Dialysis Lecture Notes
Biology of Kidney
Refer to Previous Lecture - Renal Clearance
Renal Clearance
Renal Clearance depends on GFR, tubular reabsorption, and tubular secretion.
Glomerular Filtration
Passive filtration of the blood as blood flows through the glomeruli of the kidney.
The extent to which a drug is filtered depends on the molecular size, protein binding, ionization, polarity, and kidney function in general. Smaller molecules and unbound drugs filter more readily. Highly ionized or polar drugs tend to be poorly reabsorbed.
Molecular Size: Smaller molecules are filtered more easily than larger ones.
Protein Binding: Only unbound drugs are filtered. Protein binding reduces the amount of drug available for filtration.
Ionization: Ionized drugs tend to be poorly reabsorbed, leading to increased excretion.
Polarity: Polar drugs are generally excreted more efficiently as they are less likely to be reabsorbed passively.
Kidney Function: Overall kidney health significantly influences filtration efficiency.
Tubular Secretion
Can increase the by actively secreting the drug.
The rate of secretion depends on the transporter. Different transporters have varying affinities for drugs.
If the transporter is slow, the secretion will depend on fu (fraction unbound).
Very efficient active transport (and an absence of any reabsorption) can lead to a maximum renal clearance. This is because the drug is actively removed from the blood, ensuring a high clearance rate.
Tubular Reabsorption
Some drugs may be reabsorbed after being filtered out of the blood. Thus, the may be smaller than expected (when considering only filtration and ).
If a drug is “completely” reabsorbed after filtration and no active secretion takes place, the renal clearance will be limited to the amount of drug that leaves the kidney as the urine flows into the bladder. This can be influenced by factors like urine flow rate.
Glomerular Filtration Rate (GFR) and Urine Output
Refer to Previous Lecture - Renal Clearance
Chronic Kidney Disease (CKD)
Definition: Abnormalities of kidney structure or function present for over 3 months that have implications on health.
Diagnosis:
Estimated glomerular filtration rate (eGFR) decreases to < 60 ml/min/1.73 m^2. This indicates a significant reduction in kidney function.
One or more markers of kidney damage e.g., albuminuria (elevated levels of albumin in the urine), histologically detected abnormalities (structural changes in kidney tissue).
Progressive disorder and stages classified based on the eGFR and albuminuria. The severity of CKD is categorized into stages based on these markers.
10 – 15% of the population with some degree of CDK, and over 1 million patients worldwide now receive renal replacement therapy to treat kidney failure.
Heightened risk of medication-related problems - dosing errors in patients with CKD still occur at an alarming rate. Impaired kidney function can significantly affect drug pharmacokinetics and pharmacodynamics, increasing the risk of adverse drug events.
ESRD, end-stage renal disease; also known as kidney failure. This is the final, irreversible stage of CKD requiring dialysis or kidney transplant.
Pharmacokinetic Changes in Chronic Kidney Disease (CKD)
Drug absorption and bioavailability
Delayed gastric emptying time and intestinal motility --> impact on Tmax and Cmax of drugs. This delay can reduce the rate and extent of drug absorption.
High gastric PH- Excess urea in the saliva transformed to ammonia by gastric urease
Resulting alkalinization affects the ionization and dissolution of drugs. Altered pH can change the solubility and absorption of drugs.
Drug bioavailability more variable in patient with impaired kidney function
Uremia decreases GI absorption of drugs and alters first pass hepatic metabolism
Distribution
Altered volume of distribution (e.g. dehydration or muscle wasting). Changes in body composition can affect how drugs distribute in the body.
Altered plasma protein and tissue binding of drugs. Reduced protein binding can increase the free fraction of drugs, potentially leading to enhanced effects or toxicity.
Metabolism and elimination
Uremia slows the rate of phase I metabolism – reduction, oxidation, hydrolysis – and some phase II metabolism pathways. This can result in prolonged drug half-lives.
Dependent on the kidneys for the removal of drug metabolites from the body. Reduced kidney function impairs the elimination of both drugs and their metabolites.
Complicated impact on drug metabolism including changes in the expression of several CYP enzymes (intestinal and hepatic) and transporters reported. CKD can affect the activity and expression of drug-metabolizing enzymes and transporters.
Elimination
Renal clearance depends on glomerular filtration rate (GFR), tubular reabsorption, and tubular secretion
GFR ↓ --> renal clearance ↓ --> plasma T1/2 ↑. Reduced GFR leads to decreased drug clearance and prolonged half-life, necessitating dosage adjustments.
Treatment Options for CKD
Renal replacement therapy
Hemodialysis
Also as haemodialysis, or simply dialysis
Achieves the extracorporeal removal of waste products such as creatinine and urea and free water from the blood when the kidneys are in a state of kidney failure. This process helps to maintain electrolyte balance and remove toxic substances.
Hemodialysis
Definition:
Process of removing heparinized blood from the body, passing through a semi permeable membrane on the opposite side of a dialysate.
Waste products and extra body fluid move from the blood into the dialysate and is discarded. The "clean" blood is then returned to the patients
For patients who are hemodynamically stable
Vascular access:
Intravenous catheter, arteriovenous fistula. AV fistulas are preferred for long-term access due to lower risk of infection and thrombosis.
Dialyzers
High flux (Most common)
Blood flow (~500 mL/min)
3-4 hour sessions
3 times a week
Dialyzers (High flux):
Fibers - Polysulfone, Polymethylmethacrylate, Polyacrylonitrile. These materials are chosen for their biocompatibility and efficiency in solute removal.
Dialysate
Countercurrent flow
500 - 800 mL/min
Various solutes and anticoagulants. The dialysate composition is adjusted to optimize waste removal and maintain electrolyte balance.
Waste and fluid removal:
Diffusion and Ultrafiltration
Concentration gradient against the dialyzer membrane Heparin
Dialysis prescription:
Flow rate,
Duration of dialysis
Dialyzer
Renal Replacement Therapy - Peritoneal Dialysis
A type of dialysis that uses the peritoneum in a person's abdomen as the membrane through which fluid and dissolved substances are exchanged with the blood
To remove excess fluid, correct electrolyte problems, and remove toxins in those with kidney failure.
Peritoneal Dialysis
Peritoneal dialysis:
Solution infused into peritoneal cavity.
Peritoneal membrane acts as dialyzer
For patients who are hemodynamically stable
Peritoneal physiology:
Contains 100 mL liquid
Can expand to hold several liters
Surface area of 1 - 2 m^2
Allows passage of larger MW substances
Catheters are used to gain access to peritoneal cavity
Dialysate:
High dextrose solution containing various solutes and anticoagulants. Dextrose creates an osmotic gradient to facilitate fluid removal.
Types of Peritoneal Dialysis
Continuous cyclic peritoneal dialysis
Cycler at night
Day dwell
Continuous ambulatory peritoneal dialysis
3 daily exchanges
1 long bedtime dwell
Measures of adequacy
where , D/P: dialysate to plasma urea concentration
Should be ~ 2.0 per week
Peritoneal Dialysis Prescription
Number of exchanges (CAPD)
Volume
Concentration of solutes
Properties of dialyzable drug
Vd < 1L/kg
Protein binding < 96%
Can better clear large molecules up to 15000 - 20,000 Daltons
Pharmacokinetic Changes in Patients with Hemodialysis
Changes in the expression levels of several CYP enzymes (intestinal and hepatic) and transporters reported. Hemodialysis can modulate the activity of drug-metabolizing enzymes and transporters.
Exposure (AUC) of Drugs That Are Mainly Renally Cleared in Severe Renal Impairment Patients and ESRD Patients on Chronic Hemodialysis (on a nondialysis day) as Compared With That in Subjects With Normal Kidney Function
Severe renal impairment patients compared to normal subjects
Telbivudine: 3.4-fold ↑
Entecvir: 5.2-fold ↑
Varenicline: 2.1-fold ↑
Emtricitabine: 2.9-fold ↑
Lomefloxacin: 3.4-fold ↑
ESRD patients on chronic hemodialysis compared to normal subjects
Telbivudine: 7-fold ↑
Entecvir: 8.4-fold ↑
Varenicline: 2.7-fold ↑
Emtricitabine: 4.5-fold ↑
Lomefloxacin: 7.4-fold ↑
Exposure (AUC) of Drugs That Are Mainly Cleared via Nonrenal Route in Severe Renal Impairment Patients and ESRD Patients on Chronic Hemodialysis (on a nondialysis day) as Compared With That in Subjects With Normal Kidney Function
Severe renal impairment patients compared to normal subjects
Rosuvastatin: 3-fold ↑
Maraviroc: 3.2-fold ↑
Telithromycin: 1.9-fold ↑
Lidocaine: 2-fold ↑
ESRD patients on chronic hemodialysis compared to normal subjects
Rosuvastatin: 1.5-fold ↑
Maraviroc: 2-fold ↑
Telithromycin: 1.07-fold (2-h postdialysis)
Lidocaine: 1.07-fold
Evaluating the Influence of Dialytic Therapies on the PK of a Drug
The primary questions
(1) whether the drug dosage should be adjusted because of dialysis;
(2) if so, by how much;
(3) and the timing of drug administration relative to dialysis. Understanding these factors is crucial for optimizing drug therapy in dialysis patients.
Intermittent hemodialysis (IHD)
Most common dialysis method used in ESRD patients in the United Stats
Study to include both on- and off-dialysis periods. This helps to assess the impact of dialysis on drug pharmacokinetics.
Important to record the blood flow (QB), dialysate flow (QD), and the make and model of the dialyzer used in the study to interpret study results and extrapolate to other dialysis conditions
Continuous renal replacement therapy (CRRT)
For critical care medications likely to be used in patients on CRRT, the findings from IHD studies might not be sufficient to derive dosing recommendations for patients using this modality