lec 22 - dialysis (yang)

background: kidney

• bean shaped structure

• each kidney weights ~150 grams

• consists of cortex (outer) and medulla (inner)

• millions of nephrons

• each nephron consists of

  • glomerular apparatus

  • proximal tubule

  • loop of henle

  • distal tubule

  • collecting ducts

• types of nephrons

  • cortical

  • intermedial

  • juxtamedullary

renal clearance depends on…

• GFR

• tubular reabsorption

• tubular secretion

glomerular filtration (GFR)

• passive filtration of the blood as blood flows through the glomeruli of kidney

• extent to which a drug is filtered depends on:

  • molecular size

  • protein binding

  • ionization

  • polarity

  • kidney function

tubular reabsorption

• some drugs may be reabsorbed after being filtered out of the blood

• thus, CL_R may be smaller than expected (when considering only filtration and CL_R = GFR * fu)

• if a drug is “completely” reabsorbed after filtration and NO active secretion takes place, renal CL will be limited to the amount of drug that leaves the kidney as the urine flows into the bladder

tubular secretion

• can increase the CL_R by actively secreting the drug (as opposed to only passive diffusion in GFR)

• rate of secretion depends on the transporter

  • if transporter is slow, secretion will depend on fraction unbound

• very efficient active transport (an absence of any reabsorption) → max renal CL

GFR and urine output

GFR

• kidneys receive 20% cardiac output

  • 5 L/min (cardiac output) * 0.2 = 1 L/min

• 60% of this volume is plasma

  • 1 L/min * 0.6 = 0.6 L/min

• 20% is filtered (passes thru glomerular barriers)

  • 600 mL/min * 0.2 = 120 mL/min just GFR

urine output

• rate of excretion = rate of filtration - rate of absorption + rate of secretion = 120 mL/min

  • 120 mL/min * 1440 min/day = 172.8 L day

• 120 mL/min - reabsorption (no secretion) = 172.8 L/day - 99% = 1.78 L/day * 0.01 = 1.73 L/day

chronic kidney disease (CKD)

• definition = abnormalities of kidney structure or function present for over 3 months that have implications on health

• diagnosis

  • estimated GFR decreases to <60 mL/min/1.73m²

  • 1 or more markers of kidney damage e.g. albuminuria, histologically detected abnormalities

• progressive disorder and stages classified based on eGFR and albuminuria

• 10-15% of the population with some degree of CDK and over 1 million pts worldwide now receive renal replacement therapy to treat kidney failure

• heightened risk of medication-related problems → dosing errors in pts with CKD still occur at alarming rate

• classification of kidney function → eGFR (mL/min/1.73 m²)

  • normal or high → >90

  • mildly decreased → 60-89

  • mild-to-moderately decreased → 45-59

  • moderately to severely decreased → 30-44

  • severely decreased → 15-29

  • kidney faillure (ESRD) → <15

PK changes in chronic kidney disease (CKD)

drug absorption and bioavailability

• delayed gastric emptying and intestinal motility → impact on Tmax and C max of drugs

• high gastric pH

  • excess urea in the saliva transformed to ammonia by gastric ureas → raises pH

  • resulting alkalization affects the ionization and dissolution of drugs

• drug bioavailability more variable in pts with impaired kidney function

• uremia (increased urea) decreases GI absorption of drugs and alters 1st pass metabolism

distribution

• altered volume of distribution (e.g. dehydration or muscle wasting)

• altered plasma protein and tissue binding of drugs

metabolism

• uremia slows the rate of phase I metabolism (reduction, oxidation, hydrolysis) and some phase II metabolism pathways

• dependent on the kidney for the removal of drug metabolites from the body

• complicated impact on drug metabolism including changes in the expression of several CYP enzymes (intestinal and hepatic) and transporters reported

elimination

• renal CL depends on GFR, tubular reabsorption, and tubular secretion

• decreased GFR → decreased renal CL → increased plasma half life

treatment options

• CKD → end-stage kidney disease

  • → conservative treatment: for early stages

  • → renal replacement therapy

    • → transplant

    • → dialysis: mechanically replaces kidney function by removing waste and fluid

      • → inpatient hemodialysis: done at dialysis center or hospital

      • → home hemodialysis: pt or caregiver operates dialysis machine at home

      • → automated peritoneal dialysis: done at night using a machine while the patient sleeps

      • → continuous ambulatory peritoneal dialysis: done manually during the day WITHOUT a machine

renal replacement therapy: hemodialysis

• also known 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 failure

• diagram

  • blood is removed from the body

  • blood pump actively draws blood from the dialysis circuit → ensures constant, controlled flow rate

  • dialyzer (filter) = artificial kidney

    • blood flows thru semi-permeable membranes

    • waste products, excess ions, and fluid move across the membrane into the dialysate

  • filtered blood is returned to the body

renal replacement therapy: hemodialysis (more in depth?)

• definition

  • process of removing heparinized blood (anticoagulant) from the body, passing thru a semi-permeable membrane on the opposite side of a dialysate

  • waste products and extra body fluid move from the blood → dialysate and is discarded; clean blood is then returned to the patients

  • for patients who are hemodynamically stable

• vascular access

  • IV catheter, arteriovenous fistula

• dialyzers

  • high flux (most common)

    • blood flow = ~500 mL/min

    • 3-4 hour sessions

    • 3 times a week

• dialyzers (high flux)

  • artificial fibers that mimic kidney’s filtering function

    • polysulfone

    • polymethylmethacrylate

    • polyacrylonitrile

• dialysate

  • fluid that is on the opposite side of the membrane from the blood

  • concurrent flow → dialysate moves in the opposite direction to blood → maximizes gradient and waste removal

  • flow rate = 500-800 mL/min

  • various solutes and anticoagulants

• waste and fluid removal

  • diffusion → solutes like urea, creatinine, K+

  • ultrafiltration → removal of excess water via pressure gradient

  • concentration gradient against the dialyzer membrane (pull water out)

• dialysis prescription

  • flow rate

  • duration of dialysis

  • dialyzer

• measures of adequacy

  • urea reduction ratio (URR)

    • [(BUN_pre - BUN_post)/BUN_pre]*100

    • >70% is considered adequate (KDOQI guidelines)

  • Kt/V

    • Kt = dialyzer CL of urea

    • T = duration of dialysis

    • V = volume of blood cleared from urea

    • Goal = Kt/V >= 1.3

• properties of a dialyzable drug

  • MW <5000 Da

  • Vd <1 L/kg (mostly stays in plasma)
    protein binding <90% (only free drug is dialyzable)

  • low lipid solubility (hydrophilic drugs stay in plasma)

renal replacement therapy: peritoneal dialysis pt 1

• type of dialysis that uses the peritoneum in a person’s abdomen as the membrane through which fluid and dissolve substances are exchanged with the blood

• to remove excess fluid, correct electrolyte problems, and remove toxins in those with kidney failure

renal replacement therapy: peritoneal dialysis pt 2

• peritoneal dialysis

  • solution infused into the peritoneal cavity

  • peritoneal membrane acts as dialyzer

  • for patients who are hemodynamically stable

• peritoneal physiology

  • contains ~10 mL liquid

  • can expand to hold several liters

  • surface area of 1-2 m²

  • allows passage of larger MW substances

  • catheters = used to gain access to peritoneal cavity

• dialysate

  • high dextrose solution containing various solutes and anticoagulants

renal replacement therapy: peritoneal dialysis pt 3

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

  • Kt/V where Kt = D/P * volume drained

    • D/P = dialysate to plasma urea concentration

      • should be ~2.0 per week

renal replacement therapy: peritoneal dialysis pt 4

• peritoneal dialysis prescription

  • # of exchanges (CAPD)

  • volume

  • concentration of solutes

• properties of dialyzable drug

  • Vd <1L/kg

  • protein binding <96%

  • can better clear large molecules up to 15,000 - 20,000 Dab

PK changes in patients with hemodialysis

• absorption

  • increased absorption mediated by:

    • paracellular leakage → damaged gut barrier allows more drug to pass through

    • decreased efflux transporter activity → less drug is pumped out, more stays

    • decreased P450 enzyme → less 1st pass metabolism

• distribution

  • increased free drug concentration mediated by:

    • decreased albumin → fewer binding sites for drugs

    • uremic toxin mediated decreases in protein binding → displaces drugs from protein

• metabolism

  • decreased phase I metabolism

  • decreased phase II metabolism

• excretion

  • decreased renal drug excretion

  • decreased biliary drug excretion

• hemodialysis

  • dialytic drug clearance leads to decreased plasma concentration

  • normalization of non-renal drug clearance pathways

CKD: effects on the PK of drugs

• metabolism and elimination

  • changes in the expression levels of several CYP enzymes (intestinal and hepatic) and transporters reported

• drugs that are renally cleared: impaired kidneys → less elimination b/c of the CYP enzymes that are expressed less → increased AUC

  • telbivudine

  • entecavir

  • varenicline

  • emtricatibine

  • lomefloxacin

  • clears only intermittently during HD so drug concentrations build up in between

• drugs that are NOT cleared via renal (mainly hepatic); renal impairment still increases AUC due to reduced liver metabolism and uremic toxins affecting enzyme/transporter function but dialysis helps lower AUC

  • rosuvastatin

  • muraviroc

  • telithromycin

  • lidocaine

  • HD helps by removing some toxins which may suppress some liver enzymes so the amount by which the drug increases in circulation is less

evaluating the influence of dialytic therapies on the PK of a drug

• primary questions

  • whether the drug dosage should be adjusted b/c of dialysis

  • if so, by how much

  • timing of drug admin relative to dialysis

• intermittent hemodialysis (IHD)

  • most common dialysis method used in ESRD pts in U.S.

  • study to include both on and off dialysis periods

  • important to record the blood flow (QB), dialysate flow (QD) and the make and model of the dialyzer used in 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, findings from IHD studies might NOT be sufficient to derive dosing recommendations for pts using this modality
    

monitoring drug levels in hemodialysis

• measurement of pre- and post-HD plasma concentrations

• can calculate an eliminate rate constant which describes the decay of drug plasma concentration during hemodialysis (ke_{on HD}) and OFF dialysis

  • assuming a log-linear relationship: C = C_o *e^-kt

  • C₀ = C_preHD

  • C = C_postHD

  • rearranging equation

    • ke_onHD = ln(C_preHD/C_postHD)/t_HD

    • ke_offHD = ln(C_postHD/C_preHD/t_{between sessions}

• graph

  • C_trough = lowest level before the next dose is given

• quantification of drug loss during hemodialysis

  1. calculate fraction of drug loss during hemodialysis (f_L) (fraction of drug in plasma that is removed by dialzyer)

     1. f_L = 1-e^-kt (use k_d)

  2. calculate fraction of total elimination occurring during HD (f_D) (of all the ways the body eliminates drug, what fraction of this total elimination is due to HD)

     1. f_D = 1-(t_{1/2 on HD}/t_{1/2 off HD})

  3. fraction of drug initially in the body that is eliminated by HD (f_el) (combo of how much drug is in plasma and how much total elim is done by HD; overall impact of HD on drug elimination; how much of the total drug in the body that is actually cleared during HD session)

     1. f_el = f_D * f_L

     2. may be significant if >30%