Acute Kidney Injury (AKI)

Acute Kidney Injury (AKI)
Pharmacotherapy II Second Semester 2014

References Pharmacotherapy: A Pathophysiologic Approach – Chapter 50 (Assessment) (ARF), 55 (Drug induced) Pharmacotherapy: Principles and Practice – Chapter 22 Applied Therapeutics: The Clinical Use of Drugs – Chapter 30 UpToDate: Assessment of kidney function: Serum creatinine; BUN; and GFR Diagnostic approach to the patient with acute or chronic kidney disease Urinalysis in the diagnosis of renal disease Definition of acute kidney injury (acute renal failure) National Kidney Foundation: The Renal Association. Acute kidney injury Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2: 1–138

Introduction Renal function: Maintenance of body composition:
Filtration Absorption Secretion Excretion of metabolic end products and foreign substances Production and secretion of enzymes and hormones Activation of vitamin D3/glucneogenesis/metabolism of insulin, steroids and xenobiotics The main functions of the kidneys can be categorized as follows: 1. Maintenance of body composition: The kidney regulates the volume of fluid in the body; its osmolarity, electrolyte content, and concentration; and its acidity. It achieves this regulation by varying the amounts of water and ions excreted in the urine. Electrolytes regulated by changes in urinary excretion include sodium, potassium, chloride, calcium, magnesium, and phosphate. 2. Excretion of metabolic end products and foreign substances: The kidney excretes a number of products of metabolism, most notably urea, and a number of toxins and drugs. 3. Production and secretion of enzymes and hormones: a. Renin is an enzyme produced by the granular cells of the juxtaglomerular apparatus that catalyzes the formation of angiotensin from a plasma globulin, angiotensinogen. Angiotensin is a potent vasoconstrictor peptide and contributes importantly to salt balance and blood pressure regulation. b. Erythropoietin, a glycosylated protein comprising 165 amino acids that is produced by renal cortical interstitial cells, stimulates the maturation of erythrocytes in the bone marrow. c. 1,25-Dihydroxyvitamin D3, the most active form of vitamin D3, is formed by proximal tubule cells. This steroid hormone plays an important role in the regulation of body calcium and phosphate balance.

Assessment of kidney function

Introduction Patients with kidney disease may have a variety of different clinical presentations. Some have symptoms that are directly referable to the kidney (gross hematuria, flank pain) or to extrarenal symptoms (edema, hypertension, signs of uremia). Many patients, however, are asymptomatic and are noted on routine examination to have an elevated serum creatinine concentration or an abnormal urinalysis. Once kidney disease is discovered, the presence or degree of kidney dysfunction and rapidity of progression are assessed, and the underlying disorder is diagnosed. Although the history and physical examination can be helpful, there are two major components of the diagnostic approach to the patient with renal disease: Assessment of renal function by estimation of the glomerular filtration rate (GFR), initially by measurement of the plasma creatinine concentration and (in those with stable renal function) the application of formulas which provide reasonable, but not precise, estimates of GFR. Careful examination of the urine (by both qualitative chemical tests and microscopic examination), since the urinary findings narrow the differential. Estimation of the glomerular filtration rate (GFR) is used clinically to assess the degree of kidney impairment and to follow the course of the disease. However, the GFR provides no information on the cause of the kidney disease. This is achieved by the urinalysis, measurement of urinary protein excretion, and, if necessary, radiologic studies and/or kidney biopsy.

Glomerular filtration rate (GFR)
The GFR is equal to the sum of the filtration rates in all of the functioning nephrons  the estimation of the GFR gives an approximate measure of the number of functioning nephrons. The GFR is expressed as the volume of plasma filtered across the glomerulus per unit time, based on total renal blood flow (1L/min/1.73 m2)and capillary hemodynamics (plasma volume is 60% of the blood volume). The normal value for GFR depends on age, sex, and body size, and is approximately 130 and 120 mL/min/1.73 m2 for men and women, respectively, with considerable variation even among normal individuals A reduction in GFR implies either progression of the underlying disease or the development of a superimposed and often reversible problem, such as decreased renal perfusion due to volume depletion. An increase in GFR, is indicative of improvement in renal function, or may imply an increase in filtration (hyperfiltration) due to hemodynamic factors A stable GFR in patients with renal disease implies stable disease.

Estimation of GFR GFR cannot be measured directly in humans  use special solute markers. The most common methods utilized to estimate the GFR in adults are: the serum creatinine concentration, the creatinine clearance, estimation equations based upon the serum creatinine concentration: Cockcroft-Gault equation Modification of Diet in Renal Disease (MDRD) study equation. Since all renal disorders variably affect renal function, estimation of the GFR has no diagnostic utility. In addition, serum creatinine and GFR estimation equations can only be used in patients with stable kidney function. (WHY? … Homework) With acute renal failure, the GFR is initially markedly reduced but there has not yet been time for creatinine to accumulate and for the serum creatinine concentration to reflect the degree of renal dysfunction. It is important to appreciate, however, that in most clinical settings (other than dose adjustment for medications), exact knowledge of the GFR is not required. What is important to know in the patient with kidney disease is whether the GFR (and therefore disease severity) is changing or is stable. This can usually be determined by monitoring changes in the serum creatinine or the estimated GFR in patients with a relatively constant body mass and diet.

Serum Creatinine Creatinine is the standard laboratory marker for the detection of kidney disease. The third National Health and Nutrition Examination Survey (NHANES III) revealed a mean serum creatinine of 0.96 mg/ dL in women, and 1.16 mg/dL in men in the United States. There is presently no accepted single standard for an “abnormal” serum creatinine, as it is gender, race, and age-dependent. The serum creatinine concentration alone is not an optimal measure of kidney function, however, it is often used as a marker for referral to a nephrologist. The concentration of creatinine in serum is a function of creatinine production and serum excretion. Production is dependent on muscle mass Eliminated primarily by glomerular filtration At steady state, the normal serum creatinine conc range is mg/dL for males and females.

Blood urea nitrogen (BUN)
Amino acids metabolized to ammonia are subsequently converted in the liver to urea, the production of which is dependent on protein availability (diet) and hepatic function. Urea undergoes glomerular filtration followed by reabsorption of up to 50% of the filtered load in the proximal tubule. The reabsorption rate of urea is predominantly dependent on the reabsorption of water. The excretion of urea may, therefore, be decreased under conditions which necessitate water conservation such as dehydration although the GFR may be normal or only slightly reduced. This condition is evident when a patient exhibits prerenal azotemia, or an increase of the blood urea nitrogen to a greater extent than the serum creatinine. The normal blood urea nitrogen-to-creatinine ratio is 10 to 15:1, and an elevated ratio is suggestive of a decreased effective circulating volume, which stimulates increased water, and hence, urea reabsorption. The blood urea nitrogen is usually used in combination with the serum creatinine concentration as a simple screening test for the detection of renal dysfunction.

Urine sodium excretion
With acute renal failure, measurement of the urine sodium concentration is helpful in distinguishing acute tubular necrosis (>40 meq/L) from effective volume depletion (<20 meq/L) The effect of variations in urine volume can be eliminated by calculating the fractional excretion of sodium (FENa). This is defined by the following equation: UNa x PCr FENa, percent = —————— x 100 PNa x UCr where UCr and PCr are the urine and plasma creatinine concentrations, respectively, and UNa and PNa are the urine and plasma sodium concentrations, respectively. In acute renal failure, the FENa is the most accurate screening test to differentiate between prerenal disease and acute tubular necrosis. a value below 1 percent suggests prerenal disease; a value between 1 and 2 percent may be seen with either disorder, a value above 2 percent usually indicates ATN. By comparison, among patients with chronic kidney disease, the addition of a prerenal process may not result in a low urine sodium concentration or FeNa.

Urinalysis The urinalysis is the most important noninvasive test in the diagnostic evaluation since characteristic findings strongly suggest certain diagnoses. It can be used to detect and monitor the progression of diseases such as DM, glomerulonephritis and chronic UTI. Urinalysis involves: Visual observation (volume and color) Microscopic examination of the urinary sediment to determine formed elements: erythrocytes, leukocytes, casts and crytals. Dipstick testing for protein, pH, concentration, glucose, ketones, hematuria and pyuria. Chemical analysis of urine: pH, glucose, ketone, nitrite, leukocyte esterase, heme, protein or albumin (spot albumin to creatinine), specific gravity

Virtually diagnostic of glomerular disease or vasculitis
Urinary pattern Renal disease Hematuria with red cell casts, dysmorphic red cells, heavy proteinuria, or lipiduria Virtually diagnostic of glomerular disease or vasculitis Multiple granular and epithelial cell casts with free epithelial cells Strongly suggestive of acute tubular necrosis in a patient with acute renal failure Pyuria with white cell and granular or waxy casts and no or mild proteinuria Suggestive of tubular or interstitial disease or urinary tract obstruction Hematuria and pyuria with no or variable casts (excluding red cell casts) May be observed in acute interstitial nephritis, glomerular disease, vasculitis, obstruction, and renal infarction Hematuria alone Varies with the clinical setting Pyuria alone Usually infection; sterile pyuria suggests urinary tract tuberculosis or tubulointerstitial disease Few cells with little or no casts or proteinuria (normal or near-normal) In acute renal failure, prerenal disease, urinary tract obstruction, hypercalcemia, myeloma kidney, some cases of acute tubular necrosis, or a vascular disease with glomerular ischemia but not infarction (scleroderma, atheroemboli); in chronic renal failure, nephrosclerosis, urinary tract obstruction, and tubulointerstitial disease In medicine, pyuria /paɪjʊəˈriːə/ is the condition of urine containing pus. Defined as the presence of 6-10 or moreneutrophils per high power field of unspun, voided mid-stream urine. It can be a sign of a bacterial urinary tract infection. Pyuria may be present in the septic patient, or in an older patient with pneumonia. Urinary casts are cylindrical structures produced by the kidney and present in the urine in certain disease states Acellular casts [edit]Hyaline casts The most common type of cast, hyaline casts are solidified Tamm-Horsfall mucoprotein secreted from the tubular epithelial cells of individual nephrons. Low urine flow, concentrated urine, or an acidic environment can contribute to the formation of hyaline casts, and, as such, they may be seen in normal individuals in dehydration or vigorous exercise. Hyaline casts are cylindrical and clear, with a low refractive index, so that they can easily be missed on cursory review under brightfield microscopy, or in an aged sample where dissolution has occurred. On the other hand, phase contrast microscopy leads to easier identification. Given the ubiquitous presence of Tamm-Horsfall protein, other cast types are formed via the inclusion or adhesion of other elements to the hyaline base. [edit]Granular casts The second-most common type of cast, granular casts can result either from the breakdown of cellular casts or the inclusion of aggregates of plasma proteins (e.g., albumin) or immunoglobulin light chains. Depending on the size of inclusions, they can be classified as fine or coarse, though the distinction has no diagnostic significance. Their appearance is generally more cigar-shaped and of a higher refractive index than hyaline casts. While most often indicative of chronic renal disease, these casts, as with hyaline casts, can also be seen for a short time following strenuous exercise.[2] The "muddy brown cast" seen inacute tubular necrosis is a type of granular cast. [edit]Waxy casts Thought to represent the end product of cast evolution, waxy casts suggest the very low urine flow associated with severe, longstanding kidney disease such as renal failure. Additionally, due to urine stasis and their formation in diseased, dilated ducts, these casts are significantly larger than hyaline casts. While cylindrical, they also possess a higher refractive index and are more rigid, demonstrating sharp edges, fractures, and broken-off ends. Waxy casts also fall under the umbrella of “broad” casts, a more general term to describe the wider cast product of a dilated duct. It is seen in chronic renal failure. In nephritic syndrome many additional types of casts include broad and waxy casts if the condition is chronic (this is referred to as a telescopic urine with the presence of many casts).[3] [edit]Fatty casts Formed by the breakdown of lipid-rich epithelial cells, these are hyaline casts with fat globule inclusions, yellowish-tan in color. If cholesterol or cholesterol esters are present, they are associated with the “Maltese cross” sign under polarized light. They are pathognomonic for high urinary protein nephrotic syndrome. [edit]Pigment casts Formed by the adhesion of metabolic breakdown products or drug pigments, these casts are so named due to their discoloration. Pigments include those produced endogenously, such as hemoglobin in hemolytic anemia, myoglobin in rhabdomyolysis, and bilirubin in liver disease. Drug pigments, such as phenazopyridine, may also cause cast discoloration. [edit]Crystal casts Though crystallized urinary solutes, such as oxalates, urates, or sulfonamides, may become enmeshed within a ketanaline cast during its formation, the clinical significance of this occurrence is not felt to be great. [edit]Cellular casts [edit]Red blood cell casts The presence of red blood cells within the cast is always pathological, and is strongly indicative of glomerular damage, which can occur in glomerulonephritis from various causes or vasculitis, including Wegener's granulomatosis, systemic lupus erythematosus, post-streptococcal glomerulonephritis orGoodpasture’s syndrome. They can also be associated with renal infarction and subacute bacterial endocarditis. They are a yellowish-brown color and are generally cylindrical with sometimes ragged edges; their fragility makes inspection of a fresh sample necessary. They are usually associated with nephritic syndromes or urinary tract injury. [edit]White blood cell casts Indicative of inflammation or infection, the presence of white blood cells within or upon casts strongly suggests pyelonephritis, a direct infection of the kidney. They may also be seen in inflammatory states, such as acute allergic interstitial nephritis, nephrotic syndrome, or post-streptococcal acute glomerulonephritis. White cells sometimes can be difficult to discern from epithelial cells and may require special staining. Differentiation from simple clumps of white cells can be made by the presence of hyaline matrix. [edit]Bacterial casts Given their appearance in pyelonephritis, these should be seen in association with loose bacteria, white blood cells, and white blood cell casts. Their discovery is likely rare, due to the infection-fighting efficiency of neutrophils, and the possibility of misidentification as a fine granular cast. [edit]Epithelial cell casts This cast is formed by inclusion or adhesion of desquamated epithelial cells of the tubule lining. Cells can adhere in random order or in sheets and are distinguished by large, round nuclei and a lower amount of cytoplasm. These can be seen in acute tubular necrosis and toxic ingestion, such as from mercury,diethylene glycol, or salicylate. In each case, clumps or sheets of cells may slough off simultaneously, depending of the focality of injury. Cytomegalovirus and viral hepatitis are organisms that can cause epithelial cell death as well.

Normal urine analysis Ketones – None Normal values are as follows:
Nitrates – Negative Leukocyte esterase – Negative Bilirubin – Negative Urobilirubin – Small amount ( mg/dL) Blood - ≤3 RBCs Protein - ≤150 mg/d RBCs - ≤3RBCs/hpf WBCs - ≤2-5 WBCs/hpf Squamous epithelial cells - ≤ squamous epithelial cells/hpf Normal values are as follows: Color – Yellow (light/pale to dark/deep amber) Clarity/turbidity – Clear or cloudy pH – 4.5-8 Specific gravity – Glucose - ≤130 mg/d Crystals – Occasionally Bacteria – None Yeast - None Casts – 0-5 hyaline casts/lpf

Urine volume the urine output is variable, ranging from oliguria to normal or even above normal levels. The urine output is determined, not by the GFR alone, but by the difference between the GFR and the rate of tubular reabsorption. If, for example, a patient with advanced acute or chronic kidney disease has a GFR of 5 L/day (versus the normal of 140 to 180 L/day), the daily urine output will still be 1.5 L if only 3.5 L of the filtrate is reabsorbed. The urine output is of little diagnostic value. However, little or no output is diagnostically useful in the acute setting. Causes of this finding include shock, complete bilateral urinary tract obstruction, renal cortical necrosis, and bilateral vascular occlusion (as with a dissecting aneurysm or thrombotic thrombocytopenic purpura- hemolytic uremic syndrome).

Radiologic studies and Renal biopsy
A number of radiologic studies are used to evaluate the patient with renal disease. They are principally required to assess urinary tract obstruction, kidney stones, renal cyst or mass, disorders with characteristic radiographic findings, renal vascular diseases, and, in children and young adults, vesicoureteral reflux. Renal ultrasonography – most commonly used radiologic technique Helical CT scan – generally preferred with patients with flank pain and possible urolithiasis. Magnetic resonance imaging – useful for the assessment of obstruction, malignancy and renovascular disease. A renal biopsy is most commonly obtained in patients with suspected glomerulonephritis or vasculitis and in those with otherwise unexplained acute or subacute renal failure.

Major causes of kidney disease
The causes of acute or chronic kidney disease are traditionally classified by that portion of the renal anatomy most affected by the disorder. Renal function is based upon four sequential steps, which are isolated to specific areas of the kidney or surrounding structures: First, blood from the renal arteries and their subdivisions is delivered to the glomeruli. The glomeruli form an ultrafiltrate, nearly free of protein and blood elements, which subsequently flows into the renal tubules. The tubules reabsorb and secrete solute and/or water from the ultrafiltrate. The final tubular fluid, the urine, leaves the kidney, draining sequentially into the renal pelvis, ureter, and bladder, from which it is excreted through the urethra. Renal disease can be caused by any process that interferes with any of these structures and/or functions. Identifying prerenal (reduced renal perfusion) and postrenal (obstructive) diseases is particularly important because they may be readily reversible.

Disease duration There is also a variable time course.
Acute: a rise in the plasma creatinine concentration or an abnormality on the urinalysis that has developed within days to weeks represents an acute process Subacute (rapidly progressive): evidence of renal disease extending for weeks represents a rapidly progressive process Chronic: evidence of renal disease extending for months to years is a chronic process that may be associated with acute exacerbations. The determination of disease duration is best performed by comparing the current urinalysis or plasma creatinine concentration with previous results, if available. the differential diagnosis can frequently be narrowed if the disease duration is known

Acute Kidney Injury

Definition (ARF or AKI)
Acute renal failure (ARF) is characterized clinically by an abrupt decrease in renal function over a period of hours to days, and sometimes over weeks, resulting in the accumulation of nitrogenous waste products (azotemia) and the inability to maintain and regulate fluid, electrolyte, and acid–base balance. A decrease in urine output is often observed but not required for ARF. Patients with ARF are often categorized as being: Anuric  UO <50 ml/day Oliguric  UO <500 ml/day Non-oliguric  UO >500 ml/day Regardless of the definitions used, the clinician should suspect ARF when the kidney is unable to regulate fluid, electrolyte, acid–base, or nitrogen balance, even in the presence of a normal SrCr concentration.

Traditionally, ARF has been defined as:
The loss of kidney function is most easily detected by measurement of the serum creatinine (SrCr) which is used to estimate the glomerular filtration rate (GFR) Traditionally, ARF has been defined as: a 0.5 mg/dL increase in SrCr if the baseline serum creatinine was ≤1.9 mg/dL, an 1.0 mg/dL increase in SrCr if the baseline serum creatinine was 2.0 to 4.9 mg/dL, a 1.5 mg/dL increase in SrCr if the baseline serum creatinine was ≥5.0 mg/dL These criteria are often inaccurate because SrCr and GFR do not follow a linear relationship.

problems associated with the use of the SrCr to quantitatively define ARF:
Serum creatinine does not accurately reflect the GFR in a patient who is not in steady state or who are in a high catabolic state . Creatinine is removed by dialysis. As a result, it is usually not possible to assess kidney function by measuring the serum creatinine once dialysis is initiated. Numerous epidemiologic studies and clinical trials have used different cut-off values for serum creatinine to quantitatively define ARF To help clarify much of this confusion, the Acute Dialysis Quality Initiative (ADQI) has proposed a graded definition of ARF called the RIFLE criteria. In the early stages of severe acute renal failure, the serum creatinine may be low even though the actual (not estimated) GFR is markedly reduced since there may not have been sufficient time for the creatinine to accumulate. Diagnosing ARF solely on SrCr is problematic because many patients are in a high catabolic state as a result of their critical illness. Catabolism leads to the accumulation of creatinine and noncreatinine waste products (urea nitrogen), organic acids, water, and electrolytes.

RIFLE criteria by (ADQI)
consists of: three graded levels of injury (Risk, Injury, and Failure) based upon either the magnitude of elevation in serum creatinine or urine output, two outcome measures (Loss and End-stage renal disease) RIFLR-FC (acute on chronic), RIFLE-FO (oliguria) Limitations — There are several important shortcomings to the RIFLE criteria: The "risk," "injury," and "failure" strata are defined by either changes in serum creatinine or urine output. The assignment of the corresponding changes in serum creatinine and changes in urine output to the same strata are NOT based on evidence. In the one assessment of the RIFLE classification that compared the serum creatinine and urine output criteria, the serum creatinine criteria were strong predictors of ICU mortality, whereas the urine output criteria did not independently predict mortality [12]. Thus, if the RIFLE classification is used to stratify risk, it is important that the criteria that result in the least favorable RIFLE strata be used [4]. As mentioned above, the change in serum creatinine during acute renal failure does not directly correlate with the actual change in glomerular filtration rate, which alters the assignment of that patient to a particular RIFLE level. As an example, in a patient with an abrupt decline in renal function in the setting of severe ARF, the serum creatinine might rise from 1.0 to 1.5 mg/dL (88.4 to 133 micromol/L) on day one, 2.5 mg/dL (221 micromol/L) on day two, and 3.5 mg/dL (309 micromol/L) on day three. According to the RIFLE criteria, the patient would progress from "risk" on day one to "injury" on day two and "failure" on day three, even though the actual GFR has been <10 mL/min over the entire period. This issue is intrinsic to any assessment of acute renal failure based upon the serum creatinine level. It is impossible to calculate the change in serum creatinine in patients who present with ARF but without a baseline measurement of serum creatinine. The authors of the RIFLE criteria suggest back-calculating an estimated baseline serum creatinine concentration using the four-variable MDRD equation, assuming a baseline GFR of 75 mL/min per 1.73 m2 [4]. However, this approach has not been prospectively validated. *The worst of each criteria is used

Limitations of the RIFLE criteria
There are several important shortcomings to the RIFLE criteria: The "risk," "injury," and "failure" strata are defined by either changes in serum creatinine or urine output. The assignment of the corresponding changes in serum creatinine and changes in urine output to the same strata are NOT based on evidence The change in serum creatinine during acute renal failure does not directly correlate with the actual change in glomerular filtration rate, which alters the assignment of that patient to a particular RIFLE level. It is impossible to calculate the change in serum creatinine in patients who present with ARF but without a baseline measurement of serum creatinine.

AKIN criteria The Acute Kidney Injury Network (AKIN) modified the RIFLE criteria in order to: include less severe ARF, impose a time constraint of 48 hours, allow for correction of volume status and obstructive causes of ARF prior to classification. The AKIN proposed the term acute kidney injury (AKI) to represent the entire spectrum of acute renal failure, recognizing that an acute decline in kidney function is often secondary to an injury that causes functional or structural changes in the kidneys and that the injury can have important consequences for the patient even if it does not lead to organ failure and a requirement for renal replacement therapy Varying definitions have led to difficulty in comparing studies in the literature. Recently, the Acute Kidney Injury Network (AKIN) recommended that the term acute kidney injury (AKI) replace the term ARF to include the entire spectrum of ARF, recognizing that an acute decline in kidney function is often secondary to an injury that causes functional or structural changes in the kidneys and that the injury can have important consequences for the patient even if it does not lead to organ failure and a requirement for renal replacement therapy. The AKIN defined AKI as “an abrupt (within 48 hours) reduction in kidney function, currently defined as an absolute increase in serum creatinine level of more than or equal to 0.3 mg/dL (26.4 μmol/L), a percentage increase in serum creatinine of more than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 mL/kg/hr for more than 6 hours).”

The AKIN defined AKI as “an abrupt (within 48 hours) reduction in kidney function, currently defined as an absolute increase in serum creatinine level of more than or equal to 0.3 mg/dL (26.4 μmol/L), a percentage increase in serum creatinine of more than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 mL/kg/hr for more than 6 hours).”

AKIN criteria Stage Serum creatinine criteria Urine output criteria 1
↑ SCr ≥ 0.3 mg/dL (26.4micromol/L) or ↑ SCr ≥150–200 per cent (1.5–2 fold) from baseline. Less than 0.5 mL/kg per hour for more than 6 hours 2 ↑ SCr >200–300 per cent (>2–3 fold) from baseline. Less than 0.5 mL/kg per hour for more than 12 hours 3 ↑ SCr >300 per cent (>3fold) from baseline or SCr ≥ 4 mg/dL (354micromol/L) with an acute rise of ≥ 0.5 mg/dL (44micromol/L) or treatment with renal replacement therapy. Less than 0.3 mL/kg per hour for 24 hours or anuria for 12 hours SCr: Serum creatinine. Only one criterion must be met of either the SCr criteria or the urine output criteria; if both are present, the criterion which places the patient in the higher stage of AKI is selected. The diagnostic criteria should only be applied after volume status has been optimized. Only one criterion (creatinine or urine output) has to be fulfilled to qualify for a stage. Urinary tract obstruction needed to be excluded if oliguria was used as the sole diagnostic criterion. Individuals who receive RRT are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT. The AKIN proposed the term acute kidney injury (AKI) to represent the entire spectrum of acute renal failure. The proposed diagnostic criteria are an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours. These criteria will likely be revised, and possibly replaced, as biomarkers of tubular injury are developed. * Modified from RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria. The staging system proposed is a highly sensitive interim staging system and is based on recent data indicating that a small change in serum creatinine influences outcome. The diagnostic criteria should only be applied after volume status has been optimized. Only one criterion (creatinine or urine output) has to be fulfilled to qualify for a stage. • 200 to 300 percent increase = 2- to 3-fold increase. Δ Given wide variation in indications and timing of initiation of renal replacement therapy (RRT), individuals who receive RRT are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT.

AKI severity Kidney International Supplements (2012) 2, 8–12; doi: /kisup

TABLE 51-1. RIFLE and AKIN Classification Schemes for Acute Kidney Injurya

Epidemiology Uncommon condition in the community-dwelling generally healthy population (incidence 0.02%) Causes: dehydration, exposure to selected pharmacological agents, the presence of heart failure, trauma, rhabdomyolysis, vessel thrombosis and drugs. Incidence can rise up to 13% in individuals with existing chronic kidney disease (CKD) AKI is a significant risk factor for patients with CKD. Individuals with CKD are especially susceptible to AKI, which in turn acts as a promoter of progression of the underlying CKD. Between 5% and 25% of all hospitalized patients develop ARF. A greater prevalence of ARF is found in critically ill patients. Despite improvements in the medical care of individuals with ARF, mortality generally exceeds 50%. AKI occurs outside hospitals and is common on medical, surgical, pediatric, and oncology wards where it is a predictor of immediate and long-term poor outcomes of the underlying disease processes. AKI is more prevalent in and a significant risk factor for patients with chronic kidney disease (CKD). Individuals with CKD are especially susceptible to AKI, which in turn acts as a promoter of progression of the underlying CKD.

Incidence and outcomes of AKI relative to where it occurs
Community-Acquired Hospital-Acquired ICU-Acquired Incidence Low (<1%) Moderate (2%–5%) High (6%–23%) Cause Single Single or multiple Multifactorial Overall survival rate 70%-95% 30%-50% 10%-30% Worsened outcome if RRT required Poor preadmission health Other failed organ systems Ischemic ARF cause Intrinsic renal disease Ischemic AKI cause Septic Better outcome if Nonoliguric Nephrotoxic cause Prerenal cause Postrenal cause Hyperglycemia prevented To date there is a paucity of data on the incidence of AKI whether community or hospital-acquired. The reported prevalence of AKI from US data ranges from 1% (community-acquired) up to 7.1% (hospital-acquired) of all hospital admissions6,7. The population incidence of AKI from UK data ranges from 172 per million population (pmp) per year from early data8 up to pmp/year from more recent series9-11, again depending on definition. The incidence of AKI requiring renal replacement therapy (RRT) ranges from 22 pmp/year7 to 203 pmp/year10. An estimated 5–20% of critically ill patients experience an episode of AKI during the course of their illness and AKI receiving RRT has been reported in 4·9% of all admissions to intensive-care units (ICU)12. Data from the Intensive Care National Audit Research Centre (ICNARC) suggests that AKI accounts for nearly 10 percent of all ICU bed days13.

Prognosis In patients with AKI, the chances of renal recovery and survival depend on: the underlying etiology, the duration of AKI associated comorbidities. There is increasing recognition that AKI is associated with an increased risk of dying even after discharge from hospital. AKI due to ATN is usually reversible. However, several reports have highlighted an association between AKI and subsequent risk of developing CKD, even if the episode of AKI resolves and serum creatinine returns to baseline.

Risk Factors Risk factors for development of AKI Comorbidities Clinical conditions Drugs Advanced age Diabetes CKD Heart failure Liver failure Male gender Genetic factors Low albumin Arterial disease Myeloma Sepsis Hypotension/shock Volume depletion Rhabdomyolysis Cardiac/vascular surgery Non-renal solid organ transplant Hepatic/biliary surgery Contrast media Antibiotics Chemotherapy NSAID ACE inhibitor/ARB Several risk factors have been identified for the development of AKI (see box, above). Elderly patients and patients with pre-existing chronic kidney disease (CKD) are at particular risk. The causes are grouped into pre-renal (for example, hypovolaemia and/or relative hypotension), intrinsic renal (for example, damage of glomeruli, renal vasculature, tubules and/or interstitium) and post-renal (for example, obstruction to urinary flow). The most common cause of intrinsic AKI is acute tubular necrosis (ATN), which is usually multifactorial and often occurs in the context of an acute illness. The exact aetiology of AKI is not always obvious and occasionally more than one factor contributes to its development. The exact etiology of AKI is not always obvious and occasionally more than one factor contributes to its development.

Pathophysiology There are typically three categories of AKI:
Prerenal AKI Intrensic AKI Postrenal AKI The pathophysiologic mechanisms differ for each of the categories.

FIGURE Classification of acute kidney injury (AKI) based on etiology. (ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BPH, benign prostatic hyperplasia; GI, gastrointestinal; HTN, hypertension; HUS, hemolytic uremic syndrome; NSAIDs, nonsteroidal antiinflammatory drugs; TTP, thrombotic thrombocytopenic purpura.

Category Abnormality Causing Acute Renal Failure Possible Causes Prerenal Intravascular volume depletion resulting in arterial hypotension Dehydration, Inadequate fluid intake, Excessive vomiting, diarrhea or gastric suctioning, Increased insensible losses (e.g., fever, burns)., Diabetes insipidus, High serum glucose (glucosuria), Overdiuresis, Hemorrhage, Decreased cardiac output, Hypoalbuminemia, Liver disease, Nephrotic syndrome Arterial hypotension (regardless of volume status) Anaphylaxis, Sepsis, Excessive antihypertensive use, Decreased cardiac output Heart failure, Sepsis, Pulmonary hypertension, Aortic stenosis and other valvular abnormalities, Anesthetics Isolated renal hypoperfusion Bilateral renal artery stenosis (unilateral renal artery stenosis in solitary kidney), Emboli, cholesterol, thrombotic, medications ( cyclosporine, ACEI, NSAID) Radio contrast media, hypercalcemia, hepatorenal syndrome

Prerenal AKI characterized by reduced blood delivery to the kidney.
The integrity of the renal parenchyma is not disrupted. A common cause is intravascular volume depletion due to conditions such as hemorrhage, dehydration, or gastrointestinal fluid losses. Prompt correction of volume depletion can restore renal function to normal because no structural damage to the kidney has occurred. Conditions of reduced cardiac output (e.g., congestive heart failure or myocardial infarction) and hypotension can also reduce renal blood flow, resulting in decreased glomerular perfusion and prerenal AKI. the kidney initially compensates for the diminished perfusion to preserve filtration function. With a mild to moderate decrease in renal blood flow, intraglomerular pressure is maintained by dilation of afferent arterioles (arteries supplying blood to the glomerulus), constriction of efferent arterioles (arteries removing blood from the glomerulus), and redistribution of renal blood flow to the oxygen-sensitive renal medulla. When renal compensation is maximized and the conditions causing hypoperfusion remain uncorrected, renal compensation becomes decompensation, and AKI occurs. Prerenal disease is most commonly associated with an acute time course. However, among patients with chronic kidney disease, the addition of a prerenal process may result in acute renal dysfunction.

Compensatory hormonal mechanisms of decreased renal perfusion.

Prerenal AKI – cont’d Functional AKI occurs when these adaptive mechanisms are compromised and is often caused by drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs) impair prostaglandin-mediated dilation of afferent arterioles. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit angiotensin II–mediated efferent arteriole vasoconstriction. Cyclosporine and tacrolimus, especially in high doses, are potent renal vasoconstrictors. All of these agents can reduce intraglomerular pressure (glomerular hydrostatic pressure which is the driving force for the formation of ultrafiltrate), with a resultant decrease in GFR. Prompt discontinuation of the offending drug can often return renal function to normal. Other causes of prerenal AKI are renovascular obstruction (e.g., renal artery stenosis), hyperviscosity syndromes (e.g., multiple myeloma), or systemic vasoconstriction (e.g., hepatorenal syndrome). Prerenal AKI occurs in approximately 10% to 25% of patients diagnosed with AKI.

Bladder outlet obstruction
Category Abnormality Causing Acute Renal Failure Possible Causes Postrenal Bladder outlet obstruction Prostatic hypertrophy, infections cancer, Improperly placed bladder catheter, Anticholinergic medication Ureteral Cancer with abdominal mass, Retroperitoneal fibrosis, Nephrolithiasis, Renal pelvis or tubules oxalate, Indinavir, sulfonamides, Acyclovir , Uric acid

Postrenal AKI = obstructive uropathy
Postrenal AKI accounts for less than 10% of cases of AKI. Postrenal AKI is due to obstruction of urinary outflow anywhere from the renal pelvis to the urethra. The development of renal insufficiency in patients without intrinsic renal disease requires bilateral obstruction (or unilateral obstruction with a single functioning kidney) Causes include prostatic disease (hyperplasia or cancer), metastatic cancer, or precipitation of renal calculi. The time course can be acute or chronic. Rapid resolution of postrenal AKI without structural damage to the kidney can occur if the underlying obstruction is corrected.

Category Abnormality Causing Acute Renal Failure Possible Causes Intrinsic Vascular damage Vasculitis, Polyarteritis nodosa, hemolytic uremic syndrome-thrombotic-thrombocytopinc purpura, emboli, thrombotic, accelrated hypertension Glomerular damage Poststreptococcal glomerulonephritis, SLE, Antiglomerular basement membrane disease Acute tubular necrosis Ischemic, hypotension, vasoconstriction ,exogenous toxin , contrast dye, heavy metals, drugs( amphotricin B A.G), endogenous toxin, myoglobin, hemoglobin Acute interstitial nephritis Drugs (penicillins, ciprofloxacin,PHN ,sulfonamides) Infection (viral ,bacterial)

Intrarenal AKI = Intrinsic renal failure
Caused by diseases that can affect the integrity of the tubules, glomerulus, interstitium, or blood vessels. Damage is within the kidney; changes in kidney structure can be seen on microscopy. The most common cause of intrinsic renal failure is Acute Tubular Necrosis (ATN) and it accounts for approximately 50% of all cases of AKI. ATN represents a pathophysiologic condition that results from toxic (aminoglycosides, contrast agents, or amphotericin B) or ischemic insult to the kidney. ATN results in necrosis of the proximal tubule epithelium and basement membrane, decreased glomerular capillary permeability, and backleak of glomerular ﬁltrate into the venous circulation. Maintenance of ATN is mediated by intrarenal vasoconstriction. Glomerular, interstitial, and blood vessel diseases may also lead to intrinsic AKI, but occur with a much lower incidence. Examples include glomerulonephritis, systemic lupus erythematosus, interstitial nephritis, and vasculitis. In addition, prerenal AKI can progress to intrinsic AKI if the underlying condition is not promptly corrected. Vascular disease — The vascular diseases affecting the kidney can be divided into those that produce acute and chronic disease: The major acute renal vascular disease is probably vasculitis (eg, Wegener's granulomatosis). Less common etiologies include thromboembolic disease, hemolytic-uremic syndrome or thrombotic thrombocytopenic purpura (HUS/TTP), malignant hypertension, and scleroderma. (See "Renal manifestations of systemic vasculitis" and "Clinical characteristics of renal atheroemboli".) The major chronic renal vascular diseases are benign nephrosclerosis, unilateral or bilateral renal artery stenosis, and cholesterol atheroembolic disease. Glomerular disease — There are numerous idiopathic and secondary (due to neoplasia, autoimmunity, drugs, genetic abnormalities, and infections) disorders that produce glomerular disease. Two general patterns (with considerable overlap in some diseases) are seen (table 2): A nephritic pattern, which is associated with inflammation on histologic examination and produces an active urine sediment with red cells, white cells, granular and often red cell and other cellular casts, and a variable degree of proteinuria. A nephrotic pattern, which is not associated with inflammation on histologic examination and is associated with proteinuria, often in the nephrotic range, and an inactive urine sediment with few cells or casts. Both patterns can present with an acute or insidious time course, and elements of both may be also seen in some patients simultaneously or sequentially. (See "Differential diagnosis of glomerular disease".) Tubular and interstitial disease — As with vascular disease, the tubular and interstitial diseases affecting the kidney can be divided into those that produce acute and chronic disease: Hereditary, systemic, toxic, and drug-induced causes predominate. The most common acute tubulointerstitial disorders are acute tubular necrosis, which typically occurs in hospitalized patients, acute interstitial nephritis, which is often drug-induced, and cast nephropathy in multiple myeloma. Other causes that should be considered in the appropriate setting are acute phosphate nephropathy following a phosphate-containing bowel preparation prior to colonoscopy or surgery, and tumor lysis syndrome following chemotherapy The major chronic tubulointerstitial disorders are polycystic kidney disease, hypercalcemia, and autoimmune disorders (such as sarcoidosis and Sjögren's syndrome). Reflux nephropathy should be considered in children and young adults, medullary cystic kidney disease in families with a pattern of autosomal dominant inheritance, and nephrocalcinosis should be considered in patients with one of the known causes of this disorder, such as hypercalcemia.

Schematic of acute tubular necrosis (ATN)
Schematic of acute tubular necrosis (ATN). The process is initiated by ischemia or nephrotoxin exposure that leads to tubular cell death. The cellular debris sloughs off and obstructs the proximal tubule lumen. Once the nephron is obstructed, a backleak of the glomerular ultrafiltrate occurs across the tubular basement membrane and impairment of glomerular filtration. During the recovery phase of ATN, the obstructive cellular casts are released into the urine and filtration begins to normalize. GFR, glomerular filtration rate.

ARF is also clinically described as
All cases of AKI can be classified as prerenal, intrinsic (intrarenal), or postrenal. ARF is also clinically described as Oliguric Nonoliguric Anuric These categories help to establish cause and predict prognosis. Anuria is uncommon and suggests either complete obstruction or a major vascular event, such as bilateral renal infarction, renal vein thrombosis (RVT), cortical necrosis, or high-grade ischemic acute tubular necrosis (ATN). Prerenal, intrinsic renal, and postrenal AKI can each manifest with oliguria or nonoliguria. Nonoliguric ARF is common in intrarenal ARF (e.g., nephrotoxin-induced ATN, acute glomerulonephritis, acute interstitial nephritis). Oliguria more commonly characterizes obstruction and prerenal azotemia. Regardless of the cause of decreased kidney function, management is more difficult with oliguria, because volume overload occurs earlier in the course. Patients with nonoliguric ARF have a more favorable prognosis and reduced mortality rates. Three distinct phases of ARF exist. The oliguric phase generally occurs over 1 to 2 days and is characterized by a progressive decrease in urine production. Urine production of <400 mL/day is termed oliguria, urine production of <50 mL/day is termed anuria. The oliguric stage may last from days to several weeks. Nonoliguric renal failure (>400 mL/day of urine output) carries a better prognosis compared with oliguric renal failure, although the exact reason remains unknown. Similarly, the shorter the duration of oliguria, the higher the likelihood of successful recovery. This is probably because the renal insults in these cases are less severe (e.g., dehydration, nephrotoxin exposure, postrenal obstruction). Strict fluid and electrolyte monitoring and management are required during this phase until renal function normalizes. The diuretic phase: a period of increased urine production occurs over several days; This phase signals the initial repair of the kidney insult. The diuretic phase can result, in part, from a return to normal GFR before tubular reabsorptive capacity has fully recovered. The elevated osmotic load from uremic toxins and the increased fluid volume retained during the oliguric phase may also contribute to the diuretic phase. Despite the increased urine production, patients may remain markedly azotemic for several days. Daily modifications in the fluid and electrolyte requirements are necessary based on urine output. The recovery phase occurs over several weeks to months, depending on the severity of the patient's ARF. This phase signals the return to the patient's baseline kidney function, normalization of urine production, and the return of the diluting and concentrating abilities of the kidneys.

Drug Induced AKI - Homework
Discuss the mechanism of nephrotoxicity of the following drugs: Aminoglycosides Amphotericin B Radiocontrast media Cyclosporine and Tacrolimus Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Non-steroidal Anti-Inflammatory Drugs

Is the ARF drug-induced?
Ischemia: diuretics, Nsaids, ACEI, Cyclosporine, CIN Inflammation sclerosis See Texas lectures

Renal Inflammation • Usually slower onset (weeks) than ARF due to ischemia (days) • Sites of inflammation: glomerulus, interstitium, tubular cells • Signs: fever, fatigue, protein and blood in urine, eosinophilia, MP rash, Drug-induced glomerulonephritis: extremely rare; described with gold, penicillamine interstitial nephritis: rare, but more frequently drug-induced; antibiotics (rifampin!), analgesics most frequent cause; has been reported w/PPIs

Tubular Cell Sclerosis • Direct damage of tubular cell elements, via disruption of cell organelles or interference with enzyme function Signs: subclinical; gradual rise in SCr, BUN; UA will have lots of epithelial cells, sometimes protein, WBCs AG, CP, VM

TABLE 55-1. Drug-Induced Renal Structural-Functional Alterations and Examples

TABLE 55-2. Potential Risk Factors for Aminoglycoside Nephrotoxicity

FIGURE 55-2. Glomerular autoregulation during “prerenal” states (i. e
FIGURE Glomerular autoregulation during “prerenal” states (i.e., reduced blood flow). (A II, angiotensin II; GFR, glomerular filtration rate; PGE, prostaglandin E; RBF, renal blood flow.)

FIGURE Pathogenesis of angiotensin-converting enzyme inhibitor (ACEI) nephropathy. (A II, angiotensin II; GFR, glomerular filtration rate; PGE, prostaglandin E; RBF, renal blood flow.)

TABLE 55-4. Drugs Associated with Allergic Interstitial Nephritis

CLINICAL SYNDROME CAUSATIVE AGENTS Acute renal failure Prerenal or hemodynamic Cyclosporine, tacrolimus, radiocontrast, amphotericin B, ACE inhibitors, ARBs NSAIDs, interleukin 2 Intrarenal failure Acute tubular necrosis Aminoglycosides, amphotericin B, cisplatin, certain cephalosporins Acute intterstitial nephritis Penicillins, cephalosporins, sulfonamides, rifampin, NSAIDs, interferon, interleukin 2 Postrenal or obstructive Acyclovir, analgesic abuse, methysergide, methotrexate, indinavir, sulfadiazine Chronic kidney disease Lithium, analgesic abuse, cyclosporin, tacrolimus, cisplatin, nitrosourea Nephrotic syndrome Gold, NSAIDs, penicillamine, captopril, interferon

Clinical Presentation and Diagnosis
Some clinical and laboratory findings assist in the general diagnosis of AKI, others are used to differentiate between prerenal, intrinsic, and postrenal AKI For example, patients with prerenal AKI typically demonstrate enhanced sodium reabsorption, which is reflected by a low urine sodium concentration and a low fractional excretion of sodium. Urine is typically more concentrated with prerenal AKI and there is a higher urine osmolality and urine:plasma creatinine ratio compared to intrinsic and postrenal AKI. The cause of ARF can be determined, in most cases, by following an algorithm that focuses on the patient’s history, physical examination, urinalysis findings, basic laboratory results, and in some instances, radiologic imaging of the kidneys and determination of the urine sodium level and fractional excretion of sodium (FENa) and urea (FEUN).

Presenting manifestations
Patients with renal disease may present in a variety of ways: Signs and symptoms resulting directly from alterations in kidney function, including decreased or no urine output, flank pain, edema, hypertension, or discolored urine. Laboratory findings, including elevations in the plasma creatinine concentration, hyperkalemia, and an abnormal urinalysis. Symptoms and/or signs of renal failure, including weakness and easy fatiguability (from anemia), anorexia, vomiting, mental status changes or seizures, and edema. Systemic symptoms and findings, such as fever, arthralgias, and pulmonary lesions, suggestive of a concurrent systemic disease, such as vasculitis. Incidental findings (eg, renal cyst or mass) on radiographic testing performed for some other reason.

Signs and Symptoms of Uremia
Peripheral edema Weight gain Nausea/vomiting/diarrhea/anorexia Mental status changes Fatigue Shortness of breath Pruritus Volume depletion (prerenal AKI) Weight loss (prerenal AKI) Anuria alternating with polyuria (postrenal AKI) Colicky abdominal pain radiating from flank to groin (postrenal AKI) Symptoms Patients may be asymptomatic during the early stages of AKI, which may delay the diagnosis. If patients develop symptoms, they usually have non-specific complaints, such as nausea, tiredness, lack of appetite and possibly breathlessness. These symptoms often mimic other less serious conditions, which again may delay the diagnosis, especially in the community. In some cases, patients may develop symptoms and signs which point towards a potential aetiology, for instance flank pain in the case of underlying ureteric obstruction, or a rash with myalgia and eye changes as a result of an underlying connective tissue disease or systemic vasculitis. Once AKI is diagnosed, investigations should focus on identifying the aetiology and ruling out complications of AKI (see box, below). As recommended by the NCEPOD report, all hospitalised patients with AKI should have a renal ultrasound within 24 hours to exclude underlying obstruction.

Physical Examination Findings
Hypertension Jugular venous distention Pulmonary edema Rales Asterixis Pericardial or pleural friction rub Hypotension/orthostatic hypotension (prerenal AKI) Rash (acute interstitial nephritis) Bladder distention (postrenal bladder outlet obstruction) Prostatic enlargement (postrenal AKI) Asterixis (also called the flapping tremor, or liver flap) is a tremor of the wrist when the wrist is extended (dorsiflexion), sometimes said to resemble a bird flapping its wings.

Physical Examination Findings in AKI
Bruit (pronounced /ˈbruːt/, or as French [bʁɥi]) is the term for the unusual sound that blood makes when it rushes past an obstruction (called turbulent flow) in an artery when the sound is auscultated with the bell portion of a stethoscope. Janeway lesions are non-tender, small erythematous or haemorrhagic macular or nodular lesions on the palms or soles only a few millimeters in diameter that are pathognomonic of infective endocarditis Splinter hemorrhages (or haemorrhages) are tiny lines that run vertically under nails. Splinter hemorrhage is a nonspecific finding and can be associated with subacute bacterial endocarditis, scleroderma, trichinosis, Systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic nails[1], antiphospholipid syndrome[2]:659, and trauma.[3] Roth's spots are retinal hemorrhages with white or pale centers composed of coagulated fibrin. They are typically observed via fundoscopy (using an ophthalmoscope to view inside the eye) or slit lamp exam. They are usually caused by immune complex mediated vasculitis often resulting from bacterial endocarditis. Roth's spots may be observed in leukemia, diabetes, subacute bacterial endocarditis, pernicious anaemia, ischemic events, and rarely in HIV retinopathy. A Hollenhorst plaque AKA "Eickenhorst plaque" is a cholesterol embolus that is seen in a blood vessel of the retina.

Diagnostic work-up of patients with AKI
Investigations Comments To be performed during initial assessment in primary care Urinalysis Presence of blood, protein and red cell casts suggest a glomerular cause; eosinophils suggest an interstitial nephritis. Serum creatinine and UAEs To diagnose degree of AKI and electrolyte disturbances. FBC and blood film Red cell fragments and thrombocytopaenia support the diagnosis of thrombotic microangiopathy; eosinophilia may be present with interstitial nephritis. CRP May be elevated in inflammatory diseases and/or infections.

Laboratory Tests Elevated serum creatinine concentration
(normal range approximately 0.6 to 1.2 mg/dL [53 to 106 µmol/L]) Elevated BUN concentration (normal range approximately 8 to 25 mg/dL [2.9 to 8.9 mmol/L]) Decreased creatinine clearance (normal 90 to 120 mL/minute) BUN:creatinine ratio (elevated in prerenal AKI) Greater than 20:1 (prerenal AKI) Less than 20:1 (intrinsic or postrenal AKI) Hyperkalemia Metabolic acidosis AKI usually develops over hours to days and leads to an abrupt rise in serum urea and creatinine levels, electrolyte disturbances and metabolic acidosis. Urine output can be preserved but is often reduced. Despite the fact that serum creatinine is affected by several non-renal factors, such as muscle bulk and gender, and takes 24 to 48 hours to rise after the initial renal insult, it remains the traditionally used parameter to diagnose AKI. However, newer AKI biomarkers are being investigated and validated in clinical trials. The formula to estimate eGFR is based on observations in patients with stable CKD. eGFR has never been validated in patients with acute and rapid changes in renal function, and should only be used in situations where renal function is stable. At present, the AKI Network classification is commonly used to diagnose AKI. It relies on knowing baseline renal function, which means it is important to look at previous results in order to differentiate AKI from pre-existing CKD.

Urinalysis Urine Indices Sediment
Scant or bland (prerenal or postrenal AKI) Brown, muddy granular casts (highly indicative of ATN) Proteinuria (glomerulonephritis or allergic interstitial nephritis) Eosinophiluria (acute interstitial nephritis) Hematuria/red blood cell casts (glomerular disease or bleeding in urinary tract) White blood cells or casts (acute interstitial nephritis or severe pyelonephritis)

TYPE OF ACUTE KIDNEY INJURY BUN-TO-CREATININE RATIO
Results of urinalysis and sodium, urea, blood urea nitrogen, and creatinine measurements in acute kidney injury TYPE OF ACUTE KIDNEY INJURY URINALYSIS Una (mEq/L) FENa (%) FEUN BUN-TO-CREATININE RATIO Prerenal High specific gravity <20 <1 ≤35 ≥20:1 Normal or hyaline casts Intrarenal Acute tubular necrosis Low specific gravity >40 ≥1 >50 ≤20:1 Muddy brown casts Renal tubular epithelial cells Vascular disorders Normal or hematuria >20 Variable Glomerulonephritis Proteinuria, hematuria RBC casts, dysmorphic RBCs Interstitial nephritis Mild proteinuria, hematuria WBCs, WBC casts, eosinophils Postrenal WBCs, occasional granular casts

Using the history and physical examination as tools to categorize acute kidney injury
TYPE OF ACUTE KIDNEY INJURY HISTORY PHYSICAL EXAMINATION Prerenal Volume loss (e.g., vomiting, diarrhea, diuretics, burns) Weight, supine and standing blood pressure and pulse Past weights, daily intake and output values Cardiac disease, liver disease Mucous membranes, axillary moisture Thirst Neck veins, S3 heart sound, lung examination, edema Medications (e.g., NSAIDs, ACE inhibitors, ARBs, cyclosporine) Radiographic contrast (e.g., CT, angiography) Intrarenal ATN Medications (e.g., aminoglycosides) Neck veins, S3 heart sound, lung examination, edema, volume status Alcohol abuse, trauma, muscle necrosis (e.g., rhabdomyolysis) Compartment syndrome, examination of extremities Hypotension episode

TYPE OF ACUTE RENAL FAILURE
HISTORY PHYSICAL EXAMINATION Vascular Trauma, known nephrotic syndrome, flank pain Blood pressure, livedo reticularis Vessel catheterization, anticoagulation (e.g., atheroemboli) Funduscopic examination (e.g., malignant hypertension) Progressive systemic sclerosis Thickened skin, sclerodactyly, telangiectasia Glomerular Systemic disease (e.g., SLE, vasculitis), arthritis, rash Oral ulcers, arthritis, skin lesions, footdrop Uveitis, weight loss, fatigue, intravenous drug use (e.g., hepatitis C) Pleural and pericardial rubs Cough, hemoptysis (e.g., Goodpasture’s syndrome), foamy urine Periorbital, leg, and presacral edema Interstitial Medications (e.g., antibiotics, PPIs, allopurinol, phenytoin) Fever, drug-related rash Arthralgias Postrenal Urinary urgency, hesitancy, gross hematuria Bladder distention, pelvic masses, prostate Intermittent polyuria, history of stones Medications (e.g., indinavir, acyclovir, anticholinergics)

Diagnostic parameters for differentiating causes of AKI
Evidence of preserved renal functional ability and the kidney’s attempt to compensate for the reduced perfusion in prerenal states is the maximum tubular sodium resorption that occurs and is reflected in a low urine sodium level (<20 mEq/L) or low FENa(<1%) or FEUN (<35%), or both. The FENa is a quantitative measure of the fraction of filtered sodium that is excreted and is not influenced by changes in water resorption that can affect the simple urine sodium concentration. The filtered sodium is the product of the GFR (estimated by creatinine clearance) and the concentration of plasma sodium. Therefore, using Ux for the urinary concentration of any substance x, Px for the plasma concentration of x, and V for urine volume, FENa is defined as follows:

Common Diagnostic Procedures
Urinary catheterization (insertion of a catheter into a patient’s bladder; an increase in urine output may occur with postrenal obstruction) Renal ultrasound (uses sound waves to assess size, position, and abnormalities of the kidney; dilatation of the urinary tract can be seen with postrenal AKI) Renal angiography (administration of intravenous contrast dye to assess the vasculature of the kidney) Retrograde pyelography (injection of contrast dye into the ureters to assess the kidney and collection system) Kidney biopsy (collection of a tissue sample of the kidney for the purpose of microscopic evaluation; may aid in the diagnosis of glomerular and interstitial diseases)

Radiologic studies and Renal biopsy
A number of radiologic studies are used to evaluate the patient with renal disease. They are principally required to assess urinary tract obstruction, kidney stones, renal cyst or mass, disorders with characteristic radiographic findings, renal vascular diseases, and, in children and young adults, vesicoureteral reflux. Renal ultrasonography – most commonly used radiologic technique Helical CT scan – generally preferred with patients with flank pain and possible urolithiasis. Magnetic resonance imaging – useful for the assessment of obstruction, malignancy and renovascular disease. A renal biopsy is most commonly obtained in patients with suspected glomerulonephritis or vasculitis and in those with otherwise unexplained acute or subacute renal failure.

Treatment of AKI Once AKI has developed, a detailed medical history and thorough clinical examination are essential. Independent of the cause of AKI, patients should undergo correction of volume depletion, optimisation of haemodynamics, timely treatment of sepsis, discontinuation of any nephrotoxic drugs where possible and exclusion of underlying obstruction. There is no specific pharmacological therapy proven to effectively treat AKI. However, certain types of AKI may respond to treatment of the underlying disease, for example, decompressive procedures for acute obstruction, immunosuppression for systemic vasculitis or crescentic glomerulonephritis, and plasma exchange for pulmonary renal syndrome. Attention to detail and regular re-assessment of the patient are essential to detect signs of progressive AKI and development of life-threatening complications, including hyperkalaemia, severe acidosis, fluid overload and uraemic pericarditis. Ideally, renal replacement therapy with haemodialysis or haemofiltration should be started before the onset of potentially fatal complications.

Desired Outcomes and Goals
A primary goal of therapy is ameliorating any identifiable underlying causes of AKI such as hypovolemia, nephrotoxic drug administration, or ureter obstruction. Prerenal and postrenal AKI can be reversed if the underlying problem is promptly identified and corrected, while treatment of intrinsic renal failure is more supportive in nature. There is no evidence that drug therapy hastens patient recovery in AKI, decreases length of hospitalization, or improves survival. It is important to keep in mind that AKI affects the function of other organs. Patients have an increased risk of gastritis and increased bleeding tendency as a result of platelet dysfunction. The pharmacokinetics of several drugs may be altered, and the risk of acquiring new infections is increased. The evaluation and initial management of patients with acute kidney injury (AKI) should include: an assessment of the contributing causes of the kidney injury, an assessment of the clinical course including comorbidities, a careful assessment of volume status, the institution of appropriate therapeutic measures designed to reverse or prevent worsening of functional or structural kidney abnormalities.

The evaluation and initial management of patients with acute kidney injury (AKI) should include:
an assessment of the contributing causes of the kidney injury, an assessment of the clinical course including comorbidities, a careful assessment of volume status, the institution of appropriate therapeutic measures designed to reverse or prevent worsening of functional or structural kidney abnormalities.

Things you will be asked about or will need to watch for in practice:
• How can ARF be prevented? • Is the ARF drug-induced? • How should ARF be treated? • How should drugs be dosed in ARF?

Prevention of AKI The best preventive measure for AKI, especially in individuals at high risk, is to avoid medications that are known to precipitate AKI. Nephrotoxicity is a signiﬁcant side effect of aminoglycosides, angiotensin- converting enzyme inhibitors, angiotensin receptor antagonists, amphotericin B, nonsteroidal anti-inﬂammatory drugs, cyclosporine, tacrolimus, and radiographic contrast agents. Unfortunately, an effective, non-nephrotoxic alternative may not always be appropriate for a given patient and the risks and benefits of selecting a drug with nephrotoxic potential must be considered. For example, serious gram-negative infections may require double antibiotic coverage, and based on culture and sensitivity reports, aminoglycoside therapy may be necessary. In cases such as this, other measures to reduce the risk of AKI should be instituted. Thus, identifying patients at high risk for development of AKI and implementing preventive methods to decrease its occurrence or severity is critical. Prevention of AKI is important, especially in high-risk and elderly patients. Preventive strategies include avoidance of nephrotoxic drugs, including contrast media, and timely resuscitation of patients suffering from sepsis and/or hypovolaemia. Diuretics have no role in preventing AKI.

TABLE 51-7. Prevention of Acute Kidney Injury

FIGURE 55-3. Recommended Interventions for Prevention of Contrast Nephrotoxicity

Prevention of AKI (KDIGO 2012)

Is the ARF drug-induced?
Drug list: if drug-induced, remember to remove offending agent until urine flow is re-established.

How should ARF be treated?
options are limited to: 1. prevention of adverse drug reactions by discontinuing nephrotoxic drugs/treat cause 2. adjustment of drug dosages based on the patient’s renal function is desired. 3. supportive therapy, such as fluid, 4. electrolyte, and nutritional support, 5. renal replacement therapy (RRT), 6. treatment of non-renal complications such as sepsis and gastrointestinal bleeding while regeneration of the renal epithelium occurs.

How should ARF be treated?
What to check: . Volume status • BP. hydration is key when BP low; avoid diuretics until BP normalized. Symptomatic orthostasis is a systolic drop of 30 or a diastolic drop of 10 and indicates moderate to severe volume depletion in patients not on a rate controller. Patients on a rate controller can be orthostatic with smaller volume loss. • HR: an increase in heart rate with little change in blood pressure can indicate mild dehydration. Symptomatic tachycardia will indicate at least moderate dehydration. HR inc 30 • Weight. In mild volume depletion, 2-3% body weight lost. In moderate-severe volume loss, ≥ 5 % body weight lost. BUN:Cr ratio. A BUN:serum creatinine ratio of ≥ 20:1 indicates at least moderate volume depletion . •

Volume depletion • oral rehydration. Mild volume depletion can usually be treated with oral rehydration: juice or sports drink if only dehydration • intravenous rehydration. Patients with moderate volume loss, can be treated with NS at mL/hr (usually 1-2 Liters are enough) until BP, urine flow re-establishes ,HR normal, then D5 1/2NS at 75 or 80 mL/hr) until output balances input. For severe volume depletion (e.g., pt shocky) 200ml/hr until urine flow begins to reestablish (target 0.5ml/kg/hr), then match input to output. Only switch to D5 1/2NS when BP and HR normal. Monitor BP, HR, wt, urine output, edema, chem.7.

Treating damage due to postrenal obstruction
– usually treated by waiting, NSAIDs, and collecting urine – once stone type ID’d, can avoid dietary risk Factors

Other Therapies Loop diuretics Dopamine Fenoldopam
Diuretics and vasodilators are used commonly to treat acute renal failure (ARF). Unfortunately, in large randomized studies, these agents have failed to prove effective. Atrial natriuretic factor also has been tested in a randomized double-blind study in ARF but failed to improve the course of ARF. Calcium channel blockers have been shown in animal models to be protective in ARF if given before renal insult. Their only benefit in humans is preventing ARF in renal transplant patients receiving cyclosporine. Infusion of mannitol is reported to be protective of myoglobinuric ARF if given within 6 hours of rhabdomyolysis. In addition, mannitol infusion has been shown to decrease the rate of ARF if given before cardiothoracic surgery and radiocontrast agents. No controlled studies have shown any benefit to mannitol infusion in patients with established ARF. In fact, mannitol given in high doses has been associated with ARF. Significant risks of prescribing large doses of mannitol to patients with ARF include fluid overload and hyperkalemia. Pharmacological Treatment of AKI Pharmacological interventions in AKI have targeted the prevention of renal ischemia or modulation of the ensuing inflammatory or hormonal milieus. Low-dose dopamine, historically thought to improve renal perfusion and thus prevent AKI, has recently been shown in a meta-analysis to have no effect on mortality and RRT requirement [12]. Similarly, atrial natriuretic peptide (ANP), a vasoactive endogenous hormone that increases glomerular filtration by dilating afferent and constricting efferent arterioles, was felt to be a promising therapeutic option. Anaritide, an ANP analogue, was initially shown to have no effect on dialysis-free survival and caused increased rates of hypotension in a randomized controlled trial (RCT) of AKI of variable etiology when given at a dose of 200 ng/kg/min [13]. However, in a small randomized study of 59 postcardiac surgery patients with AKI, anaritide at a lower dose (50 ng/kg/min) was found to significantly increase the rate of 21-day dialysis-free survival [14]. A recent meta-analysis of 19 different RCTs showed a trend towards reduction of RRT requirement when ANP was used in the prevention of AKI, however an overall increase in mortality was observed when ANP was used in the treatment of established AKI (particularly with higher doses) [15]. Recombinant human insulin-like growth factor 1 showed encouraging results at reducing renal tubular apoptosis and inflammation in mice when administered immediately after renal ischemia [16]. In a small RCT of 72 critically ill patients with AKI, insulin-like growth factor 1 failed to show any benefit [17]. More recently, N-acetylcysteine and sodium bicarbonate have received a great deal of attention in the setting of contrast nephropathy and postcardiac surgery AKI prevention [18, 19]. The clinical benefits of these interventions remain controversial. There are a number of other agents in preclinical studies that show promise in the prevention or early treatment of AKI. However, the efficacy of these therapies in clinical practice may depend on the early identification of AKI [20].

Management of fluid overload in AKI
Loop diuretics are the diuretics of choice for the management of volume overload in AKI. Thiazide diuretics, when used as single agents, are generally not effective for fluid removal when creatinine clearance is less than 30 mL/minute. Mannitol is also not recommended for the treatment of volume overload associated with AKI. Mannitol is removed by the body by glomerular filtration. In patients with renal dysfunction, mannitol excretion is decreased, resulting in expanded blood volume and hyperosmolality. Potassium-sparing diuretics, which inhibit sodium reabsorption in the distal nephron and collecting duct, are not sufficiently effective in removing fluid. In addition, they increase the risk of hyperkalemia in patients already at risk. Diuretics Patients with nonoliguric (rather than oliguric) ARF have better mortality and renal recovery rates, prompting many to recommend diuretics in oliguric ARF. Unfortunately, randomized double-blind controlled trials fail to show benefit. Studies conclude that diuretics are useful only in management of fluid-overloaded patients and venodilators and dialysis are more effective interventions for this indication. diuretics only if blood pressure is normal or elevated and if it is likely that the patient is not volume-depleted; beware of the patient who is intravascularly hypovolemic due to 3rd-spacing.  Loop diuretics will increase diuresis but have not been shown to alter clinical outcomes e.g., progression to CRF, mortality (Nephrol Dial Transplant 1997;12:2592); one large observational study noted no increase in risk of mortality (Crit Care Med 2004;32:1669), while another showed diuretics were detrimental (JAMA 2002;288:2547). Volume repletion not considered as a confounder in multivariate model.  Use diuretics VERY cautiously in patients with ESLD. Hepatorenal syndrome very hard to treat.

Loop diuretics There is significant controversy over the role of loop diuretics in the treatment of AKI. Theoretical benefits in hastening recovery of renal function include: decreased metabolic oxygen requirements of the kidney, increased resistance to ischemia, increased urine flow rates that reduce intraluminal obstruction and filtrate backleak, renal vasodilation. Theoretically, these effects could lead to: increased urine output, decreased need for dialysis, improved renal recovery, increased survival. Most studies demonstrate an improvement in urine output, but with no effect on survival or need for dialysis. There are some reports that loop diuretics may worsen renal function. This may be due in part to excessive preload reduction that results in renal vasoconstriction. Thus, loop diuretics are limited to instances of volume overload and edema and are not intended to hasten renal recovery or improve survival. diuretics only if blood pressure is normal or elevated and if it is likely that the patient is not volume-depleted; beware of the patient who is intravascularly hypovolemic due to 3rd-spacing.  Loop diuretics will increase diuresis but have not been shown to alter clinical outcomes e.g., progression to CRF, mortality (Nephrol Dial Transplant 1997;12:2592); one large observational study noted no increase in risk of mortality (Crit Care Med 2004;32:1669), while another showed diuretics were detrimental (JAMA 2002;288:2547). Volume repletion not considered as a confounder in multivariate model.  Use diuretics VERY cautiously in patients with ESLD. Hepatorenal syndrome very hard to treat.

Loop diuretics – the agents
furosemide, bumetanide, torsemide, and ethacrynic acid all equally effective when given in equivalent doses  Patients will not benefit from switching from one loop diuretic to another (similar MOA) A usual starting dose of IV furosemide for the treatment of AKI is 40 mg. Reasonable starting doses for bumetanide and torsemide are 1 mg and 20 mg, respectively. selection is based on the side-effect profile, cost, and pharmacokinetics of the agents. Cost: Furosemide and bumetanide are both available in generic formulations and are generally less expensive than torsemide. Side effects: The incidence of ototoxicity is significantly higher with ethacrynic acid compared to the other loop diuretics; therefore, its use is limited to patients who are allergic to the sulfa component in the other loop diuretics. While ototoxicity is a well-established side effect of furosemide, its incidence is greater when administered by the intravenous route at a rate exceeding 4 mg per minute. Torsemide has not been reported to cause ototoxicity.

There are several pharmacokinetic differences between loop diuretics.
50-60% of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.  patients with AKI may have a prolonged half-life of furosemide. liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The intravenous (IV):oral ratio for bumetanide and torsemide is 1:1, bioavailability of oral furosemide is approximately 50%, with a reported range of 10% to 100%. Pharmacodynamic properties The pharmacodynamic characteristics of loop diuretics are similar when equivalent doses are administered. Because loop diuretics exert their effect from the luminal side of the nephron, urinary excretion correlates with diuretic response. Substances that interfere with the organic acid pathway, such as endogenous organic acids which accumulate in renal disease, competitively inhibit secretion of loop diuretics. Therefore, large doses of loop diuretics may be required to ensure that adequate drug reaches the nephron lumen. loop diuretics have a ceiling effect where maximal natriuresis occurs. Thus, very large doses of furosemide (e.g., 1 g) are generally not considered necessary and may unnecessarily increase the risk of ototoxicity.

Loop diuretics – Diuretic resistance
Several adaptive mechanisms by the kidney limit effectiveness of loop diuretic therapy. As the concentration of diuretic in the loop of Henle decreases, postdiuretic sodium retention occurs. This effect can be minimized by decreasing the dosage interval or by administering a continuous infusion (easier). Prolonged administration  enhanced delivery of sodium to the distal tubule  hypertrophy of distal convoluted cells  increased sodium chloride absorption occurs in the distal tubule which diminishes the effect of the loop diuretic on sodium excretion. Addition of a distal convoluted tubule diuretic, such as metolazone or hydrochlorothiazide, to a loop diuretic can result in a synergistic increase in urine output.

Loop diuretics – Monitoring
Efficacy of diuretic administration can be determined by comparison of a patient’s hourly fluid balance. Other methods to minimize volume overload, such as fluid restriction and concentration of IV medications, should be initiated as needed. If urine output does not increase to about 1 mL/kg per hour, the dosage can be increased to a maximum of 160 to 200 mg of furosemide or its equivalent. Other methods to improve diuresis can be initiated sequentially, such as: shortening the dosage interval; adding hydrochlorothiazide or metolazone; switching to a continuous infusion loop diuretic. A loading dose should be administered prior to both initiating a continuous infusion and increasing the infusion rate. When high doses of loop diuretics are administered, especially in combination with distal convoluted tubule diuretics, the hemodynamic and fluid status of the patient should be monitored every shift, and the electrolyte status of the patient should be monitored at least daily to prevent profound diuresis and electrolyte abnormalities, such as hypokalemia.

Algorithm for treatment of extracellular fluid expansion

Algorithm for treatment of extracellular fluid expansion
Cont’d from previous slide

Dopamine Low-dose dopamine, in doses ranging from 0.5 to 3 mcg/kg per minute, predominantly stimulates dopamine-1 receptors, leading to renal vascular vasodilation and increased renal blood flow. While this effect has been substantiated in healthy, euvolemic individuals with normal kidney function, a lack of efficacy data exists in patients with AKI. Low-dose dopamine is not without adverse reactions and most studies have failed to evaluate its potential toxicities (What are these adverse reactions). Based on the results of the ANZICS trial, the lack of conclusive evidence in many earlier studies, and several meta-analyses, routine use of low-dose dopamine solely for increasing renal blood flow is not recommended. While recent surveys continue to show that low-dose dopamine is used in many ICUs, benefits of low-dose dopamine in the prevention or treatment of AKI remain unproven. Vasodilators Renal vascular vasodilators in ARF make a great deal of sense from theoretical and experimental viewpoints. However, effective blood-volume restoration is the best physiologic vasodilator. Low-dose dopamine is a potent vasodilator, increasing RBF in ARF. Unfortunately, most clinical studies fail to show that it improves recovery or mortality rates. In the majority of ARF studies, dopamine was associated only with an increase in urine output. Current recommendations for dopamine favor its use in patients with ARF and concomitant hypodynamic heart failure. Balance benefits of diuretic action with proarrhythmic side effects. The most comprehensive study evaluating the efficacy of low-dose dopamine to date is the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group study. Low-dose dopamine was compared to placebo in critically ill patients with at least one indicator of early renal failure and two indicators of the systemic inflammatory response. Results indicate that administration of low-dose dopamine compared to placebo did not alter peak serum creatinine concentration or secondary outcome endpoints such as need for renal replacement therapy (RRT), duration of stay in the intensive care unit (ICU), or survival to hospital discharge. Use of loop diuretics was similar between groups and may have been responsible for the increase in urine output demonstrated in the study. More than half of the patients in the study were non-oliguric. Therefore, the results cannot be directly extrapolated to the oliguric or anuric patient. A recent meta-analysis was performed on all published human trials that used low-dose dopamine in the prevention or treatment of AKI. A total of 61 studies were identified that randomized more than 3300 patients to low-dose dopamine or placebo. Results reveal no significant difference between the treatment and control groups for mortality, requirement for RRT, or adverse effects. Adverse reactions include: tachycardia, arrhythmias, myocardial ischemia, depressed respiratory drive, and gut ischemia. Low dose dopamine has also been postulated to impair resistance to infection through a reduction in prolactin concentrations. Furthermore, significant overlap in receptor activation occurs. Therefore, doses considered to activate only dopamine receptors may increase cardiac output and blood pressure through dopamine’s effect on ß- or α-adrenergic receptors.

Fenoldopam Fenoldopam is a selective dopamine-1 receptor agonist that is approved for short-term management of severe hypertension. Because it does not stimulate dopamine-2, α-adrenergic, and ß-adrenergic receptors, fenoldopam causes vasodilation in the renal vasculature with potentially fewer non-renal effects than dopamine. In normotensive individuals with normal kidney function, intravenous fenoldopam increases renal blood flow without lowering systemic blood pressure. Few studies are available assessing its effectiveness in the treatment of AKI. A prospective randomized study comparing fenoldopam to placebo in early ATN did not find a difference in need for dialysis or mortality. However, in two separate subset analyses, patients with ATN after cardiothoracic surgery and patients without diabetes mellitus demonstrated a decreased incidence of death or dialysis in the fenoldopam treated group. Large, prospective trials are needed before fenoldopam can be recommended. Other agents that are under evaluation for the treatment of AKI include atrial natriuretic peptide, urodilatin, and nesiritide. Renal Vasodilator Fenoldopam is a potent dopamine A-1 receptor agonist that increases blood flow to the renal cortex and outer medulla and evidence to date suggests that it reduces mortality and provides renal protection in critically ill patients with or at risk of renal failure. Because it is titratable and it reliably controls severe hypertension, fenoldopam may be ideal for treating hypertensive emergencies where the affected end organ is the kidneys.

Nonpharmacologic Therapy
Renal Replacement Therapy Supportive Therapy

Supportive therapy Supportive therapy – includes: adequate nutrition,
correction of electrolyte and acid-base abnormalities (particularly hyperkalemia and metabolic acidosis), fluid management, correction of any hematologic abnormalities. because AKI is often associated with multiorgan failure, treatment includes the medical management of infections, cardiovascular and gastrointestinal conditions, and respiratory failure. all drugs should be reviewed, and dosage adjustments made based on an estimate of the patient’s glomerular filtration rate. TABLE 37-1 -- Nondialytic Management of Acute Kidney Injury Treat or reverse underlying causes of acute kidney injury. Achieve and maintain normal hemodynamics and euvolemia, avoiding hypovolemia and prerenal states. Adjust medication dosages and frequency for level of kidney function. Avoid nephrotoxic agents if possible, including aminoglycosides, radiocontrast, NSAIDs, ACE inhibitors, and angiotensin receptor blockers. Provide adjuvant therapy, including antibiotics, mechanical ventilation, enteral or parenteral nutrition, intensive insulin therapy, and adrenal corticosteroid replacement as indicated. Enlist the assistance of nephrologists and intensivists for supportive care and to determine the need for and timing of renal replacement therapy.

Supportive therapy (KIDGO 2012)

Renal replacement therapy (RRT)
RRT may be necessary in patients with established AKI to treat volume overload that is unresponsive to diuretics, to minimize the accumulation of nitrogenous waste products, correct electrolyte and acid-base abnormalities while renal function recovers. There are two types of dialysis modalities commonly used in AKI: intermittent hemodialysis (IHD) continuous renal replacement therapy (CRRT). Indications for dialysis therapy — Accepted indications for dialysis in patients with AKI generally include: Fluid overload that is refractory to diuretics. Hyperkalemia (serum potassium concentration >6.5 meq/L) or rapidly rising potassium levels, refractory to medical therapy. Metabolic acidosis (pH less than 7.1) in patients in whom the administration of bicarbonate is not indicated, such as those with volume overload (who would not tolerate the obligate sodium load), or those with lactic acidosis or ketoacidosis in whom bicarbonate administration has not been shown to be effective. Signs of uremia, such as pericarditis, neuropathy, or an otherwise unexplained decline in mental status.

RTT Life-threatening changes: hyperkalemia, acidemia, pulmonary edema and uremic complications (pericarditis, bleeding, etc)

Dosing Drugs in Acute Renal Disease
• there are no published guidelines on what to do • most important: fix reason for renal function change • can hold every other dose of some drugs if renal function rapidly deteriorating • for vital drugs, you may need to adjust dose based on drug serum concentrations— • Can use Bennett’s tables and pharmacokinetic calculations for narrow therapeutic range drugs, but be aware that renal function will be changing rapidly, so qOd or even qd monitoring of SCr, UO, and weight will be necessary. Avoid the most potent nephrotoxins if possible. Consider metabolicallycleared drugs with inactive metabolites at these times.

Bennett’s tables

Outcome Evaluation Goals of therapy are:
to maintain a state of euvolemia with good urine output (at least 1 ml/kg per hour), to return serum creatinine and BUN to baseline, to correct electrolyte and acid-base abnormalities. Vital signs, weight, fluid intake, urine output, BUN, creatinine, and electrolytes should be assessed daily in the unstable patient.

Patient Care and Monitoring
Assess kidney function by evaluating a patient’s signs and symptoms, laboratory test results, and urinary indices. Calculate a patient’s creatinine clearance to evaluate the severity of kidney disease. Obtain a thorough and accurate drug history, including the use of non-prescription drugs such as NSAIDs. Evaluate a patient’s current drug regimen to: Determine if drug therapy may be contributing to AKI. Consider not only drugs that can directly cause AKI (e.g., aminoglycosides, amphotericin B, NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal AKI (i.e., diuretics and antihypertensive agents). Determine if any drugs need to be discontinued, or alternate drugs selected, to prevent worsening of renal function. Adjust drug dosages based on the patient’s creatinine clearance or evidence of adverse drug reactions or interactions. Develop a plan to provide symptomatic care of complications associated with AKI, such as diuretic therapy to treat volume overload. Monitor the patient’s weight, urine output, electrolytes (such as potassium), and blood pressure to assess efﬁcacy of the diuretic regimen.

TABLE 51-11. Key Monitoring Parameters for Patients with Established Acute Kidney Injury

Acute Kidney Injury (AKI)

Similar presentations

Presentation on theme: "Acute Kidney Injury (AKI)"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Acute Kidney Injury (AKI)

Similar presentations

Presentation on theme: "Acute Kidney Injury (AKI)"— Presentation transcript:

Similar presentations

About project

Feedback