L22 Dialysis

Kidney Shape and size and basic structure

Bean shaped, is 150gm and has cortex+medulla. Lots of nephrons

Nephron components (5)

glomerular apparatus

proximal tubule

Loop of henle

Distal tubule

collecting ducts

3 types of nephrons

Cortical

Intermedial

Juxtamedullary

5 Things glomerular filtration can depend on

Molecular size, protein binding, ionization, polarity and kidney function

Tubular reabsorption when full

Renal clearance limited to amount of drug that leaves kidney as urine flows into bladder when there is 100% reabsorption

What does tubular secretion depend on?

The transporter, and how fast and efficient it is. Depends on fu.

What is normal urine output?

Without reabsorption would be 172.8L, but with is 1.73 L since about 99% drug gets reabsorbed.

CKD definition

Abnormalities of kidney structure or function, present for > 3 months, with implications for health

2 things to diagnose CKD

GFR <60 mL/min

One or more markers of kidney damage

EGFR ranges

Normal:>90 /1.73 m^2 (apply for everything)

Mildly decreased: 60-89

Mild to moderately decreased: 45-59

Moderate to severe decrease:30-44

Seere decrease:15-29

Kidney failure: <15

Albuminuria(Albumin/.creatinine) ranges

Normal to mildly increased: < 3mg/mmol

Moderate increase: 3-30mg/mmol

Severe increase: 30mg/mmol

CKD effect on Drug absorption and F (4)

Delayed gastric emptying and intestinal motility affecting T and Cmax of drugs

High gastric pH: excess urea in saliva turn to ammonia, alkalinization affect drugs

Drug F is more variable

Uremia decrease GI absorption and change first pass

CKD effect on distribution 2

Altered volume of distribution: (Dehydration/muscle wasting)

Altered plasma protein and tissue binding of drugs

CKD effect on metabolism (3)

Uremia slows rate of phase I metabolism and some phase II

Dependent on kidneys for removal of drug metabolites from body

Complicated impact on drug metabolism including changes in expression of several CYP enzymes and transporters

CKD effect on elimination (2)

Renal clearance depends on GFR, tubular reabsorption, and tubular secretion

GFR down leading to renal clearance down leading to higher plasma T 1/2.

Dialysis definition

Extracorporeal removal of waste products like creatinine and urea and free water from blood when kidneys are in a state of kidney failure

Done with IV catheter or areteriovenous fistula

4 parts of dialysis

remove blood, pump blood, filter blood, return filtered blood back to body

Dialyzers component:

Fibers, poly sulfone, methylmetacrylate, acrylonitrile

Dialysate description

Countercurrent flow

500-800mL/min has multiple solutes and anticoagulants

Waste and fluid removal mechanism for dialysis

Diffusion and ultrafiltration

Concentration gradient against dialyzer membrane

3 components of dialysis prescription

Flow rate

Duration of dialysis

Dialyzer

Urea Reduction Ratio equation (URR)

>70% is adequate

BUNpre-BUNpost/BUNpre *100%

Kt/V as measure of adequacy

Kt is dialyzer CL Of urea

T is duration of dialysis

V is volume of blood cleared from urea

What Kt/V > 1-3

4 properties of dialyzable drug

MW<5000 daltons

Vd<1 L/kg

Protein binding <90%

Low lipid solubility

Peritoneal dialysis description

Uses peritoneum in person's abdomen as membrane through which fluid and dissolved substances are exchanged with blood

Remove excess fluid, correct electrolyte problems and remove toxins in those with kidney failure.

use for patients who are hemodynamically stable

Peritoneal physiology (5)

Contains 100 mL liquid

Can expand to hold several liters

Surface area of 1-2 m^2

Allows passage of larger MW substances

Catheters used to gain access to peritoneal cavity

Dialysate for peritoneal dialysis

High dextrose solution containing various solutes and anticoagulants

2 types of peritoneal dialysis

Continuous cyclic: cycler at night, day dwell (chill)

Continuous ambulatory: 3 daily exchanges, 1 longtime bedtime dwell

Kv/T for peritoneal dialysis

Kt=D/P: dialysate to plasma urea concentration

should be ~2 per week

3 components of peritoneal dialysis prescription

Number of exchanges (CAPD)

Volume

Concentration of solutes

3 properties of dialyzable drug for peritoneal dialysis

Vd<1L/kg

Protein binding<96%

Can better clear large molecules up to 15,000-20,000 daltons

Absorption changes for hemodialysis

Increased absorption from paracellular leakage, decreased efflux transporter activity and decreased CYP450 activity

Distribution changes for hemodialysis

increased fu cause decreased albumin, uremic toxin mediated decrease in protein binding

Metabolism changes for hemodialysis

Decreased Phase I and Phase II metabolism

Excretion changes for hemodialysis

Decreased renal and biliary drug excretion

Hemodialysis changes for hemodialysis

Dialytic drug clearance leading to decreased plasma conc

Normalization of non renal drug clearance pathways

How does change in CYP and transporters affect renal vs non renal cleared drugs for patients on hemodialysis

Renal has a higher AUC

Non renal has a lower AUC for those with chronic hemodialysis.

3 questions to ask for influence of dialytic therapy on PK of drug

If drug dosage should be adjusted cause of dialysis

How much?

Timing of drug admin relative to dialysis

IHD/Intermittent hemodialysis

most common method used, need to record blood flow, dialysate flow and type of dialyzer used for studies

CRTT/continuous renal replacement therapy

For critical care meds, IHD studies might not be enough.