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2013 http://informahealthcare.com/rnf ISSN: 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 renal autoregulatory 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 afferent and efferent arterioles plays a critical role in maintaining the glomerular filtration rate over a wide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agents which contribute to autoregulation and drugs which interfere with these agents may have a substantial impact on afferent and efferent arteriolar resistance. We describe a patient who suffered 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 an angiotensin receptor blocker. The episode completely resolved and we review some of the mechanisms by which these events may have taken place and suggest the term ‘‘acute renal autoregulatory dysfunction’’ to describe this syndrome. Keywords Acute kidney injury, autoregulation, glomerular hemodynamics History Received 3 June 2013 Revised 1 August 2013 Accepted 2 August 2013 Published 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 be 5 10 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 4 100 cc/h from the 16th to 28th h, and then to 4 250 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 and Hypertension, Winthrop University Hospital, 200 Old Country Road, Suite 135, Mineola, NY 11501, USA. Tel: 516 663 2169; Fax: 516 663 2179; E-mail: [email protected] Ren Fail Downloaded from informahealthcare.com by Dalhousie University on 06/02/14 For personal use only.

Reversible anuric acute kidney injury secondary to acute renal autoregulatory dysfunction

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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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