When the Brain and Kidney Collide: AKI After TBI 🧠🩺🩸

Overview 📋🧠🩸

• Traumatic brain injury (TBI) remains a major cause of mortality and morbidity 🛑🧍♂️, with nearly 50% of patients requiring ICU admission 🏥.
• 10% of ICU patients with TBI develop acute kidney injury (AKI), and 2% require kidney replacement therapy (KRT) ⚠️🩺🩸.
• Despite a lack of RCTs in this population, general principles can be applied for management 🧠📚.
• Preventing secondary brain damage—particularly through ICP reduction and CPP optimization—is a cornerstone in TBI management 🧠🧪.
• Mannitol and hypertonic saline are commonly used to manage raised ICP, but both carry AKI risk, particularly mannitol ⚠️🧪🩺.
• Achieving adequate perfusion pressure is vital for both brain and kidney; this requires fluids + vasopressors, ideally guided by hemodynamic monitoring 📊🩺.
• Resuscitation with hypotonic or balanced fluids may worsen brain edema, whereas saline can cause hyperchloremia—a known AKI risk ⚠️🧠🧪.
• Individualizing CPP targets and hemodynamic support—especially in those with chronic hypertension—is under investigation 🔬🧠.
• In TBI patients needing KRT, continuous techniques are preferred to avoid sudden osmotic shifts that can raise ICP 🧠🛑.
• Monitoring ICP and CPP is crucial, especially at KRT initiation.

Introduction 🧠📚🩺

• TBI is a major driver of hospital admissions and mortality, causing over 50,000 deaths/year in Europe ⚠️📉.
• Observational studies report variable AKI incidence in TBI depending on definitions and timing during ICU stay ⏳📊.
• The CENTER-TBI study found:

~50% of TBI patients were admitted to ICU

40% had systemic disease

25% were >65 years old

55% had extracranial lesions 🧍♂️🧠🩺

• A subanalysis of CENTER-TBI (ICU >72h) revealed:

12% developed AKI using KDIGO creatinine criteria

AKI occurred early (median day 2)

Associated with longer ICU stay and higher 6-month disability 🏥⏳📈

• The EPO-TBI trial post hoc analysis showed:

15.9% AKI incidence in first 3 weeks by KDIGO creatinine criteria ⚠️

• An Australian study found:

9.2% AKI incidence using RIFLE criteria

AKI associated with increased mortality ⚠️🩸

• A large American cohort (n=37,851) reported:

2.1% incidence of severe AKI

Strong association with mortality, morbidity, and longer hospital stay 🏥📉

• Because AKI is a frequent complication in TBI patients, this article provides a comprehensive overview of its prevention and treatment strategies 🔍🧠🩺 (see Fig. 1 and Table 1 in the article).

Pathophysiology of AKI in TBI 🧠🩺🧪

• The mechanism of AKI in TBI is not fully understood, but inflammatory mediators are likely central 📊🧪.
• TBI causes systemic and CNS cytokine release, particularly IL-6, which is linked to:

AKI post-cardiac surgery

AKI in sepsis

IL-6 levels are higher in CSF than serum due to low BBB permeability, but serum IL-6 still correlates with renal injury biomarkers like NGAL 📊🧪

• IL-6, IL-8, and IL-10 levels are strongly linked to MODS and other organ dysfunctions in TBI patients 📈🩺.
• Tubular cell studies show TBI patient serum increases neutrophil adhesion and apoptosis compared to healthy serum—suggesting direct nephrotoxic mediator effects 🔬🧬.
• However, it remains unclear whether IL-6 itself or other mediators are responsible.
• Another key mechanism is catecholamine surge post-TBI, which:

Causes renal vasoconstriction

Enhances sodium reabsorption

Correlates with TBI severity 🧠🩸

• Therapeutic strategies like vasopressors, fluids, hyperosmolar agents can all affect kidney function ⚠️🧪.
• Moreover, major trauma often coexists with TBI, contributing to AKI via:

Hypovolemia

Rhabdomyolysis

Nephrotoxins

Abdominal compartment syndrome

Direct renal trauma

Massive transfusions 💉🛑

Bidirectional Organ Crosstalk: Brain-Kidney Axis 🧠↔️🩺

• AKI itself can adversely affect the brain, worsening TBI outcomes 🧠⚠️.
• Mouse models of ischemic AKI show:

Increased brain macrophages, pyknotic neurons

Glial activation, BBB disruption

Therefore, preventing AKI is crucial in patients with TBI to maximize neurological recovery 🧠⛑️.

Management of Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) 🧠🖥️🩸

Pathophysiological Background and CPP Target 🧠📊🧪

• Secondary brain injury occurs due to hypoxia, hypotension, or elevated ICP, and arises within hours to daysafter TBI ⏳🛑.
• Prevention of secondary injury is key—requiring a multimodal approach addressing both intracranial and systemic derangements 🧠📋.
• TBI may cause:

Hematomas, contusions, hydrocephalus, diffuse swelling

All leading to increased ICP 🧠⚠️

• Guidelines recommend ICP monitoring and treatment in severe TBI 📚🩺.
• Patients with AKI often present with lower GCS and are more likely to receive ICP monitoring than those without AKI 📉🧠.

CPP Goals and Autoregulation 🩺📊🧠

• CPP = MAP – ICP. Target range is 60–70 mmHg per guidelines 📐🧠.
• Cerebrovascular autoregulation (CAR) is often impaired in TBI and varies across time and patients.
• The Pressure Reactivity Index (PRx)—a moving correlation between MAP and ICP fluctuations—is proposed to monitor CAR 🖥️📊.
• One retrospective single-center study found that a better match between CPP and PRx-based optimal CPPcorrelated with better neurologic outcomes 📈🧠.
• However, a RCT comparing PRx-based CPP management found:

No significant outcome difference

CPP targets were achieved in <50% of patients randomized to PRx strategy ⚠️📊.

Renal Autoregulation and MAP in AKI 🩺🧠📊

• Renal autoregulation is also disrupted in AKI.
• Its effective range depends on chronic blood pressure status.
• For example:

In septic patients with chronic hypertension, a higher MAP (85 mmHg) may prevent severe AKI and reduce KRT need ⚠️📈.

In contrast, patients >65 years benefited from lower MAP (60–65 mmHg) in one study (vs. 72 mmHg in usual care), showing reduced mortality 📉.

• CENTER-TBI showed >25% of patients were over 65 years, highlighting individualized MAP targets may be necessary rather than universal ones 🧠🧍♂️.
• SIBICC guidelines emphasize: when adjusting MAP, always evaluate ICP and neuromonitoring to avoid cerebral hypo- or hyperperfusion 🧠🖥️.

Resuscitation and Maintenance Fluids 💧🩺🧠

Fluid Type 🧪🩺

• A multicenter survey showed that clinicians often combine crystalloids + vasopressors to achieve CPP targets 💉📊.
• Early resuscitation fluids aim to restore volume, especially with extracranial injuries 🧍♂️🩺.
• Hypotension is consistently linked to higher mortality in TBI ⚠️📉.
• One study found that low cardiac output by ultrasound was linked to increased mortality 📉🫀.

Hypertonic Saline vs. Isotonic Solutions 🧂💧

• Hypertonic saline (7.5%) can address hypovolemia + ICP elevation.
• In trauma patients, prehospital hypertonic saline increased MAP more effectively than Ringer’s Lactate 🧪📈.
• In a RCT of 229 TBI patients, hypertonic saline lowered ICP more than isotonic solutions, though no 6-month outcome benefit noted ⚠️🧠.
• Serum sodium and chloride were significantly higher in the hypertonic saline group, but AKI data were not reported.
• Hyperchloremia can cause afferent arteriolar vasoconstriction, impairing glomerular perfusion and promoting AKI ⚠️🩸.
• A larger RCT (n=1331) comparing various hypertonic solutions also showed no difference in mortality but noted more hypernatremia—again with no renal data provided ⚠️🧠.

Albumin and Colloids 🧪⚠️

• Albumin (4%) was linked to higher mortality in TBI patients in the SAFE trial subgroup (n=460) ⚠️🧠.
• Further analysis (n=321 with ICP monitoring) showed:

Higher ICP + ICP slope

More sedative/vasopressor needs

Possibly due to BBB leak of albumin increasing cerebral edema 🧠🧪

• Despite risks, 23% of respondents in a recent survey still used albumin for TBI 💉.
• Albumin did not increase KRT use in SAFE or ALBIOS trials, but a retrospective study (>60ml/kg in 24h)found:

Higher risk of severe AKI

But lower 30-day mortality and major adverse kidney events than saline after adjustment ⚠️📈.

Starches ⚠️🛑

• Several RCTs showed higher mortality + AKI risk in ICU patients receiving starches vs. saline ⚠️.
• One RCT included TBI but sample size was too small to conclude.
• In a retrospective trauma cohort (n=2225), 6% hetastarch was linked to higher mortality and AKI, especially in major TBI ⚠️📊.
• ESICM guidelines now recommend against colloids in TBI due to AKI risk.

Crystalloids: Saline vs. Balanced 💧📊

• Multiple large RCTs (e.g., PLUS, SMART, BaSICS, PLUS-PLS) compared saline vs. balanced crystalloids.
• Results:

No major difference in AKI rates

In one Brazilian RCT, saline reduced 90-day mortality in TBI without increasing AKI ⚠️📉.

Hyperchloremia occurred more with saline, but not clearly associated with AKI 🧪.

Fluid Dose ⚖️🧠

• Both hypovolemia and fluid overload increase mortality in TBI 🩺⚠️.
• Fluid accumulation is common in AKI patients, starts before AKI onset, and worsens afterward 📈🛑.
• Excess fluid correlates with:

Higher ICU mortality

Delayed renal recovery ⏳⚠️

• The REVERSE-AKI pilot trial showed restrictive fluids + diuretics improved renal function in early AKI patients .
• TTE-guided resuscitation in TBI reduced fluid use and mortality in ED (n=72) 📉.
• New methods to evaluate volume status (e.g., occlusion maneuvers) exist, but safety in TBI is unproven 🧠🧪.

Hyperosmolar Therapy 💧🧠⚠️

• Hyperosmolar therapy is used to treat refractory ICP elevation after standard measures (sedation, ventilation, temp control) fail 🧠🔥.
• These agents increase serum osmolarity, pulling fluid from brain tissue to reduce edema and ICP 📉.
• Mannitol and hypertonic saline are the mainstays 🧂⚖️.
• CENTER-TBI data revealed:

AKI patients received more osmotic therapy

Mannitol use was associated with higher AKI risk than hypertonic saline ⚠️📊.

• Similarly, an Australian study found:

Both agents linked to AKI

But only mannitol showed time-to-AKI association in multivariate analysis ⚠️📉.

• Hypertonic saline may thus be a safer option, although hyperchloremia and hypernatremia from it also carry AKI risk 📈🛑.
• In CENTER-TBI, hypernatremia had a hazard ratio of 1.972 for AKI after adjustment ⚠️.
• A retrospective study of 123 patients showed:

Duration of hyperchloremia, not peak levels, independently predicted AKI 🧪📊.

Novel Hyperosmolar Options 🧪🧠

• A pilot trial in SAH patients evaluated low-chloride hypertonic saline (sodium acetate):

Showed lower chloride rise and less AKI (KDIGO 1-2) ⚠️

Limitations: small size, early stop, timing overlap of AKI onset and randomization

• Sodium lactate is another emerging agent:

A systematic review found it equal to mannitol in ICP reduction

Effects lasted longer, and CPP was higher after 30 mins 🧠📈

No trials yet compare it with hypertonic saline or examine its renal impact

Vasopressors 💉🧠📊

• Aim: Increase MAP to ensure CPP, but caution is needed as some may impair cerebral autoregulation (CAR) ⚠️🧠.
• Phenylephrine and norepinephrine are commonly used; dopamine is still used in ~22% of cases 📊.

Dopamine: Not Recommended 🚫🧠

• Dopamine increases ICP, despite similar MAP to norepinephrine ⚠️.
• It also unpredictably affects CPP, and disrupts pituitary hormone levels 🧪📉.
• Animal data show beta-agonists increase CBF and metabolism, but metabolism > CBF → mismatch and potential damage ⚠️.

Phenylephrine: Mixed Data 🧠📊

• Raises MAP and CPP, but can increase ICP if CAR is impaired ⚠️.
• Data from animal models show increased CBF despite vasoconstriction, but clinical relevance is unclear 🔬.

Vasopressin (AVP) 💧🧠

• Potent vasopressor with no inotropic effect—doesn’t raise cerebral metabolism 🧠⚖️.
• Acts as antidiuretic hormone, increasing water retention, potentially causing hyponatremia + cerebral edema⚠️.
• Retrospective study: AVP recipients had lower mannitol + 3% saline needs, and no sodium difference ⚖️.
• AVP also improved cerebrovascular compliance via CO2 reactivity testing 🧠📉.
• In septic patients, AVP:

Did not reduce AKI days, but lowered KRT need in one RCT

Another RCT showed less AKI in post-cardiac surgery AVP group

• In TBI, a 96-patient RCT showed higher AKI incidence with AVP vs. catecholamines—but had baseline imbalances ⚠️

Angiotensin II 🧬

• Approved for vasodilatory shock
• Effective/safe as add-on to norepinephrine in RCTs 🧪
• No TBI-specific data available yet 🔬

Bottom line:

• Norepinephrine is first-line 🧠✅
• Phenylephrine, AVP, Ang-II need further TBI-specific study 🧪🧠

Respiratory Support 🫁🖥️

• Most common non-neuro organ failure in TBI patients is respiratory 📉🫁.
• Hypercapnia → vasodilation → narrows MAP-CPP plateau
• Hypocapnia → vasoconstriction → ↓CBF ⚠️🧠
• Hence, CO₂ targets: 35–45 mmHg, unless ICP is elevated 🧠📐.
• TBI patients with AKI:

More likely to develop respiratory failure

Need longer mechanical ventilation (MV) ⏳🫁

Lung-Protective Ventilation (LPV) 🫁📊

• RCTs in ARDS show conventional MV worsens renal function vs. LPV 🧠🩺
• LPV benefits: less AKI, better neuro/respiratory outcomes
• TBI-specific RCTs are limited
• A new multicenter trial (VENTIBRAIN) will clarify MV practices in TBI 🧪

Glucose Control and Nutrition 🍽️🧠🧪

Glucose Control 🧁🩺

• Hyperglycemia = poor neurologic outcome 📉
• Van den Berghe et al. showed:

Tighter glycemic control (80–110 mg/dl) → ↓ICP + better outcomes in TBI subgroup

Also renoprotective effects 🧠🩸

• But other RCTs:

Found no neuro benefit

Reported more hypoglycemia with intensive insulin ⚠️🧠

• A large database study (n=44,964) in diabetics showed:

Moderate glycemia (110–180) → lower mortality than tight control 📉

Conclusion: Avoid both extremes; keep glucose <180 mg/dl, particularly where hypoglycemia risk is high 🩺⚠️.

Nutritional Support 🥣🧠

• BTF guidelines recommend feeding by day 5 post-injury 🧠🍽️
• Observational studies suggest early feeding → better outcomes 📈
• In general ICU populations:

Parenteral nutrition → ↑ureagenesis

May affect ICP and renal function if not monitored ⚠️🧠

• High protein intake can raise urea, potentially elevating ICP if BBB compromised 🧠🧪.
• Urea itself has been used historically to lower ICP, but later rebound risk exists ⚠️

Kidney Replacement Therapy (KRT) in TBI 🩸🧠⚙️

• 1.8% of TBI ICU patients required KRT in CENTER-TBI .
• A study showed no overall outcome difference between intermittent vs. continuous KRT, but:

In TBI with elevated ICP, continuous KRT preferred ⚠️

• Rationale:

Compartmentalization of osmoles → plasma osmolarity drops faster → brain herniation risk ⚠️🧠

• Hemofiltration may be safer than hemodialysis for high-risk patients.
• Intermittent KRT should:

Use slow flow rates

Adjust dialysate sodium

Extend session length 📉🩸

• Anticoagulation: Prefer regional citrate → longer filter survival + astrocyte protection 🧠🛡️

Future Directions 🔮📚🧠

• Need for RCTs to assess all strategies discussed.
• Prognostic calculators for AKI and TBI-specific prediction tools can help select high-risk patients for trials .
• Until then, clinicians should:

Balance potential benefits

Monitor closely for side effects

Apply individualized, cautious interventions ⚖️🧠

Reference 📖

De Vlieger G, Meyfroidt G. Kidney Dysfunction After Traumatic Brain Injury: Pathophysiology and General Management. Neurocrit Care. 2023;38(3):504–516. doi:10.1007/s12028-022-01630-z

Suggestions for Further Reading📚

1. Steyerberg EW, et al. Lancet Neurol. 2019;18(10):923–34.
2. Robba C, et al. Crit Care Med. 2021;49(1):112–26.
3. Skrifvars MB, et al. Crit Care Med. 2021;49(4):E394–403.
4. Moore EM, et al. Ren Fail. 2010;32(9):1060–5.
5. Van den Berghe G, et al. N Engl J Med. 2001;345(19):1359–67.