Facilitator Version
Module # 9 - Acute Kidney Injury
Objectives:
By the end of this module, you should be able to:
1. Define acute kidney injury (AKI)
2. Identify the main types of AKI.
3. Know the causes of AKI under each main category of AKI.
4. Identify and understand the typical laboratory tests used in working up AKI.
5. Understand the indications for initiating hemodialysis in kidney patients.
6. Identify the complications of hemodialysis.
References:
1) www.uptodate.com “Definition of acute kidney injury (acute renal failure)”
2) www.uptodate.com “Indications for initiation of dialysis in chronic kidney
disease”
3) MKSAP 16, Nephrology section.
4) www.uptodate.com “Etiology and diagnosis of prerenal disease and acute
tubular necrosis in acute kidney injury (acute renal failure)”
1) 4.Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure - definition,
outcome measures, animal models, fluid therapy and information technology
needs: the Second International Consensus Conference of the Acute Dialysis
Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204.
Case:
A 57-year old male with previous history of hypertension, DM type II,
hyperlipidemia, and osteoarthritis of the knees presents to the Emergency Room
with complaint of 2 dyas increasing fatigue, dizziness, and just not feeling good. His
current medications are amlodipine, aspirin (81mg), lisinopril, hydrochlorothiazide,
ibuprofen and atorvastatin. On physical examination, temperature is 37.2 ⁰C (99
⁰F), heart rate is 75 beats/min, blood pressure is 92/53 mmHg, respiratory rate is
12/min and oxygen saturation is 96% on room air. He seems to be in no distress as he
is lying in bed. He is positive for orthostasis on his orthostatic blood pressure and
pulse measurements. The rest of the exam is normal. On the laboratory exam today,
his creatinine is noted to be 3.4 with the creatinine of 1.1 notes 1 month ago in the
clinic.
What is the definition for AKI?
Although there are many different definitions of AKI, the one most accepted is the
RIFLE criteria.
RIFLE CRITERIA — The RIFLE criteria consists of three graded levels of injury (Risk,
Injury, and Failure) based upon either the magnitude of elevation in serum creatinine or
urine output, and two outcome measures (Loss and End-stage renal disease). The RIFLE
strata are as follows:
■Risk — 1.5-fold increase in the serum creatinine or GFR decrease by 25 percent or
urine output <0.5 mL/kg per hour for six hours
■Injury — Twofold increase in the serum creatinine or GFR decrease by 50 percent or
urine output <0.5 mL/kg per hour for 12 hours
■Failure — Threefold increase in the serum creatinine or GFR decrease by 75 percent or
urine output of <0.3 mL/kg per hour for 24 hours, or anuria for 12 hours
■Loss — Complete loss of kidney function (e.g., need for renal replacement therapy) for
more than four weeks
■ESRD — Complete loss of kidney function (e.g., need for renal replacement therapy)
for more than three months
By definition, does this patient have AKI?
Yes, this patient has AKI and falls in the “failure” category.
What are the risk factors for AKI?
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Advanced Age
Preexisting renal disease
Diabetes
Cardiac disease
Liver disease
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Use of nephrotoxic drugs
Surgery (especially associated with hypotension or hypoperfusion)
What are the risk factors for AKI in this patient?
His risk factors are his history of DM, hypotension associated with orthostasis, and use of
lisinorpil and ibuprofen (and possibly aspirin, although most do not consider 81mg
aspirin as being nephrotoxic).
What are the three main categories of AKI?
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Pre-renal (most common outpatient cause)
Post-renal
Intra-renal (or intrinsic) (most common inpatient cause when considering all
inpatient services including surgical services).
Of the above categories, which one(s) are the more likely cause for this patient’s
AKI given the information on the case so far?
The two most likely possibilities are pre-renal from volume depletion (given that patient
is on hydrochlorothiazide, is taking ibuprofen, and his blood pressure is on the low side)
or intra-renal given the patient’s low blood pressure with concomitant use of lisinopril
and ibuprofen (and possibly aspirin).
What are the three main categories of intra-renal (intrinsic) AKI?
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Acute tubular necrosis (ATN). Most common (75% of intrarenal causes of AKI).
Glomerular damage (such as acute glomerular nephritides). This accounts for
about 1% of all causes of AKI.
Acute interstitial nephritis (AIN). This accounts for about 10-15% of all causes of
AKI.
Notes:
• The two most common causes of AKI are pre-renal azotemia and ATN. These
two together account for 80% of cases.
• Pre-renal azotemia has great prognosis as compared to much poorer prognosis
with ATN.
If this patient’s AKI was caused by an intra-renal etiology, which of the three
categories of intra-renal causes would be more likely to be the cause of his AKI?
ATN due to hypotension and concomitant use of lisinopril and ibuprofen (and possibly
aspirin).
What is the definition of oliguria and anuria?
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Oliguria is defined as <400 mL/day of urine output.
Anuria is defined as <50 mL/day of urine output.
Note: Oliguric renal failure is associated with a mortality rate of 75% whereas nonoliguric renal failure is associated with a mortality rate of 25%.
What are the causes of prerenal AKI?
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volume depletion/blood loss
Renal artery stenosis or thrombosis or emboli or dissection
CHF
Cirrhosis
Nephrotic syndrome
Drugs (Diuretics, NSAIDS/Cox-2 inhibitors, ACEI/ARB, and in transplant
patients interleukin-2, cyclosporine and tacrolimus)
“Hepatorenal syndrome”
What are the usual laboratory findings associated with pre-renal AKI?
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% FENa = (UNa/PNa)(PCr/UCr)(100%) and is <1% in pre-renal AKI. Can be
>1% if patient is on a diuretic.
BUN/Cr ration is usually high (> 20).
Urine is very concentrated with urine osmolality often > 400 (a urine osmolality
>500 is highly suggestive of pre-renal disease).
Urine Na is usually < 20 (can be >20 if patient is on a diuretic)
Urine specific gravity > 1.020
Urine sediment is usually bland but can show granular or hyaline casts which are
both nonspecific.
Note: Fractional excretion of sodium is the best test in assessing AKI
• FENa percent = (UNa/PNa)(PCr/UCr)(100)
• If <1%, likely pre-renal or acute glomerulonephritis (much less likely)
• If >2%, likely not pre-renal
• If 1-2%, think more likely not pre-renal although this is a gray zone
• If patient has used diuretic in the last 24 hours, then use fractional excretion of
urea (FEUrea) in place of FENa and substitute Urea or Na in the equation above.
This is because diuretics will cause an elevation of FENa even in a setting of
prerenal azotemia. For FEUrea:
• If <35%, likely pre-renal or acute glumerulonepritis (much less likely)
• If >50%, likely on pre-renal
• If 35-50%, think more likely not pre-renal, although this is a gray zone
Notes:
• Pre-renal azotemia is often reversible within 24-48° and thus represents a low
level of acute kidney injury. Once sufficient or sustained injury occurs, many
patients progress to develop ATN.
• A low FENa or FEUrea can also be seen in acute glomerulonephritis, vasculitis
and obstruction. Glomerulonephritis and vasculitis affecting the kidneys are
associated with the following findings in the urine (which differentiates them
from pre-renal azotemia):
– RBC casts
– RBCs
– Dysmorphic RBCs
– Proteinuria (could be mild or heavy)
What are the causes of post-renal AKI?
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Anatomic urinary obstruction:
– Bladder outlet obstruction (most common)
– Bilateral ureteral outlet obstruction (much less likely)
Intra-tubular obstruction (also thought of as an intra-renal problem in some
textbooks).
Some notes about anatomic urinary obstruction:
• Is the cause of 5% of all cases of AKI.
• When diagnosed and corrected within 1 week of onset, prognosis and recovery is
excellent.
• If obstruction persists > 12 weeks, irreversible interstitial fibrosis and tubular
atrophy can occur.
• Presentation may alternate from anuria with complete obstruction to polyuria
alternating with oliguria in partial obstruction.
• Hyperkalemic renal tubular acidosis (RTA) is common.
• Recovery occurs over 1-2 weeks after resolution of obstruction.
• Tubular injury, and solute retention may result in post-obstructive diuresis.
• Post-obstructive diuresis may result in volume depletion and significant
electrolyte loss. Treatment consists of matching urinary losses with intake
(usually by intravenous fluids) and replenishing the electrolytes (may frequently
need intravenous replacement).
Some notes about intra-tubular obstruction:
• Certain drugs/compounds can precipitate in the tubules to form obstructing
crystals:
– Methotrexate
– Intravenous acyclovir
– Sulfa antibiotics
– Indinavir
– Hypercalcemia
– Ethylene glycol toxicity ~ Calcium oxalate crystals
– Urate crystal nephropathy – after cancer chemotherapy induction in
patients with highly proliferative tumors
– Myeloma Cast Nephropathy: Light chains in Multiple Myeloma
(remember the Tamm-Horsfall protein)
Note: In post-renal AKI, the BUN/Cr ratio is elevated and serum potassium may be
elevated due to associated Type 4 RTA.
How do you diagnose post-renal AKI?
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Ultrasound (the best method)
CT scan
Post-void bladder residual (for diagnosis of bladder outlet obstruction)
What are the two major categories as causes of ATN?
1) Renal hypotension or transient ischemia to the kidney such as:
– Surgery (most common)
– Trauma
– Burns
– Sepsis
– Cardiogenic
2) Toxic insult to the kidney. Examples include:
– Myoglobinuria (rhabdomyolysis)
– Hemoglobinuria (hemolysis)
– Heavy metals
– Contrast dye
– Drugs (aminoglycosides, amphotericin B, Cisplatin, foscarnet,
pentamidine, IVIG).
Note: As a general rule, toxic ATN is dose-dependent.
For the patient in our case study, if ATN was from AKI, which of the two
mechanisms mentioned above, seem to be more likely responsible for the AKI?
Renal hypotension causing ischemia to the kidney.
What are the laboratory findings in ATN?
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Urine is iso-osmolar (Osmolality <450 in almost all cases and usually <350)
Urine specific gravity is ≈ 1.010
Urine Na is >20 (often >40)
FENa >1%, usually >2%
Urine sediment : large muddy brown granular casts (nonspecific but very
sensitive although the absence of this does not completely rule out ATN).
Hint #1: In ATN the plasma creatinine concentration tends to rise progressively and
usually at a rate greater than 0.3-0.5 per day. In comparison, a slower rate of rise with
periodic downward fluctuations (due to variations in renal perfusion) is suggestive of prerenal disease.
Hint #2: Patients with pre-renal disease generally have a urine creatinine to plasma
creatinine ratio >40 whereas in ATN this ratio is usually <20.
Note: None of the criteria for diagnosis of pre-renal disease may be present in a patient
with underlying renal disease. In this setting, the ability to concentrate urine and
conserve sodium is often impaired and the urinalysis may be abnormal, reflecting the
primary disorder. As a result, a cautious trial of fluids may be given (independent of
urinary findings) if it is suspected that an acute rise in the plasma creatinine concentration
may be due to volume depletion.
Some notes about ATN:
• Even with dialysis, ½ of surgical patients and 1/3 of medical patients die.
• For those who improve, 90% do so within 3 weeks and 99% within 6 weeks.
• 25% of cases are non-oliguric.
The patient is admitted to the hospital and is started on intravenous fluids.
Laboratory workup shows: Normal CBC. Sodium is 142, potassium 5.3, BUN 65,
creatinine 3.4. The rest of metabolic panel as well as LFT’s are normal. As
mentioned before his creatinine 1 month ago in the clinic was 1.1. Urinalysis is
negative for protein, RBCs, and WBC’s. Urine specific gravity is 1.025. CXR is
negative. Given these values, what is the most likely cause of AKI?
Pre-renal due to volume depletion given the BUN/Creatinine of >20 and urine specific
gravity of 1.025. This has likely happened due to decreased fluid intake and concomitant
use of hydrochlorothiazide. Use of ACEI and NSAIDS can also contribute to worsening
of a pre-renal condition. The ibuprofen, lisinopril, aspirin, amlodipine, and
hydrochlorothiazide were held on admission. Note that aspirin does not need to be held if
the patient is on it for an important reason such as known history of CAD.
The patient is given intravenous fluids and over the next 3 days, his creatinine
improves and stays around 2.1 with BUN improving to 28. What would you do
next?
Since the patient’s AKI has improved but has not resolved with intravenous fluids, there
is likely another cause for AKI which we need to diagnose. The most likely possibility in
this case is AKI due to prolonged hypotension from volume depletion and use of antihypertensives. It is not unusual for pre-renal AKI leading to ATN if not treated on a
timely manner. The next best thing is to do a more thorough workup for the patient’s AKI
and therefore to do the following:
• FENa (no need for FEUrea as patient has been off diuretics for at least 24 hours at
this point). This is the best test in any patient with AKI.
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Renal ultrasound
Check post void bladder residual.
Careful measurements of ins and outs and daily weights.
Check urine sediments for any casts.
Recheck urinalysis.
The renal ultrasound is normal. The post void bladder residual is 15cc’s. The
urinalysis is normal except for mild protein picked up by dipstick. The urine
sediment shows muddy-brown casts. What is your diagnosis for patient’s AKI now?
Initial pre-renal AKI with now likely ATN. This is likely due to hypotension and
concomitant use of lisinopril and ibuprofen (and possibly aspirin).
On further questioning, the patient stated that 2 days prior to admission, he spent a
lot of time in the extreme heat outside doing yard work and did not drink enough
fluids except for 8 beers that day. He states that he does not drink alcohol on
chronic basis. You suspect rhabdomyolysis as a contributing factor to his AKI and
measure CPK level which is at 780. You suspect that this number was much higher
three days ago when patient presented to the Emergency Room. You also suspect
that rhabdomyolysis may have contributed to the patient’s AKI by further
contributing to an ATN picture.
What are the main measures and treatments for ATN?
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Treat the precipitating cause
Stop the offending drug or toxin.
Prevent further ischemic insult to the kidney
Equilibrate input and output to maintain normovolemia (when not sure if patient
is normovolemic or hypovolemic, give fluids, since further hypovolemia may
cause worsening of ATN and less chance of recovery).
Treat the hyperkalemia
Nutrition support (which decreases catabolism)
May need hemodialysis.
The patient is placed on strict input and output measurements as well as daily
weights and is kept euvolemic. All nephrotoxic medications were held on admission.
His amlodipine was restarted once his blood pressure improved to try to keep his
blood pressure in the 120-140 systolic range. The patient is now making about 1.2
liters of urine a day and his BUN and creatinine remain in the range of 28 and 2.1
respectively for the next four days. In respect to his prognosis in regards to
recovery from his AKI and outpatient treatment, what would you tell the patient
prior to discharge?
The patient has somewhat better prognosis as compared to some patient’s with ATN
since his ATN is non-oliguric (>400 cc/day urine output). Never the less, if his creatinine
does not improve within the next two week, he has only 10% chance of completely
recovering his kidney function and if his kidney function has not improved by next 5
weeks, he has only a 1% chance of recovering his kidney function.
The patient should be advised to measure his blood pressure regularly as outpatient in
order to keep his blood pressure in the 120-140 systolic range with the help of his
provider. He should be on low salt diet and drink adequate amount of fluid to avoid
volume depletion but also look for signs of fluid overload. He should be advised not to
take ibuprofen (or any other NSAIDS), hydrochlorothiazide, or lisinopril till further
discussing the issue with the nephrologist with whom he should follow as well as with his
PCP. At some point in the future, when his kidney function is not improving anymore
and a baseline is set, he may need to be considered for restarting an ACEI at low initial
dose for his hypertension given that he has DM type II, especially if he has
microalbuminuria.
What are the tree findings that when present should make one suspect AIN as
etiology of AKI?
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Fever
Eosinophilia
Rash (not common)
What are the typical findings in the urine and urine sediment in patients with AIN?
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Mild proteinuria (< 1gm/24hrs)
Eosinophils (Hansel’s stain; has only 40% sensitivity and 72% specificity)
RBCs
WBCs without bacteria (sterile pyuria)
WBC casts
What are some of the most common drugs that cause AIN?
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Antibiotics (especially beta-lactams, TMP/SMX, Rifampin, ciprofloxacin)
NSAIDS (differs from other forms of AIN in that time of onset is longer (3-6
months), unlikely to have rash, fever, or peripheral eosinophilia, and recovery
period much longer).
Cimetidine
Thiazides
Phenytoin
Allopurinol
PPI’s
There are many others not listed here.
Some other causes of AIN:
• Sarcoidosis
• SLE/immune medicated
• Infection (pyelonephritis)
• Transplant rejection
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Idiopathic
Some other notes about AIN:
• Fever, rash, and eosinophilia all together present in less than 10% of patients but
each alone occur in about 30% of patients.
• AIN may occur after 7-10 days of drug exposure; however, prior exposure to a
drug may result in a more sudden onset.
• Oliguria occurs in <20% cases.
• May see increased cortical echogenicity on ultrasound.
• Renal biopsy is the gold standard for dx.
• Usually reversible if detected early, and offending drug promptly discontinued
(i.e. within 1 week).
• Biphasic recovery with early rapid recovery (6-8 weeks) followed by a longer
more gradual recovery phase (1 year).
What are some general measures and treatment of all patients with AKI?
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Hold nephrotoxic drugs and NSAIDS.
Hold ACEI/ARB.
Avoid contrast studies in patients with borderline or poor renal function.
Recognize the problem as early as possible and stop the insult (drug, ischemia,
hypovolemia, infection).
Measure input and output (and daily weights if needed) and achieve euvolemia
whenever possible.
Manage electrolyte abnormalities.
Adjust the dose of all medications that are renally cleared.
In general what are some of the initial labs/tests that you would “think of ordering”
in patients with AKI?
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FENa or FEUrea
Urine and serum sodium as well as urine and serum creatinine for calculation of
FENa (urine urea and serum urea for in place of creatinine for calculation of
FEUrea)
Urine osmolality
Urinalysis
Chem 7 and CBC
Post-void bladder residual
Urine sediment (needs microscopic evaluation)
Renal/bladder US or CT
Urine eosinophils (Hansel’s stain)
Spot urine protein/creatinine and/or 24 hour urine protein
CPK
Measure Ins and outs and daily weights
When would you have considered this patient for acute dialysis?
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indications for acute dialysis in any renal patient include:
– Severe acidosis not responsive to other treatment
– Severe electrolyte abnormalities, particularly elevated potassium with
cardiac conduction effects
– Severe fluid overload unresponsive to diuresis
– Uremia with end-organ effects such as pericardial rubs
What are the indications for initiating dialysis in patients with CKD?
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Pericarditis or pleuritis (urgent indication)
Progressive uremic encephalopathy or neuropathy, with signs such as confusion,
asterixis, myoclonus, wrist or foot drop, or, in severe cases, seizures (urgent
indication)
A clinically significant bleeding diathesis attributable to uremia (urgent
indication)
Persistent metabolic disturbances that are refractory to medical therapy; these
include hyperkalemia, metabolic acidosis, hypercalcemia, hypocalcemia, and
hyperphosphatemia
Fluid overload refractory to diuretics
Hypertension poorly responsive to antihypertensive medications
Persistent nausea and vomiting
Evidence of malnutrition
The first five of the above indications are potentially acutely life-threatening and should
not be allowed to develop prior to initiation of dialysis in patients with known CKD
under medical care. The last two develop more insidiously and can also be due to other
comorbidities or drug effects. They are no less dangerous.
Relative indications for dialysis in CKD patients — Since an important goal of dialysis
is to enhance the quality of life as well as to prolong survival, it is therefore important to
consider less acute indications for dialysis such as anorexia and nausea, impaired
nutritional status, increased sleepiness, and decreased energy level, attentiveness, and
cognitive tasking. One needs to consider that the symptoms described here could also be
due to medications that the patient is taking.
Note:
• Dialysis has shown to improve albumin, prealbumin, nutritional status, and
appetite in patients with ESRD.
• Major abdominal surgery is a relative contraindication to peritoneal dialysis.
• There is no particular advantage to utilizing hemodialysis versus peritoneal
dialysis in eligible patients who require pre-transplant dialysis.
• Post-transplant outcomes appear to be worse with a longer duration of dialysis
before transplant occurs.
For patients on chronic peritoneal dialysis, infections are a relatively common
complication. What is one other concern specifically about the exchange fluid that
is used for this form of dialysis?
The exchange fluid is a fluid with a high concentration of dextrose that is instilled into
the peritoneum. Diffusion and convection aid in the movement of water, urea, and
electrolytes into the dialysate, which is then drained and discarded. This may worsen
control of diabetes from absorption of the dextrose in the peritoneal fluid.
What is the average time from withdrawal of dialysis to death in a ESRD patient
who has been established on dialysis?
Usually less than 2 weeks. The progression to death is painless, and patients typically
drift into a coma before death.
What is the leading cause of death in patients on dialysis?
Cardiovascular disease
MKSAP 16 Questions:
• Nephrology Question 4. Answer B.
• Nephrology Question 15. Answer A.
• Nephrology Question 63. Answer D.
• Nephrology Question 67. Answer D.
• Nephrology Question 77. Answer A.
• Nephrology Question 106. Answer C.
Post Module Evaluation
Please place completed evaluation in an interdepartmental mail envelope and address to
Dr. Wendy Gerstein, Department of Medicine, VAMC (111).
1) Topic of module:__________________________
2) On a scale of 1-5, how effective was this module for learning this topic? _________
(1= not effective at all, 5 = extremely effective)
3) Were there any obvious errors, confusing data, or omissions? Please list/comment
below:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
4) Was the attending involved in the teaching of this module? Yes/no (please circle).
5) Please provide any further comments/feedback about this module, or the inpatient
curriculum in general:
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
6) Please circle one:
Attending
Resident (R2/R3)
Intern
Medical student