ACUTE KIDNEY INJURY

AND DRUG INDUCED KIDNEY

DISEASE
WENNY PUTRI NILAMSARI
 DEFINITION

• Acute kidney injury (AKI) is “a clinical syndrome generally defined by an abrupt

reduction in kidney function as evidenced by changes in serum creatinine (Scr),
blood urea nitrogen (BUN), and urine output.”Increase in SCr by ≥ 0.3
mg/dl (≥ 26.5 µmol/l) within 48 hours; or increase in SCr to ≥ 1.5 times
baseline, which is known or presumed to have occurred within the prior 7
days; or urine volume < 0,5 ml/kg/ hour within 6 hours”

KDIGO, 2012
• The consequences of AKI can be serious, especially in hospitalized patients.

• Early recognition and supportive therapy is the focus of management for those with
established AKI, as there is no pharmacologic therapy that directly reverses the injury.
CLASSIFICATION OF AKI FOR ADULT
• All criteria are based on detecting an increase in Scr from its baseline

• If the baseline measure of Scr is not available and the patient has no history of kidney
disease, baseline Scr may be estimated using a contemporary eGFR
equation with an assumed normal eGFR of 75 mL/min/1.73 m2.
CONSEQUENCE OF AKI
AKI RISK PREDICTION SCORE

5 points or higher suggests an

individual patient is at high-
risk for developing AKI
 ETIOLOGY

(a)PRERENAL  Results from decreased renal perfusion in the setting of

undamaged parenchymal tissue,
(b) INTRINSICThe result of structural damage to the kidney, most
commonly the tubule from an ischemic or toxic insult
(c) POSTRENAL Caused by obstruction of urine flow downstream
from the kidney
ETIOLOGY
 CLINICAL MANIFESTATION
Highly variable and largely dependent on the underlying etiology.
• Nausea, vomit, fatique, malaise
• A change in urinary character (eg, decreased urine output or urine discoloration),
• Edema
• Electrolyte disturbances
• Sudden weight gain
• Severe abdominal or flank pain  suggestive of a urinary stone
• Rash
 PREVENTION OF ACUTE KIDNEY INJURY
(PATIENT AT RISK FOR AKI)
• Prevention of AKI is critical since there is no treatment to reverse the insult once it has
developed.
• The goals of AKI prevention are to
(a) Screen and identify patients at risk,
(b) Monitor high-risk patients until the risk has subsided,
(c) Implement prevention strategies when appropriate.
GENERAL APPROACH FOR PATIENT
AT RISK FOR AKI (KDIQO, 2012)
 GENERAL APPROACH TO PREVENTION

• Depends on the patient’s risk factors for AKI ex comorbidities, planned procedures, and
medications, to name a few.
• Sometimes, the risk of kidney injury is predictable ex in the setting of decreased perfusion
secondary to compromised cardiac function (eg, postcoronary bypass surgery) or secondary
to the administration of a nephrotoxic agent like radiocontrast dye

• In these situations, the potential insult to the kidneys cannot be avoided but may be
preventable or minimized with intravenous fluids and/or avoidance or removal of any
additional insults
 INTRAVENOUS FLUID

• Intravenous fluids have largely been studied in association with hemodynamic instability secondary
to intravascular volume depletion as well as contrast administration before a radiologic
procedure.
• The 2012 KDIGO guidelines recommend isotonic crystalloids over colloids for intravascular volume
expansion in patients at risk for AKI.

Balanced solutions (ex, ringer lactat) or isotonic saline

• Saline hyperchloremic acidosis, interstitial edema, fluid overload, and death chloride content in
isotonic saline is 1.5 times that of plasma  can lead to hyperchloremic metabolic acidosis decrease
renal artery blood flow and renal tissue perfusion.
• Albumin

• May offer additional advantages to septic patients  maintaining plasma colloid osmotic
pressure, has antioxidant and anti-inflammatory propertiesbut several studies have
found that major patient outcomes such as risk of AKI, need for RRT, and mortality are
comparable between albumin replacement therapy and isotonic saline.
• Synthetic products ex hyperoncotic hydroxyethyl starch (HES associated with impaired
kidney function  should generally be avoided.
 N-ACETYLCYSTEINE (NAC)

• N-acetylcysteine (NAC) antioxidant that has been widely studied in the prevention of
contrast induced-AKI.
• The 2012 KIDGO guidelines  suggest using NAC in combination with IV isotonic saline
in patients at risk for CI-AKI
• The latest metaanalysis showed that NAC beneficial for contrast induced AKI but the
metaanalysis based on heterogen studies need to be clarified further
 STATIN

• Statins exhibit anti-inflammatory, antioxidant, and endothelium protective effects, which have
led to research on their utility in preventing AKI.
• Statin may reduce the risk of AKI in high-risk patients exposed to contrast agents but likely
have no benefit or lead to higher incidence of AKI in surgery patients

• Randomized controlled trials are needed to clarify the role of statins in the prevention of AKI
 GLYCEMIC CONTROL

• In critical illness, both hyper- and hypoglycemia are associated with adverse patient
outcomes
• Guidelines from the American Diabetes Association recommend a glycemic target range
of 140 to 180 mg/dL and Surviving Sepsis Campaign less than 180 mg/dL in critically ill
patients.
 TREATMENT FOR ESTABLISHED AKI

• Since there is no specific treatment that can reverse AKI or hasten its recovery
supportive measures that focus on hemodynamics, fluid balance, acid- base balance, and
electrolyte homeostasis are the mainstays of therapy.
• Short-term goals of AKI management
a. Minimizing the degree of insult to the kidney,
b. Reducing extrarenal complications,
c. Expediting the patient’s recovery of kidney function.
 GENERAL APPROACH FOR PATIENT
WITH ESTABLISHED AKI (KDIQO,2012)
 GENERAL APPROACH

• Prerenal AKI  managed with hemodynamic support and volume replacement,

• Postrenal AKI  removing the cause of the obstruction
• The most effective method for managing AKI  treatment of the comorbid precipitating
event.
• Renal Replacement Therapy more severe AKI to maintain fluid, electrolyte, and acid-
base balance while removing accumulating waste products or toxins.
• Patient’s comorbidities and baseline kidney function need to be reviewed.
 INTRAVENOUS FLUIDS

• The principal of fluid therapy is to maintain or restore effective intravascular volume to

assure adequate renal perfusion.
• Need to be used judiciously as both volume depletion and fluid overload  adversely
affect kidney function and increase mortality maintaining adequate fluid balance is a
major challenge in AKI
• In addition, the patient should be monitored for fluid intake and urine output, pulmonary
and peripheral edema, blood pressure (target mean arterial pressure ≥65 mm Hg), and
and serum electrolytes.
• Urine output ≥0.5 mL/kg/hr is generally targeted during the initial fluid resuscitation
phase.
 ELECTROLYTE IMBALANCES

HYPERKALEMIA
• The most common electrolyte disorder encountered in AKI patients is hyperkalemia, as >90% of
potassium is renally eliminated.
• Life-threatening cardiac arrhythmias may occur if potassium > 6 mEq/L (mmol/L)frequent monitoring
of potassium
• Insulin, Agonis B2, Ca Gluconas
HYPERNATREMIA AND FLUID RETENTION
• Total daily sodium intake should be monitored as unintended sodium intake from intravenous drugs (ie,
antibiotics) or foods can contribute to diuretic therapy failure.
• Tx Diuretic Loop
HYPERPHOSPHATEMIA AND HYPERMAGNESEMIA
• Both are eliminated by the kidneys and, unlike potassium, are not efficiently removed by
dialysis.
• The dietary intake of phosphorus needs to be restricted in advanced stages of AKI.
 DIURETIC

• Acute kidney injury  fluid overload  Diuretic loop only used to treat volume overload
Loop diuretic
• Increased urine output.
• Decreased risk of ischemic injury by inhibiting the Na-K-Cl cotransporter and thus decreasing
oxygen demand.
• Enhanced renal blood flow due to increased availability of renal prostaglandins.
• Enhancing urine output from oliguric to non-oliguric may be beneficial in itself, as non-oliguric
AKI is associated with better outcomes than oliguric AKI
 NUTRITIONAL CONSIDERATION

• The KDIGO guidelines  caloric intake goal of 20 to 30 kcal/kg/day (84-126 kJ/kg/day)

irrespective of the stage of kidney impairment
• Protein 0.8 to 1 g/kg/day (non dialysis) and 1 to 1.5 g/kg/day if patient is receiving RRT.
RENAL REPLACEMENT THERAPY

utilized to treat fluid overload,

electrolyte disturbances (eg,
hyperkalemia), acid-base
imbalances, uremic complications,
and pulmonary edema resulting
from severe AKI
DRUGS INDUCED KIDNEY DISEASE
 PRINCIPLES FOR PREVENTION OF DRUG-
INDUCED NEPHROPATHY
• The primary principle for prevention of DIKD is to avoid the use of nephrotoxic
agents for patients at increased risk for toxicity.

• Therefore, an awareness of potentially nephrotoxic drugs and knowledge of risk factors

that increase renal vulnerability are essential.
DRUG INDUCED KIDNEY DISEASE
DRUG INDUCED KIDNEY DISEASE
 ACUTE TUBULAR INJURY/NECROSIS

• The most common presentation of

DIKD in the inpatient setting.
• Aminoglycosides, Radiocontrast media,
Cisplatin, Amphotericin B, foscarnet, and
osmotically active agents such as
immunoglobulins, dextrans, hydroxyethyl
starch, and mannitol
 AMINOGLYCOSIDE NEPHROTOXICITY

• Occur in between 10% and 25% of patients receiving a therapeutic course.

• Critically ill patients  higher risk for nephrotoxicity with reported rates as high as 58%.
• Typically seen within 5 to 7 days after initiation of therapy
• Manifests as a gradual progressive rise in Scr and BUN and decrease in creatinine clearance, usually present
with non-oliguria, and sometimes have microscopic hematuria and proteinuria.
• Full recovery of kidney function is common if aminoglycoside therapy is discontinued immediately upon
discovering signs of toxicity.
• Severe AKI may develop occasionally, and for these individuals renal replacement therapy may be required
• The diagnosis of aminoglycoside-associated nephrotoxicity is often difficult in critically ill patients with
multiple comorbidities and is confounded by other factors that are independently associated with the
development of AKI
RISK FARCTORS TO AMINOGLYCOSIDE NEPHROTOXICITY
 PREVENTION

• Use alternative antibiotics

• Avoid volume depletion,
• Limit the total aminoglycoside dose administered
• Avoid concomitant therapy with other nephrotoxic drugs.
• Concurrent use of antioxidant compounds such as alpha-lipoic acid, vitamin E, and N-
acetylcysteine
 MANAGEMENT

• if AKI is evident aminoglycoside should be discontinued or the dosage regimen revised

• Discontinue other nephrotoxic drugs if possible
• Keep patient adequately hydrated and hemodynamically stable.
• If needed  Short-term renal replacement therapy
 RADIOGRAPHIC CONTRAST MEDIA
NEPHROTOXICITY

• Usually transient, and non oligouria

• Occur within the first 24 to 48 hours after the administration of contrast.
• Peak serum creatinine usually between 3 and 4 days after exposurerecovery after 7 to
10 days.
• Irreversible oliguric AKI requiring dialysis has been reported in high-risk patients
 RISK FACTORS RADIOGRAPHIC CONTRAST
MEDIA NEPHROTOXICITY
• Pre-existing kidney disease, particularly GFR less than 60 mL/min/1.73 m2,
• Conditions associated with decreased renal blood flow  (CHF, dehydration, and hypotension), and
patients with atherosclerosis and reduced effective circulating arterial blood volume
• Diabetes
• Multiple myeloma
• Larger volumes or doses of contrast
• Intra-arterial administration of contrast
• Concurrent use of nephrotoxins and drugs that alter renal hemodynamics
PREVENTION OF CONTRAST NEPHROTOXICITY
 MANAGEMENT OF ESTABLISHED CONTRAST
INDUCED NEPHROPATY

• No specific therapy available for managing established CIN.

• Discontinued other nephrotoxic drugs.
• Supportive Care
 CISPLATIN NEPHROTOXICITY

• Occurs in up to 1/3 of patients receiving the drug and is a significant cause of morbidity

• Present with impaired tubular reabsorption increased excretion of salt and water (ie, polyuria) within 24
hours of treatment.
• Hypomagnesemia  impaired magnesium reabsorption
• Within 72 to 96 hours after cisplatin  a decrease in GFR evidenced by a rise in Scr concentration
• Scr peaks approximately 10 to 14 days after initiation of therapy recovery by 21 days

• Around 25% of patients may have reversible elevations in Scr and BUN for 2 weeks after cisplatin
treatment but with subsequent cycles of therapy the Scr concentration may continue to rise, and
irreversible kidney injury may result
 RISK FACTORS OF CISPLATIN NEPROTOXICITY

• Age more than 65 years,

• Dehydration,
• Pre-existing kidney disease,
• Renal irradiation,
• Concurrent use of nephrotoxic drugs,
• Large cumulative doses, and alcohol abuse.
 PREVENTION OF CISPLATIN
NEPROTOXICITY
• Prospective dose reduction and decreased frequency of administration,
• Preventing concurrent use of other nephrotoxic drugs
• Prior to initiating treatment Ensuring patients are euvolemic or hypervolemic
• Vigorous hydration with isotonic saline  should be initiated 12 to 24 hours
prior to and continued for 2 to 3 days after cisplatin administration (100 to
250 mL/hr, as tolerated) to achieve a urine flow of 3 to 4 L/day
 HEMODYNAMICALLY MEDIATED KIDNEY INJURY

• Any cause of AKI cause by “ an acute decrease in intraglomerular pressure,

(including hypovolemia and congestive heart failure) and medications that
affect the renin–angiotensin system (RAS)
ANGIOTENSIN CONVERTING ENZIM INHIBITOR &
ANGIOTENSIN RESEPTOR BLOCKER

• Up to 25% of hospitalized patients with congestive heart failure develop AKI within
weeks after beginning treatment with ACEIs.
• Normal respon  An increase in Scr of up to 30% within 3 to 5 days of initiating therapy
 typically stabilizes within 1 to 2 weeks
• If the increase of Scr ≥ 30% in the course of 1 to 2 weeks  necessitate discontinuation
of drug
ANGIOTENSIN CONVERTING ENZIM INHIBITOR &
ANGIOTENSIN RESEPTOR BLOCKER

ACEI/ARB inhibit
vasoconstriction of
efferent arteriole
more blood back to
circulation GFR
decrease
 RISK FACTORS FOR ACEI/ARB NEPROTOXICITY

• Bilateral renal artery stenosis or stenosis in a single kidney

• Decreased effective arterial blood volume (ie, prerenal states),
• Decompensated congestive heart failure,
• Volume depletion from excess diuresis or GI fluid loss,
• Hepatic cirrhosis with ascites,
• Nephrotic syndrome;
• Pre-existing kidney disease
• Concurrent nephrotoxic drugs, particularly that affect intraglomerular autoregulation such as
NSAIDs
 PREVENTION

• Recognizing risk factors

• For at-risk patients  initiate therapy with very low doses of a short-acting ACEI gradually
titrate the dose upward and convert to a longer-acting agent after patient tolerance has been
demonstrated.
• Outpatients may be started on low doses of long-acting ACEIs  increase gradually every 2
to 4 weeks until the maximum dose or desired response is achieved
• Monitor kidney function indices and serum potassium  daily for hospitalized patients and
every 2 to 3 days for outpatients more frequent for patients with pre-existing kidney
disease, congestive heart failure, or suspected renovascular disease.
• Don’t use of concurrent hypotensive agents and other drugs that affect renal hemodynamics
 MANAGEMENT

• If Scr increase ≥ 30%, discontinue Re initiate after correcting risk factors fo AKI
• Supportive care
NON-STEROID ANTIINFLAMMATORY DRUGS
AND COX 2 INHIBITORS
• Approximately 500,000 to 2.5 million people develop some degree of NSAID
nephrotoxicity in the United States annually.
• NSAID and COX-2 induced AKI usually occurs within 2 to 7 days of initiating therapy,
• Typically present with diminished urine output, weight gain, or edema
NON-STEROID ANTIINFLAMMATORY DRUGS

• NSAID cause
vasoconstriction of
afferent arteriole
less blood to
glomerolus GFR
decrease
 PATIENT AT RISK OF AKI

Older age, e.g. > 60

Any stage of CKD Volume depletion Diabetes Heart failure
years

CONCURRETNT
Liver disease Liver disease SLE Liver disease USE OF ACEI/ARB
AND DIURETICS

Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-
steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013;346
Dreischulte T, Morales DR, Bell S, et al. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system
inhibitors in the community increases the risk of acute kidney Injury. Kidney Int 2015;88:396–403.
 PREVENTION NSAID- AND COX-2 INHIBITOR–
INDUCED AKI
• Recognizing high-risk patients
• Avoiding potent compounds such as indomethacin and using analgesics with less prostaglandin
inhibition, such as acetaminophen, nonacetylated salicylates, aspirin, and possibly nabumetone.
• Use nonnarcotic analgesics if possible (eg, tramadol)
• Use the minimal effective dose and the shortest duration possible, and NSAIDs with short
half-lives should be considered (eg, sulindac) along with optimal management of predisposing
medical problems and frequent kidney function monitoring.
• Avoid concurrent hypotensive agents and other drugs that affect renal hemodynamics (eg,
ACEIs, ARBs, diuretics)
MANAGEMENT

• Discontinuation
• Supportive Care
 TRIPLE WHAMMY

• The concomitant use of ACEI or ARB, with a diuretic and NSAID, including COX-2
inhibitors.
• About 0,3-0,8% outpatients received triple whammy.
• Prescribing a NSAID concurrently with an ACE inhibitor/ARB and a diuretic
increases the risk of AKI by 31%.
• The risk of AKI was highest (nearly 2x increased risk) within the first 30 days for
patients taking the triple combination.

Lapi F, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-
inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013;346.
Dreischulte T. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community
increases the risk of acute kidney injury. Kidney Int 2015;88:396–403
TRIPLE WHAMMY

Triple whammy use

of NSAID, Diuretic,
NSAID together
Increase risk of AKI
 PATIENT AT RISK OF TRIPLE WHAMMY

Older age,
Any stage of Volume
e.g. > 75
CKD depletion
years

Diabetes Heart failure Liver disease

Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-
steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013;346
Dreischulte T, Morales DR, Bell S, et al. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system
inhibitors in the community increases the risk of acute kidney Injury. Kidney Int 2015;88:396–403.
 AVOIDING TRIPLE WHAMMY

• Thorough patients assessment and medication chart reviewAre there

any medications that are not needed?
• NSAID Switch to topical NSAIDs may be appropriate in some cases
• Recommend paracetamol if appropriate.
• If needed, use lowest dose of NSAID for a short period assess renal
function regularly.
• Maintain a good fluid intake to avoid volume depletion, particularly if
feeling unwell or in hot weather.

www.bpac.org.nz/2018/triple-whammy.aspx