RRI Conference 2022 | Isaac Teitelbaum "Novel Uses for Peritoneal Dialysis"

Scientific Concepts, Discoveries, and Nature/Clinical Phenomena

1) Peritoneal Dialysis (PD) and Its “Novel Uses”

PD is discussed not only in its conventional role for kidney failure, but also as a drug/toxin-removal platform. The video highlights two experimental/novel applications:

• Liposome-supported peritoneal dialysis (LSPD) for scavenging/clearing substances
• Conventional PD for acute ischemic stroke, targeting glutamate removal

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2) Liposomes and “Liposome-Supported” PD (LSPD)

Key Mechanism: Liposomes as Programmed Molecular Traps

Liposomes are spherical, nanoscale particles with:

• a phospholipid bilayer membrane
• an aqueous core

They can be “programmed” for trapping by engineering a pH gradient, for example:

• acidify the liposome core
• basic molecules entering the core become protonated and are trapped
• this enables sequestration of the target molecules

Why Peritoneal Delivery Helps vs IV Delivery

For LSPD, liposomes are introduced into the peritoneal cavity. The rationale given includes size/penetration considerations:

• Liposomes are ~8,500 Å
• Albumin diffuses to some extent (~37 Å)
• Complement components are ~100 Å and “don’t readily enter the peritoneum”

Claimed consequence:

• Much lower risk of CARPA (Complement Activation Related Pseudo-Allergy), which can occur with IV liposomes

Potential Targets for LSPD

A) Exogenous Toxins (Drug Overdoses)

Verapamil overdose is emphasized as a strong candidate because conventional extracorporeal removal is difficult:

• highly protein-bound
• lipophilic
• causes hemodynamic instability
• no specific antidote discussed
• hemodialysis may be technically difficult

Observed effects in rat experiments (time-course):

• After a very large verapamil dose in rats and delayed initiation of LSPD:
  • ~30-fold removal by 4 hours
  • ~80-fold removal by 12 hours vs conventional PD
• Hemodynamic benefit:
  • PD alone attenuated hypotension somewhat
  • LSPD better attenuated mean arterial pressure decline
  • improved recovery time (from ~20 hours to ~6–7 hours)

Other exogenous toxins evaluated:

• A list is referenced; the reported pattern is:
  • for most toxins tested (with phenobarbital not clearly significant),
  • LSPD markedly improved removal vs conventional PD

B) Endogenous Toxins

1. Ammonia

Clinical context:

• Hyperammonemia in hepatic dysfunction and some urea cycle disorders
• Leads to altered mental status and cerebral edema

Standard therapies noted:

• lactulose
• rifaximin
• sometimes hemodialysis / CRRT

Motivation:

• In critically ill patients (e.g., decompensated ESLD with cerebral edema), hemodialysis may be poorly tolerated.

Rationale for LSPD:

• Ammonia is described as lipophilic and weakly basic, potentially suited to pH-trapping in liposomes.

Animal evidence:

• Rats:
  • conventional PD showed little ammonia removal
  • LSPD showed substantial ammonia removal
• With a human acidic fluid condition (to mimic peritoneal environment in ESLD):
  • ammonia removal was maintained
• Mini-pig ESLD model:
  • reportedly no CARPA observed (per the speaker)

Drug-interference concern:

• Potential inhibitors tested:
  • beta blockers
  • vasopressors (e.g., epinephrine)
  • antibiotics
• Key detail:
  • these are small molecules (~250–360 Daltons)
  • used at 1 millimolar, described as ~200× plasma levels
• Result:
  • inhibited LSPD efficiency in the experimental setup
  • raising questions about relevance at physiological dosing

Human evidence (early trial):

• A small trial used VSO1 for ammonia removal:
  • ascites patients with overt hepatic encephalopathy (dose escalation described)
• Safety:
  • no serious adverse events reported
• Efficacy signals reported:
  • improved psychometric test results
  • increased peritoneal clearance of ammonia/metabolites
  • reduced plasma ammonia
• Note:
  • the speaker emphasizes limited access (abstract-level perspective) and need for primary data

2. Protein-Bound Uremic Toxins

Target problem: These toxins are heavily protein-bound, reducing the effectiveness of standard dialysis.

Examples explicitly named:

• indoxyl sulfate / indoxyl-3-sulfate
• doxyl sulfate
• indol-3-acetic acid (IAA)

Proposed approach:

• use albumin-facilitated dialysis or liposome-supported PD as a “binder/sink”
• conceptually: increase removal by introducing a sink for protein-bound solutes

Reported findings:

• For PCS and indoxyl sulfate:
  • no major difference between albumin-facilitated dialysis and LSPD vs standard PD
• For 3IAA / indol-3-acetic acid:
  • albumin seemed slightly better than LSPD

Practical note:

• liposomes are presented as less expensive than albumin

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3) PD as a Neuroprotective Strategy in Acute Ischemic Stroke via Glutamate Removal

Neurobiology and Pathophysiology Described

• L-glutamate is the primary excitatory neurotransmitter in the CNS.
• During stroke:
  • energy failure disrupts reuptake and ion pump function
  • glutamate accumulates extracellularly
  • causes excitotoxicity via sustained receptor activation
• Downstream cascade described:
  • influx of calcium and sodium and water
  • reactive oxygen species generation
  • inflammation
  • mitochondrial/oxidative phosphorylation uncoupling
  • apoptosis and cell death

Clinical association mentioned:

• higher blood glutamate correlates with progression in acute ischemic stroke

Therapeutic Concept Tested

• The strategy is to lower plasma glutamate to reduce injury
• With safety concerns: avoid worsening brain perfusion/edema

Alternative drug strategy mentioned (scavenger):

• Glutamate oxaloacetate transaminase (GOT) converts glutamate to 2-ketoglutarate and aspartate
• claimed effects (from animal work):
  • reduced plasma glutamate
  • decreased infarct volume
  • reduced edema

Why Dialysis (and Why PD Specifically)

• Glutamate is given a molecular weight of ~147 Da, described as suitable for dialysis removal.
• Hemodialysis concerns noted:
  • systemic blood pressure effects
  • cerebral perfusion effects
  • osmotic shifts

Therefore, the focus is on peritoneal dialysis.

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Preclinical (Rat) Stroke Model Results

• Stroke model used:
  • permanent middle cerebral artery occlusion (pMCAO)

Findings:

• stroke increases plasma glutamate
• PD started ~2.5 hours after occlusion significantly reduces the glutamate rise
• when dialysate is spiked with glutamate, the protective effect is lost

Infarct outcomes:

• infarct volume is reduced when PD is used after stroke
• delay tolerance described:
  • starting around 5 hours still yields reduction
  • reported ~40–50% reduction at 24 hours
• relationship described:
  • linear correlation between plasma glutamate concentration and infarct volume

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Clinical (Human) Evidence

1) Proof-of-Principle Study in Non-Stroke ESRD Patients (Israel)

• PD reduces serum glutamate (example):
  • ~110 down to ~60 after ~4 hours (approx.)
• Dialysate glutamate accumulates over time
• Dialysate-to-plasma ratios approach ~1 by ~3–4 hours
• implication:
  • multiple exchanges could meaningfully reduce plasma glutamate

2) European Randomized Controlled Trial in Acute Ischemic Stroke (Madrid, ~2012)

• Study type:
  • open randomized controlled study assessing safety/viability and neuroprotective effect
• Enrolled:
  • 10 patients, 5 peritoneal dialysis group vs control (as described)
• Planned protocol:
  • 6 exchanges of 2 liters every 4 hours
  • start within 13 hours of stroke

Major feasibility failure:

• only 1/5 completed the full PD protocol
• others had technical issues (e.g., misplaced catheter, incomplete exchanges)

Outcomes:

• intention-to-treat:
  • glutamate reduction not statistically significant
• excluding the catheter-misplacement case:
  • glutamate reduction became significant
• neurological function and infarct size:
  • no change overall
• single successfully treated patient:
  • reportedly good 3-month outcome (modified Rankin score 1)
  • speaker estimates such outcome would be unlikely spontaneously (~2%)

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Overall Conclusion for the Stroke Section

• PD appears able to lower serum glutamate
• Clinical benefit remains unproven, largely due to technical/implementation limitations
• Further studies needed:
  • especially improving catheter placement and earlier initiation (e.g., within 6–12 hours)

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Researchers or Sources Featured (as Named in the Subtitles)

• Isaac Teitelbaum (speaker)
• Complement system / CARPA (concept; not a person)
• Israel (country source for one study; no named investigator)
• European trial (Madrid, 2012) (no named investigators given)
• Rankin score / modified Rankin scale (named clinical scale; not an individual researcher in subtitles)