Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD) progression and de novo CKD in patients with and without underlying CKD, respectively.
In patients with diabetes mellitus (DM) type 2, any AKI episode independently increases the risk for the development of stage 4 CKD. The adverse impact of AKI on the development of CKD is similar to that seen with proteinuria.
AKI is associated with higher rates of cardiovascular events (heart failure, acute myocardial infarction) and cardiovascular mortality.
Worse stages of AKI are associated with increased mortality.
Purpose for classification system for AKI:
Table 11.1 KDIGO staging of acute kidney injury
Serum Creatinine Criteria
Urine Output Criteria
<0.5 mL/kg/h for 6-12 h
↑SCr >2.0-2.9 × baseline
<0.5 mL/kg/h for ≥12 h
<0.3 mL/kg/h for ≥24 h or anuria for ≥12 h
Abbreviations for simplified table would be as follows:
Biomarkers: As the rise in SCr occurs late after the onset of AKI, the search for an ideal biomarker for the early identification of AKI has been an active area of research. Early detection of AKI is thought to improve outcome. Selected biomarkers for the early detection of AKI are listed in Table 11.2:
NGAL is predominantly detected in proliferating nuclear antigen-positive proximal tubular cells. In healthy individuals, urine and plasma levels of NGAL are low but increase significantly with ischemic or nephrotoxic kidney injury.
A transmembrane glycoprotein that is undetectable in normal kidney tissue or urine but is expressed at high levels in dedifferentiated proximal tubular cells after ischemic or toxic injury and in renal cell carcinoma
TIMP-2 and IGFBP7 function as both autocrine and paracrine signals to arrest cell cycle and shut down cell function with early kidney injury.
Urinary levels of both TIMP-2 and IGFBP7 are increased in early kidney injury.
Current data suggest that early optimized kidney care or prompt nephrology consultation based on elevated IGFBP7*TIMP-2 values reduces the severity of AKI.
Multiple AKI risk stratification and prognostication scoring systems based on patients’ baseline characteristics and kidney function, clinical context, and early signs of kidney injury have been developed in recent years. For interested readers, see Selected Reading list.
RFR is defined as the increase in glomerular filtration rate (GFR) following protein loading.
FST may be used in euvolemic to hypervolemic patients with AKI to predict the risk for severe AKI and need for renal replacement therapy (RRT).
Infuse 1.0 to 1.5 mg/kg of furosemide (the former dose is for furosemide-naïve individuals, and the latter is for individuals with prior exposure).
Combining FST with urinary IGFBP7*TIMP-2 level has been shown to be superior to using either test alone in predicting AKI.
Proximal and distal tubules may be affected in a patchy distribution.
Loss of tubular cell polarization, that is, loss of differentiation between apical and basolateral sides, leading to reabsorption of urine instead of urine excretion. This is also known as “urine back-leak.”
Microvascular injury, vascular congestion, intraglomerular vasoconstriction
Irregular vacuolization within proximal tubular cells, loss of proximal cell brush border, disruption and sloughing of epithelial cells lining the tubule, intratubular epithelial cell casts
Necrosis of tubular cells is typically only seen in a small portion of cells.
Apoptosis of proximal tubular cells
Typically involves proximal tubular injury
Mechanisms of action are drug specific and may include alterations in intraglomerular hemodynamics, direct tubular cytotoxic effects with generation of local inflammatory response and reactive oxygen species, local or systemic drug-allergic response, systemic endothelial injury with associated immunologic and non-immunologic responses, or drug-crystallization and microtubular obstruction.
Cocaine (rhabdomyolysis, severe renal vasoconstriction with possible renal infarction, levamisole-laced cocaine with associated antineutrophil cytoplasmic antibody [ANCA] vasculitis)
Oxymorphone (Opana): thrombotic microangiopathy, rhabdomyolysis
Methamphetamines, ecstasy (rhabdomyolysis, acute tubulointerstitial nephritis [ATIN], ATN, hyponatremia, malignant hypertension [HTN])
Synthetic cannabinoids (ATN, ATIN, mild elevation of creatine phosphokinase [CPK], rare reports of rhabdomyolysis)
Heroin (amyloidosis, nephrotic syndrome, heroin crystal nephropathy, rhabdomyolysis)
Bath salts—synthetic cathinones (rhabdomyolysis, hyperuricemia)
NMDA—potent hallucinogens (rhabdomyolysis)
Ketamine (lower urinary tract dysfunction, obstructive uropathy, rhabdomyolysis)
Activation of the innate immune system in response to an inciting pathogen leads to increased oxidative stress, procoagulant state, endothelial injury, and recruitment of inflammatory cells, all acting in concert to induce a milieu favorable to promote and exacerbate underlying AKI.
The septic/shock state is also associated with increased glomerular blood flow due to dilatation of both afferent and efferent arterioles. However, net glomerular filtration pressure (hence GFR) is reduced because there is greater efferent vasodilation than afferent vasodilation. The reduced GFR may partially contribute to sepsis-related AKI. It is plausible that the use of angiotensin II (AII) in the setting of septic shock may improve sepsis-related renal and survival outcomes. More data are needed.
The use of a scoring system based on the number of granular casts (muddybrown casts) and renal tubular epithelial cells may improve the differential diagnostic and prognostic evaluation of AKI.
Evaluation of cells, cellular casts:
Predominantly made up of Tamm-Horsfall/uromodulin proteins
Indicate reduced renal perfusion (e.g., volume depletion, reduced cardiac output)
Red blood cell (RBC) casts: acute glomerulonephritis until proven otherwise
White blood cell (WBC) casts: pyelonephritis or tubulointerstitial nephritis
Granular casts: nonspecific, indicates the presence of cells that have degenerated
Broad casts: chronic low urine flow
Muddy-brown casts: ATN
Waxy casts: degraded cellular casts seen in CKD with poor urine flow
Consider drug-induced crystals
High amount of uric acid crystals may be observed with tumor lysis syndrome (TLS).
Anuria is more likely seen with complete urinary obstruction, vascular catastrophe, bilateral renal cortical necrosis, severe ATN, or severe rapidly progressive glomerulonephritis.
FeUrea versus FeNa: FeUrea is typically used in patients receiving diuretics because urea reabsorption occurs primarily in the proximal tubules and is less affected by loop and thiazide diuretics. In contrast, Na+ excretion, hence FeNa, can be elevated with diuretic use even in the prerenal state.
Kidney size is generally normal to enlarged with AKI. However, enlarged kidneys may be seen in advanced subacute/chronic diabetic kidney disease, infiltrative disease, amyloidosis, HIV-infected-related nephropathy, or the presence of large cysts.
Bladder ultrasound with postvoid retention volume may be indicated in at-risk individuals (e.g., enlarged prostate, neurogenic bladder [associated with DM, neurologic complications, or drug induced], AKI posttraumatic Foley insertion).
Other imaging studies are listed in Table 11.3.
Table 11.3 American College of Radiology appropriateness criteria for the diagnosis of acute kidney injury 2013
May be seen with overly rapid treatment of HTN or acute volume loss
True volume depletion: bodily fluid loss, no access to adequate fluid intake
Reduced effective circulating volume: heart failure, cirrhosis, nephrosis
May be seen in sepsis, severe acute pancreatitis or muscle trauma
Pathologic disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ induces acute or chronic dysfunction of the other
Abrupt worsening of cardiac function (e.g., acute pulmonary embolism, myocardial infarction, valvular rupture, rapid [re]-accumulation of pericardial effusion) → AKI
Chronic abnormalities in cardiac function → progressive CKD
CRS type 3 (acute renocardiac syndrome):
AKI → acute cardiac dysfunction
CRS type 4 (chronic renocardiac syndrome):
CKD → decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events
Systemic condition → both cardiac and renal dysfunction
Reduced cardiac output leads to renal hypoperfusion.
Reduced cardiac output with associated venous congestion or severe right ventricular dysfunction also leads to increased renal venous pressure, increased renal resistance, and, ultimately, impaired intrarenal blood flow.
Endothelial stretch from peripheral venous congestion leads to a vascular endothelial proinflammatory state.
Neurohormonal activation involving the sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), and nonosmotic vasopressin release leads to systemic vasoconstriction and enhanced renal Na+ and H2O excretion.
Optimization of cardiac function per underlying etiology. Management of heart failure is discussed in Chapter 1
Predominant afferent vasoconstrictors: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, calcineurin inhibitors, amphotericin, contrast agents
Ascites International Club criteria for the diagnosis of HRS (Table 1.5) and underlying mechanisms of ascites formation and HRS are discussed in Chapter 1.
Note: Routine evaluation for causes of AKI other than HRS must be performed in patients with end-stage liver disease. Etiologies relevant to this setting include intra-abdominal hypertension (IAH) (tense ascites with or without peritonitis), concurrent infections or nephrotoxins leading to both kidney and liver failure, and pigmented cast nephropathy (particularly in cases with total bilirubin level >20 mg/dL).
Type 1: ≥Doubling of initial SCr to >2.5 mg/dL or a 50% reduction of the initial creatinine clearance (CrCl) to <20 mL/min within 2 weeks; type I may occur spontaneously, but frequently occurs in close relationship with a precipitating factor: severe bacterial infection (spontaneous bacterial peritonitis [SBP]), gastrointestinal (GI) hemorrhage, major surgical procedure, or acute hepatitis superimposed on cirrhosis.
Type 2: Moderate and stable reduction in GFR. Renal failure does not have a rapidly progressive course; type 2 is thought to represent the extreme expression of renovasoconstriction; dominant clinical feature of type 2: severe ascites with poor or no response to diuretics.
Incidence: 18% at 1 year; 39% at 5 years
Prophylactic antibiotic therapy for SBP in at-risk individuals:
Short-term prophylactic therapy:
Patients hospitalized for GI bleed (ceftriaxone 1 g/d); transition to oral quinolone or trimethoprim-sulfamethoxazole twice daily ×7 days after stabilization
Patients hospitalized for other reasons with ascitic total protein <1 g/dL
Prolonged prophylactic therapy (quinolone or trimethoprim-sulfamethoxazole double strength daily):
Patients with ≥1 episode of SBP
Patients with cirrhosis and ascitic fluid total protein <10 g/L with Child-Pugh score >9, serum bilirubin >3 mg/dL, SCr >1.2 mg/dL or blood urea nitrogen (BUN) >20 mg/dL or S[Na+] <130 mmol/L
The use of pentoxifylline, a tumor necrosis factor inhibitor, in severe alcoholic hepatitis (AH) may reduce risk of HRS, but not short-term survival. Corticosteroid remains the key therapeutic option. The American College of Gastroenterology does not support the use of pentoxifylline for patients with severe AH based on existing evidence. Severe AH is defined as a Maddrey discriminant function score >32 or model for end-stage liver disease (MELD) score >20.
Avoidance of nephrotoxins, NSAIDs, and overly aggressive diuresis
Albumin infusion for the following conditions:
Large volume paracentesis >4 to 5 L:
6 to 8 g/L of ascitic fluid removed. Note: Patients without peripheral edema are at increased risk for circulatory collapse and development of AKI following large volume paracentesis.
Divert portal blood flow to hepatic vein, thereby redistribute portal/splanchnic blood to central volume
Table 11.4 Management of hepatorenal syndrome
Prophylactic antibiotic in at-risk individuals
Albumin infusion in patients who present with SBP
Acute alcoholic hepatitis
Pentoxifylline may reduce HRS, but not survival
Diversion of portal blood to hepatic vein and central venous circulation to reduce splanchnic blood pooling thereby improving central venous volume
Transjugular intrahepatic portosystemic shunt
Limited to patients with less advanced liver disease due to high risk of complications with advanced liver disease
Treatment of HRS
Terlipressin plus albumin (not available in the United States)
Norepinephrine plus albumin
Vasopressin plus albumin
Midodrine plus octreotide plus albumin
Angiotensin II (ongoing study)
If positive response, effect is generally seen within 3 days. Consider therapy switch if no response to any selected combination above after 3 days.
Serelaxin (ongoing studies)
Removal of protein-bound toxins
Molecular Adsorbent Recirculating System
Fractionated plasma separation and adsorption
Single-pass albumin dialysis
a See text for specific indications and drug dosing.
Improve variceal bleed and renal perfusion
Complications: bleeding, infections, hepatic encephalopathy, kidney failure
Typically, TIPS is not well tolerated in patients with end-stage liver failure due to high risk for complications above (Child-Pugh class C).
Improve short-term mortality (i.e., 15 days), but not beyond
The International Club of Ascites recommends the use of vasoconstrictors in patients with HRS stage 2 or 3 AKI.
Therapy with vasoconstrictors may be considered once HRS criteria are fulfilled and no response observed over 48 hours following volume expansion with albumin.
Clinically available vasoconstrictors:
Terlipressin plus albumin:
Terlipressin is a synthetic analog of vasopressin-1a receptor agonist. It raises peripheral vascular resistance, hence BP, and decreases portal venous blood flow and hepatic venous pressure gradient. Its use is contraindicated in patients with ischemic cardiovascular disease. Terlipressin is available in Europe, but not in the United States (not Food and Drug Administration [FDA] approved).
Terlipressin 1 mg over 4 to 6 hours infusion, increase to maximum of 2 mg over 4 to 6 hours if SCr decreases by <25% at day 3. Alternatively, terlipressin may be given at 2 mg/d mixed with 250 mL of 5% dextrose water as a continuous infusion. Treatment is maintained until SCr has decreased <1.5 mg/dL.
Norepinephrine (NE) plus albumin:
2014 meta-analysis revealed equivalent reversal of HRS with terlipressin as it is a combination of NE and albumin.
Vasopressin plus albumin:
Vasopressin 0.01 U/min, increase dose to a maximum of 0.8 U/min to achieve increase in MAP ≥10 mm Hg
Albumin dosing as above
Monitor for hyponatremia
Combination midodrine (systemic vasoconstriction) plus octreotide (splanchnic vasoconstrictor) plus albumin has been widely used in the United States due to the unavailability of terlipressin. Octreotide is a synthetic analog of the pancreatic hormone somatostatin, a hormone that normally serves as a splanchnic vasoconstrictor by inhibiting glucagon, a splanchnic vasodilator.
It should be noted, however, that a randomized trial revealed a lower response rate in patients receiving midodrine/octreotide combination compared to those receiving terlipressin (4.8% vs. 55.6%, p < 0.01).
Data for comparative efficacy between midodrine/octreotide combination versus NE are not available. Nonetheless, midodrine/octreotide combination is likely inferior to NE because NE has been shown to be comparable in efficacy compared with terlipressin whereas midodrine/octreotide combination has been shown to be inferior to terlipressin.
Midodrine (systemic vasoconstrictor): start at 7.5 mg orally three times daily (tid), titrate up to 12.5 to 15 mg tid to increase MAP by at least 15 mm Hg plus
Octreotide (splanchnic vasoconstrictor): start at 100 µg tid subcutaneously, then, if necessary, increase to 200 µg tid plus
Albumin dosing as above
Predictors of response to vasopressors:
Baseline serum bilirubin level <10 mg/dL and increase in MAP ≥5 mm Hg
If positive response, effect is generally seen within 3 days. Therapy switch should be considered if there is no response to any selected combination therapy above after 3 days (e.g., failure to midodrine plus octreotide plus albumin after 3 days should prompt a switch to NE plus albumin or vasopressin plus albumin).
Serelaxin: a recombinant form of the human peptide hormone relaxin-2, shown to increase renal blood flow by 65% in a pilot study involving cirrhotic patients. More data are needed.
An albumin circuit is used to compete for protein-bound toxins not metabolized by the diseased liver.
Systems designed with albumin dialysis include Molecular Adsorbent Recirculating System (MARS), fractionated plasma separation and adsorption (Prometheus), and single-pass albumin dialysis.
Currently, data suggest improvement with the use of albumin dialysis in hepatic encephalopathy and reduction of bilirubin level, but not survival.
Definitive data to support routine use are still lacking.
Updated consensus definitions and practice guidelines from the World Society of the ACS
IAH is defined as sustained intra-abdominal pressure (IAP) ≥12 mm Hg. IAP is measured at end expiration in supine position after ensuring absence of abdominal muscle contractions, with transducer zeroed at level of midaxillary line.
ACS is defined as a sustained IAP ≥20 mm Hg and/or abdominal perfusion pressure (APP) <60 mm Hg that is associated with new organ dysfunction/failure, where APP is defined as
Diminished abdominal wall compliance: abdominal surgery, major trauma/burns, prone positioning
Increased intraluminal contents: gastroparesis/gastric distention/ileus, ileus, colonic pseudo-obstruction, volvulus
Increased intra-abdominal contents: acute pancreatitis, distended abdomen, hemo-/pneumoperitoneum or intraperitoneal fluid collections, intra-abdominal
or retroperitoneal tumors, laparoscopy with excessive insufflation pressures, liver dysfunction/cirrhosis with ascites, peritoneal dialysis (PD)
Capillary leak/fluid resuscitation: acidosis, damage control laparotomy, hypothermia, massive fluid resuscitation or positive fluid balance, polytransfusion
Others: age, bacteremia, coagulopathy, increased head of bed angle, massive incisional hernia repair, mechanical ventilation, obesity or increased body mass index, positive end-expiratory pressure (PEEP) >10 mm Hg, peritonitis, pneumonia, sepsis, shock or hypotension
Increased IAP with typically tense abdomen
Increased peak inspiratory pressure, decreased tidal volume (due to abdominal compartment encroaching into thoracic cavity)
Increased CVP, pulmonary arterial wedge pressure
Reduced cardiac index (blood pumped against high-pressure abdominal cavity)
Oliguria (reduced blood flow in renal vein and direct cortical pressure)
Therapeutic measures to reduce IAP:
Evacuate intraluminal contents: nasogastric and/or rectal tube, initiate gastro-/colo-prokinetic agents, minimize or discontinue enteral nutrition, lower bowel decompression with enemas or even colonoscopy as needed.
Evacuate intra-abdominal space occupying lesions or fluids as applicable (e.g., large volume paracentesis if safely tolerated).
Improve abdominal wall compliance, ensure adequate sedation and analgesia, remove constrictive dressings, consider reverse Trendelenburg position and/or neuromuscular blockade.
Minimize fluid administration, remove excess fluids with use of diuretics or even ultrafiltration (UF) if necessary, consider hypertonic fluids, colloids.
Optimize systemic/regional perfusion.
If IAP >20 mm Hg and new organ dysfunction/failure occurs despite maximal medical intervention, consider surgical abdominal decompression.
Results from external compression of kidney (e.g., perinephric subcapsular hematoma, lymphocele around transplanted kidney, large simple cyst, retroperitoneal compression)
Compression of intrarenal vessels leads to renal hypoperfusion, ischemia, activation of the RAAS and associated HTN.
Treatment: decompression of underlying cause
This is seen with the rapid infusion of large quantities of osmotically active substances such as mannitol, dextran, and hyperoncotic albumin.
Aortic dissection extending into renal artery, renal artery aneurysm
May occur spontaneously or following invasive arterial procedure, arteriography, vascular surgery, or thrombolytic therapy
May occur up to months following inciting event
unexplained fevers, weight loss, myalgias, anorexia, end-organ infarction/injury occurring weeks to months following inciting event (e.g., stroke, myocardial/bowel/renal infarction, pancreatitis, adrenal failure, muscle infarction)
Clinical risk above plus classic triad of livedo reticularis, AKI, and eosinophilia
Fundoscopic examination may be reveal cholesterol emboli, known as Hollenhorst plaque.