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2013
http://informahealthcare.com/rnfISSN: 0886-022X (print), 1525-6049 (electronic)
Ren Fail, 2014; 36(1): 111–113! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2013.832858
CASE REPORT
Reversible anuric acute kidney injury secondary to acute renalautoregulatory dysfunction
Louis J. Imbriano, John K. Maesaka, James Drakakis, and Joseph Mattana
Department of Medicine, Winthrop-University Hospital, Mineola, NY, USA
Abstract
Autoregulation of glomerular capillary pressure via regulation of the resistances at the afferentand efferent arterioles plays a critical role in maintaining the glomerular filtration rate over awide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agentswhich contribute to autoregulation and drugs which interfere with these agents may have asubstantial impact on afferent and efferent arteriolar resistance. We describe a patient whosuffered an episode of anuric acute kidney injury following exposure to a nonsteroidal anti-inflammatory agent while on two diuretics, an angiotensin-converting enzyme inhibitor, and anangiotensin receptor blocker. The episode completely resolved and we review some of themechanisms by which these events may have taken place and suggest the term ‘‘acute renalautoregulatory dysfunction’’ to describe this syndrome.
Keywords
Acute kidney injury, autoregulation,glomerular hemodynamics
History
Received 3 June 2013Revised 1 August 2013Accepted 2 August 2013Published online 13 September 2013
Introduction
The approach to the patient with acute kidney injury (AKI)
involves a process with the aim of characterizing it as being
due to prerenal, intrinsic renal, or postrenal factors.
Autoregulation of glomerular capillary pressure (Pgc) acts
to attenuate the impact of decreased renal perfusion pressure
which would otherwise lead to a reduction in the glomerular
filtration rate (GFR). While a prerenal state can cause a
decrease in GFR, complete anuria would be extremely
unlikely to occur. Various medications, both over the counter
and prescription, can interfere with autoregulation and
potentially reduce Pgc and the GFR. The combination of a
diuretic, a nonsteroidal anti-inflammatory drug (NSAID), and
angiotensin-converting enzyme inhibitor (ACEI) or angioten-
sin receptor blocker (ARB) may be particularly disruptive to
autoregulation. Here we describe a patient who developed
anuric AKI on this drug combination with complete recovery
and review mechanisms for autoregulation and how this may
become disrupted.
Case
A 53-year-old woman with type 2 diabetes mellitus and
hypertension was admitted to the ambulatory surgery depart-
ment at 0700 h for elective total knee replacement at 1200 h.
She took her usual medications up to the day prior to surgery
and at 0400 h on the day of surgery, which included lisinopril
(20 mg daily), olmesartan (40 mg daily), hydrochlorothiazide
(25 mg daily), and furosemide (40 mg daily). Her serum
creatinine was 1.1 mg/dL two weeks prior and also on the
morning of surgery. On admission her blood pressure (BP)
was 132/76 mmHg, heart rate 84/min, the lungs were clear,
and there was no edema. At 1000 h, she was administered
200 mg celecoxib. Surgery was initiated at 1215 h with
intrathecal hydromorphone anesthesia and a urinary catheter
was inserted. Left total knee replacement proceeded unevent-
fully with estimated blood loss of 50 cc and a stable mean
arterial pressure of approximately 75 mmHg throughout
surgery. However, her urine output was noted to be510 cc/h,
and 1500 cc of isotonic saline was administered with no
increase in urine output. At 1500 h, she was brought to the
recovery room and was now noted to be anuric. Her creatinine
was again 1.1 mg/dL at this time. Renal ultrasound revealed
no hydronephrosis and normal renal arterial and venous blood
flow. Isotonic saline was continued at 150 cc/h and 80 mg of
furosemide was administered intravenously followed by an
infusion at 10 mg/h but her anuria persisted for 16 h
postoperatively, at which time the creatinine had increased
to 2.4 mg/dL. Her urine output then increased to 4100 cc/h
from the 16th to 28th h, and then to4250 cc/h after the 28th h,
while the creatinine improved to 1.5 mg/dL at 48 h post-
operatively, and then to baseline at 1.1 mg/dL at 60 h
postoperatively. Urinalysis was negative for protein, blood,
white blood cells or casts though markers of tubular injury
such as neutrophil gelatinase-associated lipocalin (NGAL) or
kidney injury molecule-1 (KIM-1) were not measured. Forty-
eight hours postoperatively her urine osmolality was
629 mOsm/L with a fractional excretion of sodium of
Address correspondence to Joseph Mattana, Division of Nephrology andHypertension, Winthrop University Hospital, 200 Old Country Road,Suite 135, Mineola, NY 11501, USA. Tel: 516 663 2169; Fax: 516 6632179; E-mail: [email protected]
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0.15%, implying intact tubulointerstitial function and making
acute tubular necrosis (ATN) and interstitial nephritis
unlikely. Sixty-eight hours postoperatively her creatinine
was 0.9 mg/dL. These events are summarized in Table 1.
Discussion
AKI may result from prerenal conditions, renal parenchymal
disease, or obstruction. Severe, prolonged prerenal states and
parenchymal disorders may lead to ATN. These two disorders
account for475% of all AKI in hospitalized patients.1 In our
patient, despite almost 24 hours of anuria, she completely
recovered normal renal function and did not manifest any
signs of renal parenchymal damage. There was also no
evidence of any systemic hemodynamic disturbance sufficient
to cause such an event. Given the combination of medications
she was on, we hypothesize that exposure to the NSAID
celecoxib on a background of two diuretics and both an ACEI
and ARB resulted in combined afferent arteriolar constriction
and efferent arteriolar dilatation causing a profound decrease
in Pgc to cause a reversible episode of anuria.
In the absence of such drugs, prerenal conditions and
profound hypoxia are countered by compensatory renal
autoregulatory mechanisms to preserve renal blood flow
(RBF) and maintain pO2. These protective mechanisms
include prostaglandins, nitric oxide, adenosine, and tubulo-
glomerular feedback, and the fall in GFR which results in the
setting of ATN has been termed ‘‘acute renal success’’ given
that the decrease in GFR prevents uncontrolled volume losses
that would otherwise occur with a sudden impairment of
tubular reabsorption of solute and water.2 A normal GFR is
the product of several Starling forces present in the glomeru-
lar microcirculation, namely, hydrostatic and oncotic pres-
sures within the glomerular capillary and within Bowman’s
space. The GFR is kept constant over a broad range of BPs by
the effects of angiotensin II on the afferent and efferent
arteriole, the effects of prostaglandin E2, nitric oxide, and
adenosine on the afferent arteriole, and other mechanisms. A
reduction in blood flow and oxygen to the afferent arteriole is
compensated by constriction of the efferent arteriole and
dilatation of the afferent arteriole which helps to maintain Pgc
and GFR. ACEIs and ARBs impair efferent arteriolar
constriction, lowering Pgc and GFR. NSAIDs block afferent
arteriole dilatation, preventing inflow to the glomerulus.
Fortunately, most individuals with normal cardiac output and
renal microcirculation do not require prostaglandin-mediated
afferent vasodilatation in the basal state and will maintain a
normal GFR while taking NSAIDs. In contrast, the GFR of a
patient with low effective arterial volume is dependent upon
angiotensin II-mediated efferent arteriolar constriction and
prostaglandin-mediated afferent arteriolar dilatation, hence
sensitizing them to drugs that disturb these mechanisms. It
should be emphasized, however, that these relationships are
complex and there are other factors which could also interfere
with autoregulation. For example, while nitric oxide plays a
physiological role in the regulation of vascular tone, excessive
nitric oxide production can interfere with autoregulation and
could be a contributing factor in scenarios such as that
described here.3
Hypotension is a relative term when describing AKI in a
susceptible individual, as described by Abuelo.4 He described
AKI occurring in the absence of frank hypotension, in
susceptible individuals with preexisting renal microvascular
disease, or in patients with an altered microcirculation due to
NSAIDs, cyclosporine, tacrolimus, radiocontrast agents,
ACEIs, ARBs, hypercalcemia, hepatorenal syndrome, or
renal artery stenosis. Abuelo called this ‘‘normotensive
ischemic acute renal failure’’, as renal perfusion pressure
drops below the autoregulatory range. Normal renal auto-
regulation is sustained down to a mean arterial pressure
(MAP) of 80 mmHg. However, in patients with impaired
autoregulation, the GFR falls even while the MAP remains in
the normal range. In contrast to prerenal azotemia, where the
reduction in renal function results from the consequences of
low effective arterial volume, the present case is an example
of a scenario in which the problem appears to be a
hemodynamic one at the level of the glomerulus itself, with
a reduction in Pgc sufficient to cause anuria with apparently
preserved effective arterial volume.
Our patient was hemodynamically stable throughout her
uneventful surgery but had several variables present which
increased her susceptibility to a decrease in Pgc including
diabetic microvascular disease, hypertensive vascular disease,
and the concomitant use of an ACEI, ARB, diuretics, and the
NSAID that she was given shortly before the procedure. The
concurrent use of diuretics, NSAIDs, and ACEIs or ARBs has
been referred to as ‘‘the nephrotoxic triple whammy’’.5,6 Lapi
et al. reported a 30% increased incidence of AKI when
patients were treated with this combination, especially at the
start of treatment.7 Our patient likely had a severe enough
perturbation of the renal microcirculation to result in anuria,
with blood flow, and pO2 sufficient to prevent necrosis, but
not enough to maintain the GFR8 — a syndrome which
perhaps could be described as ‘‘acute renal autoregulatory
dysfunction’’ (‘‘ARAD’’). Despite the apparent decrease in
her Pgc, flow through the efferent arteriole and the vasa recta
presumably remained sufficient to maintain tubular integrity
and avoid ATN, attested to by the increased urine osmolality
and volume, and to the rapid recovery of renal function after
the withdrawal of the offending medications and increasing
her intravascular volume.
There are a number of limitations which must be kept
in mind in attempting to draw conclusions from this case.
Table 1. Summary of events, urine output and serum creatinine levels.
Time EventsSerum
creatinineUrineoutput
�0600 Lisinopril 20 mgOlmesartan 40 mgHydrochlorothiazide 25 mgFurosemide 40 mg
�0200 Celecoxib0 Surgery 510 mL/h0300 Saline 1.1 mg/dL 0 mL/h
Furosemide1600 2.1 mg/dL2000 2.4 mg/dL 4100 mL/h2800 4250 mL/h4800 1.5 mg/dL6000 1.1 mg/dL6800 0.9 mg/dL
112 L.J. Imbriano et al. Ren Fail, 2014; 36(1): 111–113
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First, despite the patient starting out with a normal serum
creatinine this does not exclude the possibility that her renal
function had declined sooner than was detected with serum
creatinine levels. Cystatin C or urinary markers of tubular
injury might have been able to assess this. It should also be
noted that a surgical procedure, even if overtly uneventful,
may induce numerous changes in levels of various cytokines
and inflammatory mediators that can also impact upon renal
function aside from the effect of medications. Hence, it needs
to be emphasized that this episode of AKI with these three
classes of drugs took place in the context of surgery and might
not occur in this manner in another clinical scenario.
In conclusion, the patient we have discussed is an example
of a scenario that could best be described as a profound,
pharmacologically induced marked decrease in Pgc due to
disrupted autoregulation sufficient to cause sustained but
completely reversible anuria in the setting of surgery. We
suggest using the term ‘‘ARAD’’ to describe rapidly revers-
ible AKI which appears to be due to factors which derange
autoregulation of Pgc at the level of the glomerulus and
without systemic hemodynamic abnormalities altering renal
perfusion. Greater awareness of this syndrome and the role of
medications in inducing it will hopefully reduce the incidence
of this event, perhaps by lowering the dose or temporarily
withholding such agents during procedures or intercurrent
illnesses.
Declaration of interest
The authors report no conflicts of interest. The
authors alone are responsible for the content and writing of
the paper.
References
1. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl JMed. 1996;334:1448–1460.
2. Thurau K, Boylan JW. Acute renal success: the unexpected logic ofoliguria in acute renal failure. Am J Med. 1976;61:308–315.
3. Guan Z, Gobe G, Willgoss D, Endre ZH. Renal endothelialdysfunction and impaired autoregulation after ischemia-reperfusioninjury result from excess nitric oxide. Am J Physiol Renal Physiol.2006;291:F619–628.
4. Abuelo JG. Normotensive ischemic acute renal failure. N Engl JMed. 2007;357(8):797–805.
5. Thomas MC. Diuretics, ACE-inhibitors and NSAIDs – the triplewhammy. Med J Aust. 2000;172(4):184–185.
6. Onuigbo MA. The nephrotoxic ‘‘triple whammy’’ of combiningdiuretics, ACE-inhibitors and non-steroidal anti-inflammatorydrugs. BMJ. 2013;346:f678.
7. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use ofdiuretics, angiotensin converting enzyme inhibitors and angiotensinreceptor blockers with non-steroidal anti-inflammatory drugs andrisk of acute kidney injury: nested case control study. BMJ. 2013;346:e8525.
8. Rosen S, Stillman IE. Acute tubular necrosis is a syndrome ofphysiologic and pathologic dissociation. J Am Soc Nephrol. 2008;19:871–875.
DOI: 10.3109/0886022X.2013.832858 Acute renal autoregulatory dysfunction 113
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