAS inhibitors in ischemic
acute kidney injury (AKI). But when patients develop AKI, clinicians
usually discontinue RAS inhibitors b/c it's been assumed that they may
worsen the severity of AKI; despite the fact that their effects on glomerular
filtration rate (GFR) reduction are modest. Consider postoperative AKI; a
very common encounter that is associated with hospital mortality. The use
of a RAS inhibitor preoperatively has been a concern b/c they, theoretically,
can blunt the compensatory activation of the RAS during surgery: resulting
in intraoperative hypotension or ?vasoplegia?--> postoperative AKI.
Unfortunately, there's been a lot of conflicting information about the effect
of RAS inhibitors on developing post-op AKI. So when a recent
meta-analysis suggested an increased postoperative AKI risk in patients
who received preoperative RAS inhibitors, clinicians continued to stop
RAS inhibitors before the day of surgery. It's just too bad that the
incidences of postoperative AKI and AKI-associated mortality have not
significantly reduced with this preventative measure.
Looking closely @ this meta-analysis reveals a statistical faux-pas: no
adjustment for the odds ratios of the included studies; Sounds boring, but
this statistical omission could introduce confounding. Specifically patients
who use RAS inhibitors usually have other co-morbidities (CHF, HTN, &
DM) which can result in a higher risk of postoperative AKI. Rather than
wait for a new meta-analysis to be done, I decided to help conduct a new
one! In our meta-analysis we included more recent studies & a
pre-specified sensitivity analysis based on propensity score-based studies to
evaluate the risk of postoperative AKI in patients who received preoperative
RAS inhibitors. In other words, we designed a meta-analysis that accounted
for these confounders. Twenty-four studies with 102,675 patients were
included. In most of these studies, patients received RAS inhibitors ?2
weeks before surgery and continued the medication until a day before or on
the day of surgery.

When all studies, both adjusted and non-adjusted for potential confounders
were included in the analysis, we found an insignificant association between
postoperative AKI and preoperative use of RAS inhibitors! In fact, in the
pre-specified analysis of RCTs and cohort studies with propensity score
analyses, we found a significant association between preoperative RAS
inhibitor use and a lower incidence of AKI (pooled RR of 0.92, 95% CI:
0.85?0.99, I2 = 78%).
That led us to wonder: are we causing more AKI by discontinuing RAS
inhibitors preoperatively? In major surgeries, the RAS system can be
over-activated from 1) hemodynamic changes & 2) interruptions to blood flow
(causing renal ischemia and a fall in GFR). Reducing the RAS response to
renal ischemia during surgery has been demonstrated to lower systemic
vascular resistance and improve renal plasma flow. In addition, the
preoperative discontinuation of RAS inhibitors is associated with hypertension,
higher emergency operations, and post-op intra-aortic balloon procedures.
By reducing bias in this meta-analysis, we found remarkably different results.
However, a causal relationship needs to be cautiously interpreted, and future
RCTs are required to confirm an association between the preoperative use of
RAS inhibitors and lower incidence of AKI. In the meanwhile, RAS inhibitors
should not be routinely discontinued preoperatively to reduce the risk of
developing AKI.

To learn more about preoperative RAS inhibition and the risk of developing
postoperative AKI, contact the author @wisit661 or or visit the following resources:

JACC 2007; 50:2148

CCM 2003; 31: 1421

Ann Int Med 2008;


Br J Anaest 2001; 86:169

AJKD 2013; 62:1077

AJKD 2015; 65:p82

NDT 2015; 22





Shown above is an abdomen-pelvis un-enhanced
CT scan of a 62 year-old women who presented
with the classic signs and symptoms of uremia.
She was started on emergent renal replacement
therapy after labs revealed a BUN > 100 mg/dl
and creatinine ~ 13 mg/dl. During her workup the
calcium-phosphate product was noted to be 80.
She complained of abdominal pain which was
evaluated through an abdominal XR.
Interestingly, the XR (& subsequent CT) did not
show vascular calcifications. Shown above is one
section of that CT showing ectopic calcifications:
the cause of her abdominal pain. Green arrows
represent normal bone.
Image courtesy of Dr. Francesco Iannuzzella (@caioqualunque )

2 These antibodies are not necessarily positive in vasculitic disorders, nor are they
necessarily negative in healthy patients
3 ANCAs cause tissue damage by activating monocytes and these cells

11 Acronym of the trial that compared azathioprine to

cyclophosphamide for maintenance therapy in granulomtosis with

4 The pathogenic molecule in anti-GBM disease


5 A large percentage of Churg-Strauss patients suffer with this

6 Acronym of the trial that compared oral versus intravenous cyclophosphamide as
induction therapy against granulomatosis with polyangiitis
7 Acronym of the scoring system used to assess the degree of remission or relapse
of a small vessel vasculitis
8 The former name for Granulomatosis with Polyangitis
10 Acronym of the trial that showed potential benefit of using plasma exchange in
patients with granulomatosis with polyangiitis who suffer from severe kidney
damage (Cr 5.7 mg/dl) or alveolar hemorrhage

1 PR3-ANCA is positive 75% of the time in this type of small
vessel vasculitis
9 A common method of classifying systemic vasculitides relies
upon this blood vessel characteristic