CONTENTS

definitions & basics

• Definition & subtyping
• Causes of AKI
  • Nephrotoxins

diagnostic approach to AKI (including oliguria)

• [#1] Order laboratory test package
• [#2] Evalute for post-renal renal failure (obstruction)
• [#3] IF OLIGURIC: Evaluate for hypoperfusion (pre-renal)
• [#4] Etiology must be intrinsic renal failure

management

• Core management for AKI of any etiology
  • [#1] Treat the underlying cause
  • [#2] Medication adjustment & tailoring
  • [#3] Hemodynamic optimization
  • [#4] Fluid management
  • [#5] Potassium management
  • [#6] Treatment of acidosis
  • [#7] Phosphate binder
  • [#8] Dialysis
• Additional management for HRS-AKI
  • [#9] Albumin
  • [#10] Vasoconstrictors
  • [#11] Paracentesis
  • [#12] Dialysis

related topics

• HRS-AKI
  • Clinical presentation
  • Approach to diagnosis
  • Hepatorenal physiology & prevention
  • (HRS management)
• CNS complications
  • Uremic encephalopathy
  • Dialysis disequilibrium syndrome
• Dialysis modalities
• Other tests for AKI:
  • AKI diagnostic tests that aren't helpful (FeNa)
  • Furosemide stress test (FST)
  • Urine albumin to creatinine ratio (uACR)

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definitions & subtyping

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KDIGO criteria for acute kidney injury (assigned based on the most severe feature)

• Stage I AKI
  • Cr 1.5-1.9 times baseline.
  • Cr increase >0.3 mg/dL.
  • Urine output <0.5 ml/kg/hr for 6-12 hours.
• Stage II AKI
  • Cr 2-2.9 times baseline.
  • Urine output <0.5 ml/kg/hr for 12-24 hours.
• Stage III AKI 
  • Cr >3 times baseline.
  • Cr >4 mg/dL.
  • Initiation of dialysis.
  • Urine output <0.3 ml/kg/hr for >24 hours.
  • Anuria >12 hours.

AKD (acute kidney disease)

• AKD is defined as any of the following within a <3 month timeframe:
  • AKI.
  • GFR <60 ml/min/1.73 m².
  • GFR decreased by >35%.
  • Increase in serum creatinine by >50%.
• AKD encompasses AKI (the most severe form) and less severe forms as well.

CKD (chronic kidney disease)

• CKD is defined as a GFR <60 ml/min/1.73 m² for >3 months.
• CKD staging is based on the GFR category.
  • Stage 1: GFR <90 ml/min/1.73 m² but kidney damage is present (e.g., proteinuria).
  • Stage 2: GFR 60-90 ml/min/1.73 m² – mild decrease in kidney function.
  • Stage 3a: GFR 45-60 ml/min/1.73 m² – mild-to-moderate decrease in kidney function.
  • Stage 3b: GFR 30-45 ml/min/1.73 m² – moderate-to-severe decrease in kidney function.
  • Stage 4: GFR 15-30 ml/min/1.73 m² – severe decrease in kidney function; symptoms may occur.
  • Stage 5: GFR <15 ml/min/1.73 m² – dialysis or transplant is typically required.

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subtyping AKI

Prognosis depends on changes in urine output and creatinine: (25568178)

isolated oliguria

• This refers to patients with low output who maintain stable creatinine levels.
• These patients rarely require dialysis, unless oliguria is profound (Stage 3).
• This may often represent “pre-renal” renal failure – the kidney is compensating for hypoperfusion by reducing urine output, but is continuing to function adequately.
• ⚠️ Be careful, however, because sometimes patients maintain a stable creatinine from a dilutional effect due to receiving lots of intravenous fluid. In that situation, creatinine may overestimate the renal function.
• Oliguria should be taken seriously and evaluated adequately. However, oliguria for <12 hours isn't necessarily a disaster, especially if the creatinine remains stable.

non-oliguric renal failure

• This refers to patients with elevated creatinine who maintain a normal urine output.
• The vast majority of these patients (99.7% overall) won't require dialysis.
• Non-oliguric renal failure excludes pre-renal renal failure. Most cases are reflective of intrinsic renal failure, but partial obstruction can also manifest with non-oliguric renal failure.

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causes of AKI

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“pre-renal” (disorders of perfusion)

• Shock of any etiology:
  • Septic shock.
  • Hypovolemic shock.
    • Over-diuresis.
    • Poor oral intake.
  • Hemorrhagic shock.
  • Cardiogenic shock.
  • Tamponade.
  • Excessive PEEP or intrathoracic pressure.
  • Abdominal compartment syndrome.
  • (Further discussion of shock: 📖).
• Hepatorenal syndrome (only accounts for ~20% of AKI in cirrhosis, so a full evaluation is mandatory). (32832400) 
• Congestive nephropathy (fundamentally a reflection of RV failure).
• Hypertensive emergency.
• Thrombotic thrombocytopenic purpura & hemolytic uremic syndrome.

intrinsic renal failure

• Nephrotoxic medications (listed below).
• Cellular lysis:
  • Rhabdomyolysis.
  • Hemolysis.
  • Tumor lysis syndrome.
• Acute glomerulonephritis.
• ATIN (acute tubulointerstitial nephritis).
• ATN (acute tubular necrosis).

post-renal: urologic obstruction

• Prostate obstruction.
• Occluded or malpositioned Foley catheter.
• Nephrolithiasis.
• Retroperitoneal fibrosis.
• Malignancy.
• Postoperative complication.

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nephrotoxins

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cardiovascular medications

• Direct:
  • ACEi & ARBs.
  • Triamterene.
• Indirect:
  • For patients with borderline cardiac output, medications that reduce cardiac output may be nephrotoxic (e.g., beta-blockers, diltiazem).
  • For patients with borderline hypotension, antihypertensives may be nephrotoxic.

antibiotics

• Aminoglycosides.
• Trimethoprim-Sulfamethoxazole (and other sulfonamides).
• Vancomycin.
• Beta-lactams rarely cause interstitial nephritis (especially penicillins such as nafcillin, piperacillin, and ampicillin).
• Colistimethate (Colistin).

antifungals

• Amphotericin.
• Pentamidine. (31665764)

antivirals (not exhaustive)

• Acyclovir, ganciclovir, valacyclovir, valganciclovir (crystal deposition).
• Cidofovir.
• Foscarnet.
• Indinavir.
• Tenofovir.

chemotherapy (not exhaustive)

• Many newer biologics and small-molecule inhibitors (not listed individually).
• Bevacizumab.
• Busulfan.
• Carboplatin.
• Checkpoint inhibitors.
• Cisplatin.
• Cyclophosphamide
• Ifosfamide.
• Melphalan.
• Methotrexate.
• Mitomycin.
• Oxaliplatin.

miscellaneous

• Antiepileptics (topiramate, zonisamide).
• Bisphosphonates (pamidronate, zoledronic acid).
• Immunosuppressives:
  • Calcineurin inhibitors (cyclosporine, tacrolimus).
  • mTOR inhibitors (sirolimus, everolimus).
• Inflammatory bowel disease medications (mesalamine, sulfasalazine).
• Intravenous immunoglobulin (IVIG).
• Mannitol.
• NSAIDs. (39230007)

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[1/4] order the AKI laboratory package

Labs are usually not terribly revealing, but it's important to be thorough. So it's often useful to order the laboratory package and then continue down the algorithm (don't wait for the labs to come back before evaluating further).

(interpretation of urinalysis in AKI)

• Glomerulonephritis:
  • Urinalysis: Hematuria; proteinuria (can be >2-3 grams/day).
  • Urine microscopy: RBC casts; dysmorphic RBCs.
  • Other clues: Associated diseases (e.g., ANCA vasculitis, SLE, infection).
• Acute interstitial nephritis (AIN):
  • Urinalysis: WBCs without bacteria (culture-negative pyuria); hematuria; proteinuria (mild, <2-3 g/d).
  • Urine microscopy: WBC casts.
  • Other clues: Fever, rash, blood eosinophilia, causative drug exposure (often NSAIDs, antibiotics).
• Pyelonephritis:
  • Urinalysis: WBCs, bacteria, nitrites (“positive for infection”).
  • Urine microscopy: WBC (sometimes with casts); bacteria.
  • Other clues: Fever, flank pain, lower urinary tract symptoms.
• Acute tubular necrosis (ATN):
  • Urinalysis:
  • Urine microscopy: Muddy brown casts.
  • Other clues: Sustained hypoperfusion/shock.
• Rhabdomyolysis or hemolysis:
  • Urinalysis: Positive “hemoglobin” without RBCs.
  • Urine microscopy: No erythrocytes seen.
  • Other clues:
    • Rhabdomyolysis: CK elevation.
    • Hemolysis: Anemia; elevation of LDH; hemolyzed electrolytes.

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[2/4] evaluate for post-renal renal failure

begin with one/more of the following

• Review recent radiological data (a recent CT scan of the abdomen/pelvis may exclude hydronephrosis).
• POCUS of the kidneys and bladder.
• Flushing or changing out the Foley catheter:
  • This isn't ideal, but it may be used if POCUS windows are poor.
  • If there is significant concern about Foley catheter dysfunction (e.g., obstruction), have a low threshold to insert a new catheter.
  • Marked anuria or renal failure generally implies bilateral renal failure, so the presence of a functional Foley catheter will argue against this possibility.

subsequent actions

• If obstruction is discovered: This is probably the cause of renal failure. Treatment varies depending on the cause of obstruction (e.g., Foley placement for urethral dysfunction or a urology consultation).
• If the possibility of obstruction remains unclear: Order a formal renal ultrasound & proceed down the algorithm (obstruction is unlikely, so don't delay further workup while awaiting the ultrasound). 👇
• If obstruction is excluded: Proceed down the algorithm. 👇

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[3/4] IF OLIGURIC then assess & treat for renal hypoperfusion (if non-oliguric then proceed to #4)

definition & significance of oliguria

• Oliguria is a subset of acute kidney injury defined by low urine output (<0.3-0.5 ml/kg/hr for several hours, or roughly <500 ml/day). (29156029)
• Oliguria may be caused by any type of renal failure, if sufficiently severe (figure above).
• If the patient is not oliguric, this basically excludes pre-renal etiologies (so you don't need to evaluate renal perfusion; skip to step #4 below 👇).

evaluation for renal hypoperfusion (including POCUS)

• History review:
  • ? Diuresis.
  • ? Fluid administration; fluid balance; sources of fluid loss.
• Perfusion evaluation:
  • Evaluate for hypotension (or relative hypotension).
  • Consider the shock index (SBP/heart rate).
  • Evaluate signs of tissue perfusion (e.g., capillary refill, pulse oximetry pulsatility index, mottling).
• Evaluation for fluid responsiveness. 📖
• POCUS:
  • Evaluation for cardiac function.
  • Evaluation for volume status.
    • ? Evidence of hypovolemia.
    • ? Evidence of systemic congestion (e.g., VEXUS, femoral vein doppler 📖).
  • Exclude other specific etiologies of shock (e.g., pericardial tamponade).

diagnostic/therapeutic maneuvers to test for pre-renal renal failure

• If the evaluation suggests hypoperfusion due to an identifiable problem, then try to fix it, for example:
  • Volume excess & congestive nephropathy: diurese.
  • Volume depletion: give fluid.
  • Cardiogenic shock: trial an inotrope or inopressor.
  • BP below patient's baseline: trial norepinephrine.
  • Other etiologies of shock identified (e.g., tamponade, PE, septic shock): specific treatment.
  • (Evaluation for the presence & etiology of shock is discussed here.)
• If evaluation doesn't suggest hypoperfusion (or if hemodynamic manipulations fail to improve urine output), then consider a furosemide stress test (FST):
  • Adequate urine production following FST: This indicates a pre-renal etiology (hypoperfusion). Re-evaluate hemodynamics and look further for causes of renal and systemic hypoperfusion (i.e., shock).
  • Inadequate urine production following FST: This indicates intrinsic renal failure. In this situation, further hemodynamic manipulation is unlikely to be helpful (this can support a decision to stop giving the patient fluids).
  • (Further discussion of the furosemide stress test below. ⚡️)

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[#4/4] after excluding hypoperfusion & post-renal causes: the etiology must be intrinsic renal failure

• Causes of intrinsic renal failure are listed above.
• Evaluation often focuses on urinalysis (with evaluation discussed above).

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management of AKI

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[1/8] treat the cause of AKI 

• This depends on the etiology of AKI (listed above).
• Some examples include:
  • Post-renal failure: relieve obstruction.
  • Shock: resuscitation, shock reversal.
  • Hepatorenal: norepinephrine, albumin.
  • Congestive nephropathy: treat RV failure, diuresis.
  • Glomerulonephritis, ATIN: steroids, address triggers.
  • Tumor lysis syndrome: rasburicase.
  • Hemolysis, rhabdomyolysis: prevent further cellular lysis.

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[#2/8] medication adjustment & tailoring

discontinue nephrotoxins 📖

dose-adjust renally cleared medications

• Note that calculations of the glomerular filtration rate (GFR) based on creatinine level will be misleading in acute kidney injury.
• Formulas for the GFR only work in steady-state (equilibrium) conditions. This usually isn't the case in acute kidney injury.
• For example, with complete renal failure, creatinine often increases by roughly 1 mg/dL per day. So, if a patient's creatinine increases from 0.7 mg/dL to 1.7 mg/dL, their GFR may be extremely low (much lower than the calculated GFR).

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[#7/8] phosphate binder

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additional management for HRS-AKI

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[9/12] albumin in HRS-AKI

dosing of albumin

• Day #1:
  • 1 gram/kg (up to max 100 grams).
  • Concentrated albumin (20% or 25%).
  • Some sources suggest dividing the dose (e.g., 25 grams Q6hr). (31723234)
• Subsequent days:
  • 40 grams/day of concentrated albumin (20% or 25%).
  • The optimal duration of albumin therapy remains unclear. (37939273)

why give albumin?  

• Combining albumin with vasoconstrictors is evidence-based as front-line therapy for HRS-AKI.
• The mechanism by which albumin functions is unclear (proposals include adsorption of circulating toxins or perhaps improving the endothelial glycocalyx).
• Concentrated albumin has a low volume load and doesn't substantially affect volume status. Therefore, optimizing volume status should be performed independently of albumin administration (ignoring the effects of albumin).

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[10/12] vasoconstrictors in HRS-AKI

indication for vasopressors

• Most data on HRS-AKI were based on an outdated definition that required a creatinine value >2.5 mg/dL. (37939273) This may leave it unclear when vasopressors are indicated for patients with a creatinine level <2.5 mg/dL.
• Guidelines:
  • European guidelines recommend reserving vasoconstrictors for patients with HRS-AKI Stage IB (serum creatinine >1.5 g/dL) since milder forms are likely to resolve with fluid expansion alone. (29653741)
  • ACG guidelines (2021) and AASLD guidelines (2024) recommend vasoconstrictors for stages 2-3 AKI. (35006099, 37939273)
• In practice, for patients who are already admitted to the ICU, there may be little reason to delay vasopressor initiation.

norepinephrine is the frontline agent

• RCTs have generally found norepinephrine to be equally as effective as terlipressin, possibly with a superior safety profile (terlipressin may cause pulmonary edema). (25203311)
• Norepinephrine is more titratable than terlipressin, allowing immediate achievement of the target MAP.
• For patients who are admitted to an ICU, norepinephrine is easier to use and generally preferred.

BP target

• Achieving an increased MAP has been associated with improvements in renal function. (32928750) 
• A usual target is a MAP >15 mm above baseline. (31723234, 40473434, 38527522)

duration of IV vasopressors & transition to oral midodrine

• The optimal duration of IV vasopressor therapy is unknown, with clinical studies ranging from 5 to 14 days. (31723234)
• ADQI/ICA 2024 guidelines recommend stopping vasopressors when one of the following criteria is reached:
  • (a) Serum creatinine returns to within 0.3 mg/dL of baseline.
  • (b) Patient clearly fails to respond to vasopressors (e.g., persistent renal failure for >48 hours, or hemodialysis, or intractable anuria).
  • (c) Maximum of 14 days of therapy.
  • (d) Severe adverse reaction develops to the vasopressors. (38527522)
• Initiating oral midodrine may help facilitate weaning off IV vasopressors.
  • One RCT among outpatients with cirrhosis and refractory ascites found that chronic therapy with midodrine improved control of ascites and reduced mortality. (21749847) Although this is a small study, it does support the concept of using chronic midodrine therapy to support patients with cirrhosis and chronic systemic vasodilation.
  • The MIDAS trial did not support the use of oral midodrine in a general population of ICU patients being weaned off vasopressors. (32885276) However, midodrine may be more beneficial among patients with cirrhosis, chronic vasodilation, and poor renal function (impaired renal function may allow midodrine to accumulate and exert a smoother effect).

(other pressor options)

• Terlipressin:
  • Terlipressin is a selective agonist of V1 vasopressin receptors.  It is often recommended as the front-line vasopressor for HRS-AKI. However, there isn't clear evidence that terlipressin is actually superior to other vasoconstrictors. (28953318) 
  • Terlipressin has been associated with pulmonary edema, so it may be contraindicated among patients with evidence of intravascular volume overload (e.g., anasarca, jugular venous distension, hypoxemia, pulmonary congestion on chest radiograph, or elevated right ventricular systolic pressure on echocardiography). (36812435)
  • The strength of terlipressin is that it may avoid ICU admission. However, patients with HRS-AKI have an in-hospital mortality of 30-40% so they probably should be in an ICU anyway. ICU admission may facilitate interventions such as intra-abdominal pressure measurement, hemodynamic optimization, and vasopressor titration (with rapid acquisition of target MAP goals). Failing to treat HRS-AKI aggressively up-front may increase subsequent downstream costs.
• Vasopressin:
  • Vasopressin might be expected to have a similar efficacy compared to terlipressin, since it also hits the V1 vasopressin receptor.  However, this has not been investigated.
• Midodrine plus octreotide combination:
  • This combination has been found to be substantially less effective than terlipressin or norepinephrine. (25644760) Midodrine-octreotide could be considered in low-resource contexts, but it shouldn't be utilized for patients admitted to an ICU.
  • Midodrine is started at 10 mg PO q8hrs and aggressively uptitrated to increase the MAP by >10-15 mm (this strategy will not work if midodrine isn't adequately uptitrated). Octreotide may be given at a dose of 200 micrograms subcutaneously every 8 hours.
  • 🎶 Please note that octreotide is unnecessary for patients who are being treated with norepinephrine or vasopressin. The only evidence-based role of octreotide is as part of a cocktail combined with midodrine. (12830007)

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[11/12] paracentesis in HRS-AKI

• Moderate to large-volume ascites may elevate intra-abdominal pressure, thereby impairing renal perfusion (in these circumstances, renal perfusion pressure = MAP – IAP).
• Therapeutic paracentesis should be considered for patients with moderate to large-volume ascites and evidence of elevated intra-abdominal pressure. A frankly tense abdomen on examination is insensitive to abdominal compartment syndrome, so measuring bladder pressure may be more precise.
• Large-volume paracentesis plus albumin has been shown to improve renal function. (18197961, 18802688) 
• Some caution is warranted, as large-volume paracentesis without albumin administration is a known trigger of HRS-AKI. However, available evidence suggests that paracentesis combined with albumin may actually improve (rather than worsen) renal function. (32775831)
• Large-volume paracentesis combined with aggressive albumin repletion, along with intensive hemodynamic support and monitoring, is probably safe and effective.  
• (Further discussion of abdominal compartment syndrome: 📖)

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[12/12] hemodialysis in HRS-AKI

dialysis may be beneficial in some situations

• Bridge to liver transplantation or recovery from a reversible kidney insult.
• Diagnosis of HRS is unclear or dubious (e.g., kidney dysfunction is disproportionately severe compared to the degree of hepatic dysfunction).

dialysis may be nonbeneficial in other situations:

• Dialysis isn't generally recommended as a stand-alone therapy for HRS-AKI unless patients are candidates for liver transplantation. If liver transplantation isn't possible, then dialysis is unlikely to affect the overall course or prognosis of the disease. (32928750, AASLD guidelines 37939273)
• Patients with hepatorenal syndrome often have relative hypotension and endothelial dysfunction (causing difficulty retaining fluid within their vasculature). Intermittent hemodialysis may be difficult or impossible in this context, as patients may be unable to tolerate the hypotension and fluid shifts involved. Continuous renal replacement therapy (CRRT) is better tolerated, but this requires ongoing ICU admission, which isn't conducive to a high quality of life.

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HRS-AKI (background, presentation, diagnosis)

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clinical presentation of HRS-AKI

[#1/3] substrate: at-risk patients

• HRS-AKI usually occurs in the context of advanced cirrhosis with ascites (although it can occur in acute liver failure or alcoholic hepatitis).
• The greatest risk is among patients with chronically borderline perfusion due to vasodilation. Clinically, this may be revealed by:
  • Chronic hypotension.
  • Chronic hyponatremia.

[#2/3] precipitating factor may be present

• Any hemodynamic stress, such as:
  • Infection (especially spontaneous bacterial peritonitis).
  • Volume depletion (e.g., large volume paracentesis without albumin, hemorrhage, overdiuresis).
  • Volume overload (e.g., portopulmonary hypertension with systemic congestion).
  • Vasodilatory medications (e.g., ACE inhibitors).
  • Increased intra-abdominal pressure due to tense ascites.
  • Surgery.
• Deterioration in liver function (e.g., acute-on-chronic liver failure).

[#3/3] kidney injury due to hypoperfusion 

• This presents in a similar fashion to any other form of renal failure due to malperfusion, typically:
  • Oliguria (although the absence of oliguria doesn't exclude HRS-AKI). Early, abrupt anuria is uncommon in HRS-AKI and suggests an alternative diagnosis, such as urinary obstruction or dense ATN. (40473434)
  • Bland urine sediment (without evidence of glomerulonephritis or tubular necrosis).
• Elevated creatinine. When interpreting creatinine in patients with cirrhosis, bear in mind that these patients often have low muscle mass and enhanced renal creatinine secretion, leading to artificially low creatinine values. Therefore:
  • (#1) The creatinine level tends to overestimate renal function. For example, a patient with cirrhosis and a creatinine of 1.0 mg/dL may have substantial renal dysfunction.
  • (#2) Small changes in creatinine may be significant. For example, if the creatinine rises from a baseline of 0.3 mg/dL to 1 mg/dL, that may reflect a major reduction in renal function (and meet criteria for acute kidney injury).

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approach to diagnosing HRS-AKI

revised diagnostic criteria for HRS-AKI

• The following criteria are required:
  • [1] Cirrhosis.
  • [2] Ascites.
  • [3] AKI (based on KDIGO criteria, as described above).
  • [4] Intravascular volume status is deemed adequate. If volume resuscitation is deemed warranted, crystalloid should be provided, and the patient should fail to respond within 24 hours of the resuscitation. (38527522)
  • [5] Absence of strong evidence for an alternative explanation as the primary cause of AKI. This should include an evaluation with renal structure (CT/US), urinalysis, and relevant laboratory studies (further discussion of the approach to AKI is above).
• Historically, the diagnosis of HRS-AKI was only reached after a two-day fluid challenge with 1 gram/kg/day of 20-25% albumin. This prevented timely therapy of HRS-AKI (often allowing renal failure to worsen prior to intervention, thereby missing the optimal window for intervention). (32928750) Furthermore, some patients with HRS-AKI may actually be volume overloaded (rather than hypovolemic), so blindly loading every patient with a fixed dose of fluid doesn't make sense.
• This current definition of HRS-AKI is a huge improvement upon prior definitions. However, it must still be borne in mind that HRS-AKI can co-exist with other etiologies of renal failure (especially in more complex patients). Therefore, the presence of additional renal insults doesn't necessarily exclude a component of HRS-AKI:

defining and utilizing the entity of probable HRS-AKI 

• HRS-AKI is a medical emergency. If allowed to progress without intervention, it will worsen and become harder to treat (eventually, profound hypoperfusion may cause a transition from HRS-AKI to ATN). (32928750)
• Probable HRS-AKI refers to patients who are believed to likely have HRS-AKI following a thorough history, physical examination, review of prior medical records, and POCUS evaluation. The diagnosis of probable HRS-AKI can and should be made at the time of AKI diagnosis, without delay. Patients with probable HRS-AKI are likely to have HRS-AKI as either a sole cause of AKI or as a contributing factor.
• Criteria for probable HRS-AKI:
  • [1] Cirrhosis.
  • [2] Ascites.
  • [3] AKI.
  • [4] Initial evaluation (including H&P and POCUS) doesn't reveal an obvious alternative etiology.
  • [5] Chronically low or low-normal BP, especially if combined with chronic hyponatremia (noting, however, that sodium may be altered by other factors such as lactulose administration).
    • Baseline MAP <65 mm is suggestive of HRS-AKI.
    • Baseline MAP >80-85 mm argues somewhat against HRS-AKI.
    • Baseline MAP >90-95 mm argues strongly against HRS-AKI. (40473434)
• Management of probable HRS-AKI:
  • [1] Empiric therapy for HRS-AKI should be initiated immediately (e.g., albumin, vasoconstrictors). In the presence of probable HRS-AKI, the potential benefits of these therapies outweigh the risks.
  • [2] Ongoing thorough evaluation for any causes of AKI should occur as well. Excessive focus on HRS shouldn't lead to premature diagnostic closure. (A thorough evaluation for AKI is discussed above.)

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hepatorenal physiology, evolution, prevention

hepatorenal physiology: systemic vasodilation and renal vasoconstriction

• Liver failure causes systemic vasodilation by releasing vasodilators (e.g., nitric oxide) from the hepatic circulation. This causes:
  • Low systemic vascular resistance (SVR)
  • Low blood pressure
  • Increased cardiac output
• In attempts to compensate for this systemic vasodilation, the sympathetic nervous system and the renin-angiotensin-aldosterone system are activated (releasing endogenous norepinephrine and angiotensin-II).
  • Initially, these systems can compensate.
  • Beyond a certain point, patients develop refractory systemic vasodilation. Unfortunately, endogenous norepinephrine and angiotensin II remain effective at causing renal vasoconstriction. The ultimate result is systemic vasodilation and renal vasoconstriction, leading to inadequate renal perfusion.

relationship of HRS-AKI to acute tubular necrosis (ATN)

• HRS-AKI is due to intense renal vasoconstriction, causing renal hypoperfusion. As such, it may be conceptualized as a reversible form of “pre-renal” renal failure. If hemodynamic abnormalities are reversed, HRS-AKI is expected to resolve.
• However, if HRS-AKI is left untreated, hypoperfusion may eventually lead to dysfunction of the renal tubules (acute tubular necrosis), with intrinsic renal failure. Thus, HRS-AKI may eventually transition to a state of acute tubular necrosis (ATN). (31723234)

prevention of HRS with albumin administration

• For large volume paracentesis (>~5 liters), administration of ~8 grams albumin per liter of fluid removed may reduce the risk of hepatorenal syndrome. (3360270, 38527522)
• In spontaneous bacterial peritonitis, albumin has been proven to dramatically reduce the risk of hepatorenal syndrome (more on this here).

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dialysis modalities

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hemodialysis (hemodialyzer machine)

IHD (intermittent hemodialysis)

• Diffusion promotes solute clearance.
  • Urea, creatinine, and potassium usually leave blood.
  • Bicarbonate and usually calcium enter the blood.
  • Sodium may enter or leave (to equilibrate with dialysate).
• Convection (via ultrafiltration) allows for volume removal.
• High blood flow rate (~350-400 ml/min) and high dialysate flow rate (500-800 ml/min). (Schmidt 2024)

SLED (sustained low-efficiency dialysis) 🛷

• May be used as a PIRRT (prolonged intermittent renal replacement therapy).
• The blood flow rate is lower than with IHD (150-250 ml/min), as is the dialysate flow rate (100-200 ml/min). (Schmidt 2024)
• Typically, a slow hemodialysis session is performed over 8-12 hours daily. (Vincent 2024)
• The primary advantage of SLED is that it may allow for patient mobilization during the day.
• SLED is rarely used, usually in response to resource constraints. (Irwin 2023)

UF (ultrafiltration)

• Isolated ultrafiltration is performed, which solely removes fluid.
• Used for patients with isolated volume overload.

dialysate composition

• Potassium level: 1-4 mM.
  • 1 mEq/L used for severe hyperkalemia (does carry the risk of arrhythmias due to rapid potassium clearance). (Irwin 2023)
• Bicarbonate:
  • Usually 33-35 mM.
  • 40 mEq/L may be used for chronic hypercapnia, or severe acidosis.
• Calcium:
  • Usually 2.5 mM.
  • 3-3.5 mM may be used to avoid hypocalcemia (especially with acidosis correction). (Irwin 2023)

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CRRT (continuous renal replacement therapies using a hemofilter)

SCUF (slow continuous ultrafiltration)

• Fluid removal with minimal solute clearance.
• Similar to ultrafiltration (used for volume removal).

CVVH (continuous venovenous hemofiltration)

• CVVH = SCUF plus replacement fluid. Convection is used to achieve solute clearance and fluid removal.
• Ultrafiltrate is generated at 1-4 liters/hour and replaced with RF (replacement fluid). This creates high volumes of ultrafiltrate (~48-96 liters/day). (Irwin 2023)
• Convective clearance removes small and middle-sized molecules (<5000 Da), including cytokines. (Schmidt 2024)

CVVHD (continuous venovenous hemodialysis)

• This is purely dialysis, causing solute clearance via diffusion.
• The blood flow rate is slower than IHD (~100-250 ml/min), but the major difference is that the dialysate flow rate is much slower (25-30 ml/min, or ~1-2 liters/hour). This causes complete equilibration of solutes with the dialysate. (Irwin 2023)
• Effectively clears small molecules (<100 Da).

CVVHDF (continuous venovenous hemodiafiltration)

• This combines dialysis (diffusive clearance) and filtration (convective clearance).
  • Dialysate is infused at 1-2 liters/hour.
  • Replacement fluid is added at 1-2 liters/hour.
• May be unnecessarily complex (newer CVVHD machines are adequate and more straightforward). (Irwin 2023)

anticoagulation with CRRT

• Heparin is often necessary (e.g., bolus of 1000-2000 IU, followed by 10 IU/kg/hr to target an aPTT of 1.5-2 times normal). (Irwin 2023)
• Regional citrate anticoagulation limited to the CRRT circuit is recommended for patients without contraindications by the KDIGO-AKI Clinical Practice Guidelines. (Irwin 2023)
  • Advantages of regional citrate anticoagulation may include prolonged filter life, lower transfusion requirement, and reduced incidence of hemorrhagic complications. (Vincent 2024)
  • Ionized calcium must be monitored carefully, especially in patients with hepatic dysfunction (who may accumulate citrate, leading to reduced ionized calcium levels with elevated anion gap metabolic acidosis). Other risks include hypernatremia and hypomagnesemia.

electrolyte monitoring and adjustments

• Hypophosphatemia is common, but this may be mitigated by adding phosphate to dialysate.

dose of CRRT

• CRRT is dosed in terms of the effluent flow rate, with a range of 20-35 ml/kg/hr.
  • Effluent reaches equilibrium with the blood, so the effluent rate equals the clearance rate.
• A minimum dose of 20-25 ml/kg/hr should be delivered. (Schmidt 2024)
• Risk of inadequate dosing: poor metabolic control of acidosis or uremia.
• Risk of excessive dosing: micronutrient deficiency, excessive clearance of medications.

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selection of IHD vs. CRRT

advantages of CRRT

• [1] CRRT promotes greater hemodynamic stability (avoiding hypotension may promote renal recovery).
• [2] CRRT is superior for volume management. (CRRT is capable of slowly and continuously removing volume, which may achieve much higher amounts of fluid removal when multiple across 24 hours. Alternatively, IHD leads to intra-dialytic fluid accumulation.)
• [3] CRRT is preferred for patients with ICP elevation:
  • Less fluctuation in cerebral perfusion pressure and intracranial pressure.
  • Recommended by KDIGO guidelines for patients with cerebral edema.
• [4] CRRT is preferred in ALF (acute liver failure):
  • IHD may cause rapid clearance of water and solutes, causing elevated intracranial pressure.
  • EASL (European Association for the Study of the Liver) and KDIGO-AKI recommend CRRT instead of IHD.
  • Hyperammonemia may be an indication for dialysis in the context of acute liver failure to avoid intracranial pressure crises (discussed further: 📖).
• [5] CRRT can be safely utilized in severe hyponatremia:
  • IHD will immediately increase the sodium to a normal level. It is often impossible to reduce the dialysate sodium concentration to <130 mM.
  • CRRT may avoid rapid sodium shifts by adjusting the dialysate fluid (table below). An alternative strategy is to run a separate infusion of hypotonic fluid independent of the dialysate. (34218456)
• [6] Rhabdomyolysis or tumor lysis syndrome.
  • CRRT may be more effective than IHD for clearance of hyperphosphatemia.

advantages of IHD

• Preferred for intoxications due to more rapid toxin clearance.
• Preferred for extreme hyperkalemia.
• May facilitate physical therapy.
• May facilitate off-unit testing or procedures.

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criteria for discontinuation of CRRT in acute kidney injury

Criteria utilized in the ATN study: 

• Urine output >30 ml/hour.
• Six-hour timed urine collection is utilized to calculate creatinine clearance:
  • Creatinine Clearance = (Urine [Cr])x(Urine volume)/(Plasma [Cr])(360 minutes)
  • Creatinine clearance <12 ml/min: continue CRRT.
  • Creatinine clearance 12-20 ml/min: Individualize ongoing CRRT.
  • Creatinine clearance >20 ml/min: Discontinue CRRT. (18492867)

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tests not to order

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general utility of FeNa & urine eosinophils

• Urine electrolytes & fractional excretion of sodium (FENa):
  • Previously, it was believed that urine sodium excretion and fractional excretion of sodium (FENa) could help differentiate between “prerenal” and “intrinsic renal” failure. However, more recent evidence shows that FENa performs poorly. (27236480, 26689284, 27670788)
• Urine eosinophils have limited diagnostic value for acute tubulointerstitial nephritis. (24052222)

urine electrolytes in HRS-AKI aren't well supported by evidence

• Urine sodium and urinary fractional excretion of sodium (FeNa) are no longer part of the diagnostic criteria for HRS-AKI, due to inability to distinguish HRS-AKI from acute tubular necrosis.(32928750)
• Fractional excretion of urea (FeUrea) might be more useful. It can be calculated using MDCalc. A recent study found the following values:(29315697)
  • HRS-AKI: Median FeUrea ~17 (interquartile range ~5-30).
  • Prerenal azotemia: Median FeUrea ~26 (interquartile range ~15-48).
  • Acute Tubular Necrosis: Median FeUrea ~44 (interquartile range ~33-59).
• Values of FeUrea overlap considerably, so this test should be interpreted with caution. Furthermore, this study requires replication.
• Overall, currently there is no solid evidence-based medicine justification to use urine electrolytes to diagnose HRS-AKI. Urine electrolytes may be more likely to delay therapy and to mislead, rather than to provide useful information.

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furosemide stress test

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definition of a furosemide stress test

• Administration of a defined dose of furosemide:
  • 1 mg/kg for patients who are furosemide naive.
  • 1.5 mg/kg for patients with prior exposure to furosemide.
• Monitoring urine output
  • >200 ml within two hours indicates adequate response.

significance

• Failure to respond to a furosemide stress test suggests renal failure (with an increased risk of requiring hemodialysis). 🌊
• Please note that failure to respond doesn't exclude the possibility of renal recovery – especially if other resuscitative steps are available to improve renal function (e.g., improvement in blood pressure and/or perfusion).

clinical utility of a furosemide stress test?

• (1) The oliguric patient: Will additional hemodynamic manipulation help?
  • A furosemide stress test may be useful to obtain a concept of whether the patient has intractable intrinsic renal failure.
  • Failure to respond to furosemide implies that the kidneys are less likely to respond to hemodynamic manipulation (e.g., volume administration) and more likely to progress toward dialysis. Thus, a fluid-conservative strategy might be more beneficial.
  • Response to a furosemide stress test reveals that the kidneys are functional. Therefore, hemodynamic manipulations to maintain urine output (e.g., volume administration, inotropes, vasopressors) may be more likely to succeed.
• (2) A patient who is volume overloaded and requires diuresis:
  • Using the dose of furosemide prescribed in the furosemide stress test can help interpret the patient's response more rigorously.

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urine albumin to creatinine ratio (uACR)

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The value of uACR in acute kidney injury is debatable. Overall, its performance is superior to the traditional FeNa index (discussed above). Another advantage of uACR is that it can be used simultaneously as an indicator of intrinsic renal failure and as a screening test for severe glomerular disease (using different cutoff values).

quick guide to reference range(s)

• General reference range:
  • Normal <30 ug/mg.
  • Moderately elevated: 30-300 ug/mg.
  • Severely elevated: >300 ug/mg.
• uACR >70 may be consistent with preeclampsia. (38763516)
• uACR >85-100 ug/mg may support acute intrinsic renal failure. (26042740, 40473434)
• uACR >>300 ug/mg more specifically suggests glomerular disease.
• uACR >2,200 ug/mg is consistent with nephrotic-range proteinuria.

causes of elevation

• Acute intrinsic renal failure (due to impaired tubular reabsorption of albumin or glomerular disease):
  • ATN may be suggested by uACR >85 ug/mg (75% sensitive and 85% specific in one study of patients with cirrhosis). (26042740, 24375576, 21147844)
  • Among acutely ill patients, uACR functions as an indicator of intrinsic renal injury with performance that may be similar to other renal biomarkers (E.g., NGAL). (21147844, 26113474)
• Acute renal stress marker (analogous to a “renal troponin”):
  • uACR may elevate prior to renal failure, reflective of early injury/stress on the kidney.
  • Among patients with occlusive MI, elevated uACR predicts subsequent development of renal failure. (26113474)
• Chronic microalbuminuria: may be caused by chronic glomerular disease (e.g., often due to hypertension and/or diabetes).

interpretation of uACR in the context of AKI

• uACR <85-100 ug/mg supports isolated hypoperfusion (e.g., hypovolemia, HRS-AKI). (40473434)
• uACR >85-100 ug/mg supports a component of intrinsic renal failure or renal stress. However, this is nonspecific. For example, it may be seen chronically among patients with chronic hypertension or diabetes. Or it may indicate very early tubular injury that hasn't yet progressed to clinically overt renal injury.
• uACR >>300 ug/mg may more specifically suggest glomerular disease.

the relationship between uACR and total protein/creatinine ratio

• uACR may be roughly approximated as ~50-60% of the total protein/creatinine ratio.
• At lower values, the correlation is weaker.

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questions & discussion

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