Acute Kidney Injury/Intensive Care Unit Nephrology

Phuong-Chi T. Pham

Son V. Pham

Cynthia C. Nast

Phuong-Anh T. Pham

Phuong-Thu T. Pham

ACUTE KIDNEY INJURY

Clinical Impact of Acute Kidney Injury

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.
AKI episode prior to incident end-stage kidney disease (ESKD) is associated with higher adjusted odds of 1-year mortality compared with pre-ESKD without AKI episodes.

Classification of AKI

Purpose for classification system for AKI:
- Early identification and management of AKI
- Standardized AKI definitions for AKI-related research

KDIGO definition of AKI (Table 11.1):

Table 11.1 KDIGO staging of acute kidney injury

Stage	Serum Creatinine Criteria	Urine Output Criteria
1	↑SCr 1.5-1.9 × baseline within 7 d or ↑SCr by ≥0.3 mg/dL within 48 h	<0.5 mL/kg/h for 6-12 h
2	↑SCr >2.0-2.9 × baseline	<0.5 mL/kg/h for ≥12 h
3	↑SCr >3.0 × baseline or ↑ in SCr to ≥4.0 mg/dL or initiation of KRT	<0.3 mL/kg/h for ≥24 h or anuria for ≥12 h
Abbreviations for simplified table would be as follows: Abbreviation: KDIGO, Kidney Disease Improving Global Outcomes; SCr, serum creatinine; KRT, kidney replacement therapy.

Increase in serum creatinine (SCr) by ≥ 0.3 mg/dL within 48 hours or
Increase in SCr to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days or
Urine volume <0.5 mL/kg/h for 6 hours or longer

Early Identification of AKI

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:

Neutrophil gelatinase-associated lipocalin (NGAL)

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.

Kidney injury molecule 1 (KIM-1)

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

Table 11.2 Selected biomarkers that have been studied in the setting of AKI: The ideal biomarker is expected to have an early increase in level with AKI, correlate with AKI course and severity, and clear with AKI recovery

Biomarkers	Comments
Liver-type fatty acid-binding protein	Involves in fatty acid transport; protects against oxidative stress injury Detected within 1 h, peaks within 6 h
Neutrophil gelatinase-associated lipocalin (NGAL)	Functions as chelator of labile iron released from damaged tubules; upregulates the renoprotective enzyme heme-oxygenase-1 Detected at 3 h, peaks at 6 h with sustained elevation up to 5 d NGAL level may be affected by systemic infections, inflammatory conditions, anemia, hypoxia, and malignancies
Interleukin-18	Upregulated in acute kidney injury; proinflammatory Detected within 6 h, peaks at 12-18 h
Kidney injury molecule-1	Activates immune cells and promotes apoptotic and necrotic cell clearance and remodeling of injured epithelia Detected within 6 h, peaks at 48-72 h
Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein	Induces transient cell cycle arrest in face of injury Detected within 12 h
Cystatin-C (Cys-C)	Cysteine protease inhibitor Detected at 12-24 h, peaks at 24-48 h Note: Albuminuria ↑urinary Cys-C due to competitive proximal tubular endocytosis of albumin

Tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue insulin-like growth factor binding protein 7 (IGFBP7)

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.

AKI Risk Stratification and Prognostication

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.

Renal functional reserve testing (RFR)

RFR is defined as the increase in glomerular filtration rate (GFR) following protein loading.
An increase in GFR <15 mL/min/1.73 m² following a protein load of 1.2 g/kg body weight has been suggested to predict an 11.8-fold increase in postoperative risk for AKI among patients undergoing elective cardiac surgery.

Furosemide stress test (FST)

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).
Protocol:
- 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).
- Urine output <200 mL within 2 hours in patients with stage 1 AKI predicts risk of progression to stage 3 AKI and need for RRT. In the kidney transplant recipient, poor FST response predicts delayed graft function.
Combining FST with urinary IGFBP7*TIMP-2 level has been shown to be superior to using either test alone in predicting AKI.

Proteinuria

Preexisting proteinuria (albuminuria) predicts AKI risk, AKI requiring RRT, unfavorable prognosis for renal recovery in those who develop AKI requiring RRT, and prolonged hospital stay.

Mechanisms of AKI

Ischemia-related acute tubular necrosis (ATN)

Proximal and distal tubules may be affected in a patchy distribution.

Functional changes

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

Histopathology (Fig. 11.1)

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

Nephrotoxin-related AKI

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.

Recreational drugs associated with AKI

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)

FIGURE 11.1 Acute tubular necrosis. Acute tubular cell injury and necrosis in proximal tubules. A. There is acute tubular injury with loss of the microvillus brush border and cell cytoplasm with epithelial cell flattening (arrows) and relative dilatation of the tubular lumens (Jones silver ×40). B. In addition to tubular cell loss of brush borders and cytoplasm, there are tubular cell necrosis (long arrow), a mitotic figure (short arrow) reflecting regeneration and repair, and epithelial cell detachment with a focus of denuded tubular basement membrane (arrowhead) (periodic acid methenamine silver ×40).

Ketamine (lower urinary tract dysfunction, obstructive uropathy, rhabdomyolysis)
See Chapter 10, for specific drug-related AKI.

Sepsis-related AKI

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.

Routine Diagnostic Tools for the Diagnosis of AKI

Microscopic examination of urinary sediment

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:
- Hyaline 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
Crystalluria:
- Consider drug-induced crystals
- High amount of uric acid crystals may be observed with tumor lysis syndrome (TLS).

Urine eosinophils

Poor sensitivity and specificity in the diagnosis of ATIN
No longer recommended in the evaluation of ATIN

Urine volume

Anuria is more likely seen with complete urinary obstruction, vascular catastrophe, bilateral renal cortical necrosis, severe ATN, or severe rapidly progressive glomerulonephritis.
Oliguric AKI, defined as urine output <500 mL/d, is associated with worse outcome than nonoliguric AKI.

Fractional excretion of sodium (FeNa) and fractional excretion of urea (FeUrea)

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.
In nonoliguric AKI, FeNa <1% or FeUrea <35% generally indicates prerenal AKI as opposed to ATN.

Kidney/bladder ultrasound

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

Imaging Study	Comments	ACR Rating
Ultrasound	Assess kidney size Exclude obstruction Doppler may be added to assess renal perfusion or vascular stenosis/thrombosis	9
Tc-99m MAG3 kidney scan	May be useful if SCr is elevated May be performed as a follow-up after ultrasound as needed	4
MRI of the abdomen without IV contrast	Evaluate unclear causes of ureteral obstruction	3
MRI of the abdomen with and without IV contrast	Gadolinium-enhanced studies are very effective for renal artery evaluation; gadolinium use should be avoided in patients with eGFR <30 mL/min/1.73 m² due to increased risk of nephrogenic systemic fibrosis.	3
MRA without IV contrast	Assess renal arterial or venous patency when vascular stenosis or thrombosis may account for AKI	3
Arteriography of the kidney	Potentially helpful in trauma evaluation for renal artery occlusion. Consider using CO₂ to avoid nephrotoxicity.	3
CT of the abdomen without IV contrast	Trauma evaluation Noncontrast helical CT is more sensitive than KUB for the evaluation of calculi. Evaluation of ureteral obstruction due to retroperitoneal fibrosis or masses	3
ACR rating scale: 7-9: Usually appropriate; 4-6: May be appropriate; 1-3: Usually not appropriate Abbreviations: ACR, American College of Radiology; CT, computed tomography; eGFR, estimated glomerular filtration rate; IV, intravenous; KUB, kidney urinary tract bladder; MRA, magnetic resonance angiogram; MRI, magnetic resonance imaging; SCr, serum creatinine; Tc-99m MAG3, technetium-labeled mercaptoacetyltriglycine.

HEMODYNAMIC (PRERENAL) AKI

Etiologies of Prerenal AKI (Fig. 11.2)

Rapid fall in baseline blood pressure (BP)

May be seen with overly rapid treatment of HTN or acute volume loss

Volume depletion

True volume depletion: bodily fluid loss, no access to adequate fluid intake
Reduced effective circulating volume: heart failure, cirrhosis, nephrosis

Third-spacing

May be seen in sepsis, severe acute pancreatitis or muscle trauma

Cardiorenal syndrome (CRS)

Pathologic disorder of the heart and kidneys whereby acute or chronic dysfunction of one organ induces acute or chronic dysfunction of the other

Cardiorenal syndrome types

CRS type 1 (acute CRS):
- Abrupt worsening of cardiac function (e.g., acute pulmonary embolism, myocardial infarction, valvular rupture, rapid [re]-accumulation of pericardial effusion) → AKI
CRS type 2 (chronic CRS):
- 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
CRS type 5 (secondary CRS):
- Systemic condition → both cardiac and renal dysfunction

Risk factors

Older age, female gender, baseline CKD, Caucasian American race, diastolic heart failure, history of congestive heart failure (CHF), DM, systolic BP (SBP) >160 mm Hg

FIGURE 11.2 Differential diagnoses for prerenal acute kidney injury. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; PEEP, positive end-expiratory pressure.

Pathophysiology of CRS

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.

Management

Optimization of cardiac function per underlying etiology. Management of heart failure is discussed in Chapter 1

Renovascular compromise

Examples include acute obstruction of renal artery, such as aortic dissection extending into renal artery, use of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker [ACEI/ARB] in severe bilateral renal artery stenosis

Intraglomerular hemodynamic compromise

Predominant afferent vasoconstrictors: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, calcineurin inhibitors, amphotericin, contrast agents
Predominant efferent vasodilators in patients with suboptimal baseline glomerular filtration: ACEI/ARB

Hepatorenal syndrome (HRS)

Definition of HRS by the Ascites International Club: HRS is a clinical condition that occurs in patients with chronic liver disease, advanced hepatic failure, and portal hypertension characterized by impaired renal function and marked abnormalities in the arterial circulation and activity of the endogenous vasoactive systems. In the kidney, there is marked renal vasoconstriction that results in a low GFR. In the extrarenal circulation, there is predominance of arterial vasodilation that results in reduction of total systemic vascular resistance and arterial hypotension.

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).
Urinary biomarkers in AKI and HRS:
- Urinary NGAL levels have been shown to be much higher in ATN (417 µg/L) compared with prerenal azotemia and HRS (30 and 76 µg/L, respectively). Urinary NGAL measurements may be useful when clinically available.

Subtypes of HRS

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
Prognosis: Renal function rarely spontaneously improves (<5%). Median survival without dialysis support for type 1 HRS: 2 weeks; type 2 HRS: 6 months

Management of HRS (Table 11.4)

Preventive measures to reduce HRS risk

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:
  - Initial presentation of kidney injury as volume expanding challenge:
    - 1 g/kg/d up to 100 g/d for ≥48 hours
  - At diagnosis of SBP:
    - 1.5 g/kg at diagnosis and 1 g/kg intravenous (IV) 48 hours later
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.

Transjugular intrahepatic portosystemic shunt (TIPS)

Divert portal blood flow to hepatic vein, thereby redistribute portal/splanchnic blood to central volume

Table 11.4 Management of hepatorenal syndrome

Category	Specifics	Therapeutic Options^a
Prophylactic therapies	Spontaneous peritonitis	Prophylactic antibiotic in at-risk individuals
		Albumin infusion in patients who present with SBP
	Acute alcoholic hepatitis	Glucocorticoids Pentoxifylline may reduce HRS, but not survival
Improve hemodynamics	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	Systemic/splanchnic vasopressors	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.
	Renal vasodilators	Serelaxin (ongoing studies)
Removal of protein-bound toxins	Albumin dialysis	Molecular Adsorbent Recirculating System Fractionated plasma separation and adsorption Single-pass albumin dialysis
Liver replacement		Liver transplant
^aSee text for specific indications and drug dosing.
Abbreviations: HRS, hepatorenal syndrome; SBP, spontaneous bacterial peritonitis.

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).

Vasoconstrictors

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).
  - Dosing:
    - 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.
    - Albumin 1 g/kg/d up to 100 g/d on day 1, followed by 20 to 40 g/d; may increase to 40 g daily if central venous pressure (CVP) <12 mm Hg (or plasma renin activity [PRA] not reduced by >50% of basal value after 3 days of treatment)
Norepinephrine (NE) plus albumin:
- 2014 meta-analysis revealed equivalent reversal of HRS with terlipressin as it is a combination of NE and albumin.
- Dosing:
  - NE 0.5 mg/h, to increase mean arterial blood pressure (MAP) by ≥10 mm Hg or increase in 4-hour urine output >200 mL. If goals are not met, increase dose every 4 hours in steps of 0.5 mg/h, up to maximum dose of 3 mg/h.
  - Albumin dosing as above
Vasopressin plus albumin:
- Dosing:
  - 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.
- Dosing:
  - 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).

Renal vasodilators

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.

Albumin dialysis

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.

Liver transplantation

Currently only cure to end-stage liver disease. The incidence of ESKD following liver transplantation is 7% in patients with HRS versus 2% in those without HRS.
Prioritization for liver allocation is based on United Network of Organ Sharing (UNOS) MELD Score in Liver Disease (See Appendix A).

IAH leading to abdominal compartment syndrome (ACS)

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
  
  APP = MAP – IAP

Risks for IAH/ACS

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

Clinical manifestations of IAH/ACS

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)

Management of IAH/ACS

If IAP ≥12 mm Hg, begin medical therapy to reduce IAP:
Measure IAP ≥ every 4 to 6 hours. Titrate therapy to maintain IAP ≤15 mm Hg
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.

Page kidney

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

Hyperoncotic AKI

This is seen with the rapid infusion of large quantities of osmotically active substances such as mannitol, dextran, and hyperoncotic albumin.
Glomerular oncotic pressure far exceeds glomerular hydrostatic pressure, resulting in net reduction in glomerular filtration, hence oliguric/anuric AKI (Fig. 11.3).

FIGURE 11.3 Reduction in net glomerular filtration with rapid increase in intra-arteriolar oncotic pressure. The lower intra-arteriolar oncotic pressure in (A) provides a greater net glomerular filtration compared with (B) where the higher oncotic pressure drives the force of filtration into the intra-arteriolar space. Abbreviations: AA, afferent arteriole; EA, efferent arteriole; P_ART, arteriolar hydraulic pressure; π_ART, arteriolar oncotic pressure; P_US, urinary space hydraulic pressure; π_US, urinary space oncotic pressure.

PARENCHYMAL (INTRINSIC) AKI

Vascular Causes of AKI

Acute intrinsic diseases

Microangiopathy and hemolytic anemia (MAHA), thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP/HUS), scleroderma, malignant HTN
Renal vasculitis (see Chapter 7)

Large vessel involvement

Aortic dissection extending into renal artery, renal artery aneurysm
Systemic thromboembolism

Atheroembolic disease

May occur spontaneously or following invasive arterial procedure, arteriography, vascular surgery, or thrombolytic therapy
May occur up to months following inciting event

Presentation

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)