Therapeutics

Acute Kidney Injury

Dr Sura Al Zoubi

PhD,

MClinPharm

Lecture 17

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References

• Pharmacotherapy: A Pathophysiologic

Approach, 11e. Chapter 60: Acute Kidney

Injury

• Guidelines from the Kidney Disease:

Improving Global Outcomes (KDIGO).

https://kdigo.org/guidelines/

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INTRODUCTION

• Acute kidney injury (AKI) is a clinical syndrome generally defined by an abrupt reduction in kidney functions as evidenced by changes in serum creatinine (Scr), blood urea nitrogen (BUN), and urine output.

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

• Early recognition along with supportive therapy is the focus of management for those with established AKI, as there is no pharmacologic therapy that directly reverses the injury.

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INTRODUCTION

• Individuals at risk, such as those with history of chronic kidney disease (CKD), need to have their hemodynamic status carefully monitored and their exposure to nephrotoxins minimized

• RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Renal Disease), AKIN (Acute Kidney Injury Network), and the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines are three criteria-based classification systems developed to define and stage AKI in different patient populations.

• All three staging systems have been validated across different patient populations and their staging correlates closely with hospital mortality, cost, and length of stay.

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RIF

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and K

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EPIDEMIOLOGY

• The epidemiology of AKI varies widely depending on the patient population studied and the criteria used to evaluate the patient.

• AKI occurs in 3.0% to 18.3% of hospitalized noncritically ill patients and 30% to 60% of critically ill adults

• Risk factors associated with AKI include the presence of CKD, diabetes, heart or liver disease, albuminuria, major surgery (especially cardiac surgery), acute decompensated heart failure, sepsis, hypotension, volume depletion (diarrhea, vomiting, or dehydration), medications (exposure to angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], aminoglycosides, etc.), advanced age, male gender, and African American race.

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ETIOLOGY

• The etiology of AKI can be divided into three broad categories based on the anatomic location of the injury associated with the precipitating factor(s).

• Traditionally, the causes of AKI have been categorized as:

1. Prerenal, which results from decreased renal perfusion in the setting of undamaged parenchymal tissue,

2. Intrinsic, the result of structural damage to the kidney, most commonly the tubule from an ischemic or toxic insult,

3. Postrenal, caused by obstruction of urine flow downstream from the kidney.

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ET

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PATHOPHYSIOLOGY

• AKI can be categorized as:

1. Prerenal (resulting from decreased renal perfusion in the setting of undamaged parenchymal tissue),

2. Intrinsic (resulting from structural damage to the kidney, most commonly the tubule from an ischemic or toxic insult), and

3. Postrenal (resulting from obstruction of urine flow downstream from the kidney)

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Prerenal Acute Kidney Injury

• Results from hypoperfusion of the renal parenchyma, with or without systemic arterial hypotension.

• Renal hypoperfusion associated with systemic arterial hypotension may be caused by a decline in either the intravascular volume or the effective circulating blood volume.

• Intravascular volume depletion may result from several conditions, including hemorrhage, excessive gastrointestinal (GI) losses (severe vomiting or diarrhea), dehydration, extensive burns, and diuretic therapy.

• Effective circulating blood volume may be reduced in conditions associated with a decreased cardiac output and systemic vasodilation.

• Renal hypoperfusion without systemic hypotension is most commonly associated with bilateral renal artery occlusion or unilateral occlusion in a patient with a single functioning kidney.

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Intrinsic Acute Kidney Injury

1. Renal Vasculature Damage: Occlusion of the larger renal vessels resulting in AKI is not common but can occur if large atheroemboli or thromboemboli occlude the bilateral renal arteries or one vessel of the patient with a single kidney

2. Glomerular Damage: Kidney injury may develop when circulating immune complexes deposit in the glomeruli and cause an inflammatory reaction (eg, lupus nephritis, IgA nephropathy).

3. Tubular Damage: Most intrinsic AKI cases are due to ATN, which can either result from renal ischemia or nephrotoxin exposure (eg, aminoglycosides, contrast dyes).

4. Interstitial Damage: Acute interstitial nephritis (AIN) is an idiosyncratic delayed hypersensitivity immune reaction that is most commonly caused by drugs and less commonly by infections, autoimmune diseases, or idiopathic causes

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Postrenal Acute Kidney Injury

• Postrenal AKI accounts for less than 5% of all cases of AKI and may develop as the result of obstruction at any level within the urinary collection system.

• However, if the obstructing process is above the bladder, it must involve both kidneys (one kidney in a patient with a single functioning kidney) to cause clinically significant AKI, as one functioning kidney can generally maintain a near-normal GFR.

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CLINICAL PRESENTATION

• Patient presentation varies widely and depends on the underlying cause.

• Outpatients often are not in acute distress; hospitalized patients may develop AKI after a catastrophic event (eg, shock or acute cortical necrosis).

• Symptoms in the outpatient setting include acute change in urinary habits, sudden weight gain, or severe abdominal or flank pain.

• Signs include edema, colored or foamy urine, and, in volume-depleted patients, postural hypotension.

• AKI in hospitalized patients is often detected much earlier in its course due to frequent laboratory studies and daily patient assessment.

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DIAGNOSIS

• Thorough medical and medication histories, physical examination, assessment of laboratory values, and, if needed, imaging studies are important in the diagnosis of AKI.

• Scr cannot be used alone to diagnose AKI because it is insensitive to rapid changes in glomerular filtration rate (GFR) lagging behind the GRF’s decline by 1 to 2 days leading to a potential delay in diagnosis.

• The use of BUN in AKI is very limited because urea production and renal clearance are heavily influenced by extrarenal factors such as critical illness, volume status, protein intake, and medications.

• Urine output measured over a specified period of time allows for short-term assessment of renal function, but its utility is limited to cases in which it is significantly decreased. 14

DIAGNOSIS

• In addition to BUN and Scr, selected blood tests, urinary chemistry, and urinary sediment are used to differentiate the cause of AKI and guide patient management

• Simultaneous measurement of urine and serum electrolytes and calculation of the fractional excretion of sodium (FENa) can help determine the etiology of AKI.

• The FENa is one of the better diagnostic parameters to differentiate the cause of AKI and is calculated as FENa = (UNa × SCr × 100)/(UCr × SNa)

• Where UNa = urine sodium, SCr = serum creatinine, UCr = urine creatinine, and SNa = serum sodium.

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DIAGNOSIS

Diagnostic Parameters for Differentiating Causes of AKI

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PREVENTION

• The goals of prevention are to screen and

identify patients at risk; monitor high-risk

patients until the risk subsides; and implement

prevention strategies when appropriate.

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GENERAL APPROACH TO

PREVENTION

• Nonpharmacologic Therapies

1. Electronic alert system

2. Intravenous fluids

3. Remote ischemia preconditioning

• Pharmacological Therapy

1. Ascorbic acid

2. N-acetylcystine

3. Statin

4. Glycaemic control

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Electronic Alert Systems

• Recent advances in electronic health record

(EHR) systems have led to the development of

clinical decision support systems and electronic

alerts designed to improve and standardize care in

certain high-risk patient populations.

• Electronic alerts have been used for early

detection of AKI and increased surveillance of

patients on nephrotoxic medications.

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Intravenous Fluids

• Intravenous fluids are one of the primary interventions that have consistently shown benefit and are routinely used in the prevention of AKI.

• 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.

• When using crystalloid solutions, options include either balanced solutions or isotonic saline. The main concerns associated with the use of large amounts of saline are hyperchloremic acidosis, interstitial edema, fluid overload, and death

• Balanced solutions appear to reduce the incidence of AKI and need for RRT in critically ill patients, but not in noncritically ill patients. Overall, it appears that balanced solutions do not increase risk of AKI or other harmful outcomes and could provide some benefit compared to normal saline solutions.

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Intravenous Fluids

• There is no consensus on the optimal rate and duration of fluid infusions, CI-AKI hydration protocols may vary across different institutions.

• A common sodium bicarbonate regimen is 154 mEq/L (mmol/L) infused at 3 mL/kg/hr for 1 hour before the procedure and at 1 mL/kg/hr for 6 hours after the procedure.

• The rate and duration of normal saline infusion vary, but one frequently cited regimen is 1 mL/kg/hr for 12 hours before and 12 hours after the procedure.

• The rate of administration may need to be adjusted depending on the patient's cardiopulmonary and volume status

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Remote Ischemic Preconditioning

• Remote ischemic preconditioning (RIPC) consists of a transient period of blood supply deprivation to a particular organ or tissue followed by a period of reperfusion.

• This priming process before a definitive ischemic injury or insult occurs may stimulate release of cytoprotective molecules and attenuate ischemic damage.

• Even when ischemia is induced at a nontarget site such as limb, it can confer protection at a more distant site including brain, lung, and kidneys.

• As a result, RIPC is typically performed using a blood pressure cuff to a remote extremity (eg, upper arm). It consists of three cycles of 5-minute cuff inflation up to 200 mm Hg, or at least 50 mm Hg higher than the patient's systolic blood pressure, followed by a 5-minute cuff deflation period to allow for reperfusion to occur.

• While the exact mechanism of protection is unknown, it is thought to involve the activation of the humoral, neuronal, and immunomodulatory pathways.

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Ascorbic Acid

• Ascorbic acid has mainly been studied for the prevention of CI-AKI, as its antioxidant properties are thought to alleviate oxidative stress caused by ischemia reperfusion injury.

• To date, inconsistent results ranging from modest to no benefit have been observed.

• Overall, despite an excellent safety profile and low cost, inadequate evidence exists to support use of ascorbic acid in the treatment or prevention of CI-AKI.

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N-acetylcysteine

• N-acetylcysteine (NAC) is another antioxidant that has been widely studied in the prevention of CI-AKI. However, its therapeutic benefit is thought to be quite modest and has not been consistently demonstrated.

• The PRESERVE trial found that a 5-day course of oral NAC did not reduce risk of CI-AKI, need for RRT, or death in high-risk individuals undergoing angiography when compared to placebo.

• The 2012 KIDGO guidelines suggest using NAC in combination with IV isotonic saline in patients at risk for CI-AKI; however, these guidelines pre-date the landmark PRESERVE trial, which indicates no benefit of NAC in the prevention of CI-AKI.

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Statins • Statins, are one of the first-line therapies for the treatment of

hyperlipidemia and prevention of cardiovascular events.

• Statins also exhibit anti-inflammatory, antioxidant, and endothelium protective effects, which have led to research on their utility in preventing AKI.

• So far, statins have largely been studied for prevention of CI-AKI or AKI secondary to major cardiac surgery with mixed results.

• Statins may reduce the risk of AKI in high-risk patients exposed to contrast agents.

• Statins 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. 25

Glycemic Control

• In critical illness, both hyper- and hypoglycemia are associated with adverse patient outcomes

• Tight glycemic control with target glucose levels of 80 to 110 mg/dL may significantly decrease the risk of AKI and this has been adopted in the ICU setting

• However, tight glycemic control protocols may also increase risk of hypoglycemia and mortality. As a result, a more moderate approach to glycemic control is currently favored in the critically ill.

• Guidelines from the American Diabetes Association recommend a glycemic target range of 140 to 180 mg/dL in critically ill patients.

• Surviving Sepsis Campaign recommend a glycemic target of less than 180 mg/dL in critically ill patients.

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TREATMENT OF ACUTE

KIDNEY INJURY

• 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.

• Desired Outcomes

• Short-term goals of AKI management include minimizing the degree of insult to the kidney, reducing extrarenal complications, and expediting the patient's recovery of kidney function. Therapy should focus on maintaining organ functions while sustaining mean arterial pressure.

• The ultimate goal is to have the patient's kidney function restored to pre-AKI baseline.

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General Approach to Treatment

• Identification and management of AKI should be prompt.

• Prerenal sources of AKI should be managed with hemodynamic support and volume replacement

• Postrenal AKI therapy should focus on removing the cause of the obstruction.

• At the same time, patient's comorbidities and baseline kidney function need to be reviewed. Loss of kidney function combined with other clinical conditions, such as cardiac and liver failure, is associated with higher mortality.

• At times, the most effective method for managing AKI may be treatment of the comorbid precipitating event.

• In patients where CKD is also present, the kidneys have less reserve, and there is a greater likelihood that full recovery may not occur.

• In more severe AKI, RRT may be necessary to maintain fluid, electrolyte, and acid-base balance while removing accumulating waste products or toxins 28

Intravenous Fluids

• The principal of fluid therapy is to maintain or restore effective intravascular volume to assure adequate renal perfusion.

• 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 serum electrolytes. Urine output ≥0.5 mL/kg/hr is generally targeted during the initial fluid resuscitation phase.

• In patients with anuria or oliguria, slower rate should be considered to reduce the risk for pulmonary edema, especially if heart failure or pulmonary insufficiency exists.

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Intravenous Fluids

• If AKI is a result of blood loss or is complicated by symptomatic anemia, red blood cell transfusion to a hemoglobin >7g/dL is the treatment of choice.

• Once a hemoglobin of >7g/dL is reached, balanced solutions or normal saline can be used to restore intravascular volume.

• Albumin is typically preferred in individuals with severe hypoalbuminemia secondary to cirrhosis or nephrotic syndrome.

• In critically ill patients with vasodilatory shock, vasopressors such as norepinephrine, vasopressin, or dopamine may be used in conjunction with fluids in order to maintain adequate hemodynamics and renal perfusion

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Electrolyte Management

• Hypernatremia and fluid retention are frequent complications of AKI.

• Hyperkalemia (most common). Life-threatening cardiac arrhythmias may occur with serum potassium concentrations greater than 6 mEq/L (mmol/L), so frequent monitoring of potassium is essential.

• Some foods and drugs contain substantial amounts of potassium.

• Some medications may promote potassium retention by the kidneys and should also be avoided or closely monitored if used

• In general, exogenous potassium supplementation should be avoided in patients with AKI unless warranted by the presence of hypokalemia.

• Phosphorus and magnesium should be monitored, especially in patients with significant tissue destruction due to increased amounts of released phosphorus; neither is efficiently removed by dialysis.

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Nutritional Considerations in AKI

• Nutritional management of critically ill

patients with AKI can be extremely complex,

as it needs to account for metabolic

derangements resulting from both impaired

kidney function and underlying disease

processes

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Renal Replacement Therapy • Renal replacement therapy is often utilized to treat fluid overload,

electrolyte disturbances (eg, hyperkalemia), acid-base imbalances, uremic complications, and pulmonary edema resulting from severe AKI

• The choice of continuous versus intermittent RRTs is a matter of considerable debate and usually depends on physician preference and the resources available.

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Diuretics

• Loop diuretics are frequently prescribed for the management of fluid overload in patients with established kidney injury.

• Loop diuretics have several theoretical advantages:

1. Increased urine output;

2. Decreased risk of ischemic injury by inhibiting the Na-K-Cl cotransporter and thus decreasing oxygen demand; and

3. Enhanced renal blood flow due to increased availability of renal prostaglandins

• However, clinical studies have found that even though the loop diuretics increase urine output, they neither reduce the incidence of AKI nor improve patient outcomes for patients with established AKI

• Therefore, the KDIGO guidelines recommend limiting the use of loop diuretics to the management of fluid overload and avoiding their use for the sole purpose of prevention or treatment of AKI.

• Diuretic resistance is a relatively common problem. Increase the dose, add another diuretic or continuous infusions of loop diuretics appear to overcome diuretic resistance

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• Optimization of drug therapy for patients with AKI is often challenging.

• The multiple variables influencing responses to the drug regimen include the

1. patient's residual drug clearance,

2. fluid accumulation,

3. delivery of RRT.

• For renally eliminated drugs, particularly for agents with a narrow therapeutic range,

serum drug concentration measurements and assessment of pharmacodynamic responses

are likely to be necessary.

• If hepatic function is intact, choosing an agent eliminated primarily by the liver may be

preferred

• Pharmacokinetic studies in patients with established AKI (and CKD) are fairly limited.

The use of dosing guidelines based on data derived from patients with stable CKD may

not reflect the clearance and volume of distribution in critically ill AKI patients

• Regimen decisions should further take into consideration four distinct phases of AKI

DRUG-DOSING CONSIDERATIONS

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• Edema, which is common in AKI, can significantly increase the volume of distribution of many drugs, particularly water-soluble ones with relatively small volumes of distribution thereby reduce the proportion of drug in the plasma that is available to be removed by RRT

• If rapid onset of activity is desired, a loading dose may be necessary to promptly achieve desired serum concentrations. Why?

• Drug therapy individualization for the AKI patient who is receiving any form of RRT is complicated by the fact that patients with AKI may have a higher residual nonrenal clearance than patients with CKD who have a similar CLcr

• If a patient with AKI has higher than anticipated nonrenal clearance, this would result in lower than expected, possibly subtherapeutic, drug serum concentrations

DRUG-DOSING CONSIDERATIONS

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Drug Dosing Considerations in RRT

• Characteristics that can alter drug clearance during RRT, including

1. molecular weight,

2. protein binding,

3. volume of distribution, and

4. degree of renal clearance or fraction eliminated by the kidneys

• There are marked differences in drug removal between the different RRT modalities

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EVALUATION OF THERAPEUTIC

OUTCOMES

• Vigilant monitoring of patients with AKI is essential, particularly in those who are critically ill.

• Key Monitoring Parameters for Patients with Established AKI (table next slide)

• Therapeutic drug monitoring should be performed for drugs that have a narrow therapeutic index if results can be obtained in a timely fashion

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Thank you

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