6 - Renal Dosing

Which populations have low serum creatinine?

• elderly (>80yrs)

• cachectic

• female

• spinal cord injury

• malnutrition

• fat>muscle

• vegetarian

What is the normal serum creatinine value?

0.5-1.5 mg/dL

How is serum creatinine eliminated?

glomerular filtration

• as renal function declines, SCr levels increase

Define glomerular filtration rate

sum of all functioning nephrons

• filters ~180 L/day of plasma

• depends on age, gender, body size

• decrease could be progression of underlying disease or development of reversible problem

What is normal GFR for men?

~130 ml/min/1.73m²

What is normal GFR for women?

~120 ml/min/1.73m²

How is creatinine clearance found using the 24hr collection method?

CrCl = (UCr*V)/PCr

• UCr = creatinine urinary concentration

• V = urine flow state

• PCr = avg plasma creatinine concentration during timer interval of urine collection

What are the requirements for active GFR measurement?

compound that is:

• freely filtered at glomerulus

• nontoxic

• neither secreted nor reabsorbed by tubules

• not changed during excretion by kidney

What markers could be used for GFR measurement?

• inulin

• 125I-iothalamate

• 99mTc-DPTA

• 51Cr-EDTA

• iohexol

these are expensive

What markers are most often used to measure GFR?

cystatin C: produced by nucleated cells

• not affected by muscle mass, but many other factors

• low accuruacy, limited clinical utility

serum creatinine: affected by tubular secretion (low accuracy)

• widely used, high clinical utility

What equations are used to estimate GFR?

estimate CrCl

• adults:

  • cockroft-gault equation

  • MDRD

• children:

  • schwartz

  • counahan-barratt

What is most drug dosing based on?

cockcroft-gault

What is the cockcroft-gault equation?

CrCl = [(140-age)*body weight)] / (SCr*72) * 0.85 if female

What body weight is used if underweight (BMI <18.4)?

total BW

What body weight is used if normal weight (BMI 18.5-24.9)?

ideal BW

What body weight is used if overweight (BMI ≧25)?

adjusted BW

What is the equation for BMI?

weight in kg/(height in m)²

What is the equation for ideal body weight for men?

50kg + (2.3kg* # of in >5ft)

What is the equation for ideal body weight for women?

45.5kg + (2.3kg* # of in >5ft)

What is the equation for adjusted BW?

IBW + 0.4(TBW-IBW)

What are the limitations of cockcroft gault?

• tends to overstimate CrCl

• not used for very young children, ESRD, fluctuating renal function

What should be assumed about CrCl if on dialysis?

<15 mL/min regardless of SCr

T/F: weight used in CG equation must be the same as the weight used to calculate a weight-based dose

false, i.e. use of AdjBW for CG but total BW for dosing

How can renal insufficiency interfere with medications?

• decreasing clearance due to reduce glomerular filtration

• altering tubular secretion/reabsorption

• changes in renal & non-renal metabolism

What are the 2 approaches to dose alteration?

1. reduce the dose & maintain the dosage interval

2. maintain the dose & extend the dosage interval

What are common medications requiring dose reductions?

• most antibiotics

• direct oral anticoagulants

• gabapentin/pregabalin

• oral hypoglycemic agents

• insulin

• chemotherapeutic agents

• opiates

• gadolinium-based contrast agents

What is the effect of renal insufficiency on direct oral anticoagulants?

enoxaparin clearance is reduced in patients with renal insufficiency

What should be the dose of enoxaparin for DVT prophylaxis if CrCl <30 mL/min?

30mg SC once daily

What should be the dose of enoxaparin for DVT treatment if CrCl <30 mL/min?

1mg/kg SC daily

What antibiotics are effected by renal insufficency?

• aminoglycosides (gentamicin, tobramycin, amikacin)

• cephalosporins

• penicillins

• fluoroquinolones

• vancomycin

What is the effect of renal insufficiency on aminoglycosides?

• reduced clearance

• increased risk of ADE: ototoxicity/nephrotoxicity

• avoid in CKD if possible

• follow serum levels if used

• PK equations

What is the effect of renal insufficiency on cephalosporins & penicillins?

• most are cleared renally & require dosing adjustments

• concern for neurotoxicity

Which cephalosporin does not require renal dosing adjustment?

ceftriaxone

What penicillins do not require renal adjustment?

• nafcillin

• dicloxacillin

What is the effect of renal insufficiency on fluoroquinolones?

• require renal dosing adjustments

• ADE: tendonopathy, aortopathy, neuropathy, arrhythmia, hypoglycemia, hyperglycemia

Which fluoroquinolone agent does not require renal dosing adjustment?

moxifloxacin

What is the effect of renal insufficiency on vancomycin?

• requires renal dosing adjustment

• dosed based on serum levels & PK

• may follow random levels in AKI & ESRD

• may extend interval especially in dialysis pts

What is the effect of renal insufficiency on antihypertensives (ACEI/ARBs)?

• most cleared renally

• acute but sustained decrease in GFR (may see 25-30% decrease within 3-7 days, not a reason to d/c)

Which cardiac medications are affected by renal insufficiency?

• alpha-blockers

• beta-blockers

• digoxin

What is the effect of renal insufficiency on alpha-blockers?

• active metabolites can accumulate

• doxazosin, prazosin, methyldopa

Which alpha-blocker is unaltered in CKD?

terazosin

What is the effect of renal insufficiency on beta-blockers?

• some may need adjustment (i.e. atenolol, nadolol)

• hepatically metabolized preferred in advanced CKD (i.e. metoprolol, labetalol, propranolol)

What is the effect of renal insufficiency on digoxin?

• Vd is reduced by 30-50% in ESRD

• not dialyzable (antidote DigiFab)

• you can:

  • extend the dosing interval

  • reduce the dose

What GI medications are affected by renal insufficiency?

• metocloperamide

• H2-antagonists

What is the effect of renal insufficiency in metoclopramide?

• clearance reduced by ~30%

• dose reduction in CrCl <50 ml/min

• ADE: tardive dyskinesia

What is the effect of renal insufficiency on H2-antagonists?

• dependent on agent

• requires dosing adjustment CrCl <50 ml/min

• ADE: CNS effects

What narcotics are affect by renal insufficiency?

• morphine

• meperidine

What are the affects of renal insufficiency on morphine?

• metabolized in the liver to 5 metabolites → accumulation

• dose reduction CrCl <60ml/min

• ADE: CNS depression, resp. depression

• consider avoiding

What are the affects of renal insufficiency on meperidine?

• active metabolite → normeperidine accumulation

  • neurotoxic

  • ½ analgesic effect, 2x convulsant effect

• avoid use

What diabetic medications are affected by renal insufficiency?

• insulin

• sulfonylureas

• sitagliptin

• metformin

What are the affects of renal insufficiency on insulin?

• dosing reduction may be required

• degradation occurs in liver, muscles, kidneys

What are the affects of renal insufficiency on sulfonylureas?

active metabolites may accumulate

What are the affects of renal insufficiency on sitagliptin?

requires dosing adjustment

What are the affects of renal insufficiency on metformin?

potential to cause lactic acidosis

What is the dose recommendation for metformin for a GFR ≧60?

no dose adjustments required

What is the dose recommendation for metformin for a GFR 45-59?

may continue treatment but monitor renal function every 3-6mo

• max dose 2g/day

What is the dose recommendation for metformin for a GFR 30-44?

• do NOT initiate

• continue existing therapy at reduced dose

• max 500mg BID

What is the dose recommendation for metformin for a GFR <30?

use contraindicated

When is maintenance dialysis indicated?

CKD stage 4 (GFR <30)

What are the types of dialysis?

hemodialysis & peritoneal dialysis

What symptoms usually develop when dialysis is indicated and when do they develop?

• symptomatic uremia

• inability to control volume status or blood pressure

• cognitive impairment

• deterioration in nutritional status

usually develop when GFR ~5-10

What is hemodialysis?

1. blood is removed from patients through a blood pump

2. dialyzer drains fluid & pumps fresh fluid

3. waste is removed from blood by diffusion

4. purified blood is returned to patients

What is peritoneal dialysis?

1. dialysate bag drains into peritoneal space

2. waste products are drawn from the blood stream into the peritoneal space w/ dialysate

3. dialysate & waste product are drained from peritoneal space into a drainage bag

What are the pros of hemodialysis?

• intermittent

• defined parameters to detect under-dialysis early

• low technique failure rate

• hemostasis parameters better corrected

• close monitoring

What are the cons of hemodialysis?

• 3x weekly for several hours

• disequilibrium, hypotension, muscle cramps

• infections

• thrombosis

• more rapid residual kidney decline

What are the pros of peritoneal dialysis?

• hemodynamic stability

• higher clearance of large solutes

• convenient route for antibiotics

• suitable for elderly, very young who don’t tolerate HD

• independence, freedom from machine

• less blood loss/iron deficiency

• no systemic heparinization

• lower physiologic EPO doses

What are the cons of peritoneal dialysis?

• amino acid loss through peritoneum → malnutrition

• peritonitis

• catheter malfunction

• inadequate ultrafiltration & solute clearance

• patient burnout, high rate of technique failure

• risk of obesity w/ excessive glucose absorption

• hernias, dialysate leaks, hemorrhoids, back pain

• abdominal surgery precludes

What are the common types of access for HD?

• fistula

• graft implantation

• tunnelled central venous catheter

What is a fistula?

connection of superficial vein & artery to create a vein with high blood flow

What is a graft implantation?

insertion of a synthetic tube that connects a vein → artery

What is a tunnelled central venous catheter?

inserted centrally into the heart

What are the 2 main considerations determining if a drug requires dose reduction in dialysis?

1. renal clearance

2. therapeutic index

What are additional factors to consider for medications with dialysis?

• increased availability of highly protein-bound drugs due to hypoalbuminemia

• altered Vd

• presence of comorbid hepatic dysfunction

What are the most common complications of dialysis?

• stenosis

• thrombosis

• infection

What are thrombosis rates among types of access?

catheter > AV grafts > AV fistula

When & why does thrombosis typically occur?

early dysfunction (<5 days after placement):

• intracatheter or cather-tip thrombosis or a malpositioned catheter

1 week after placement:

• outside catheter or within catheter

• intrinsic thrombosis → catheter failure

What are the rates of infection among types of access?

catheters > AV grafts > AV fistula

What is the result of infection in dialysis?

• 2nd leading cause of mortality in dialysis patients, ~20% of complications

• local → antibiotic

• extensive → antibiotic + surgical revision

• can lead to endocarditis, osteomyelitis, septic arthritis, septic pulmonary emboli, septic syndrom

How is thrombosis in dialysis prevented?

catheters are “locked” with anticoagulant

• instillation of solution in catheter lumen

• low dose unfractionated heparin 5000 units twice weekly

• sodium citrate 4%

• alteplase 1mg weekly

How is thrombosis in dialysis treated nonpharmacologically?

• force saline flush

• referral to vascular surgeon

How is thrombosis in dialysis treated pharmacologically?

• alteplase 2mg/2mL for 30mins

• dose instilled into lumen for 30mins, then attempt to aspirate

What should be done for patients who experience a fever during HD?

• immediate blood culture collected

• temporary catheter → removed & cultured

How are catheter-related infections prevented?

• minimize use, access, & duration of catheters

• proper handling, disinfection, sterile technique

• use of exit-site mupirocin or povidone-iodine ointment

What are antibiotic locks?

solution that contains a concentrated amount of antibiotic along with heparin

• instilled into infected catheter or port and left to dwell between dialysis session

What are the available antibiotic locks?

• vancomycin 1-5mg/mL

• gentamicin 0.4-1mg/mL (more than 10 will precipitate with heparin)

• cefazolin 5mg/mL

• ceftazidime 2-5mg/mL

What factors increase risk of intradialytic hypotension with HD?

• autonomic insufficiency

• heart disease

• advanced age

What is acute management of intradialytic hypotension with HD?

• trendelenburg position (lower head)

• decrease ultrafiltration rate

• 100-200mL NS bolus

T/F: antihypertensives should be routinely held on dialysis days

false, however they should be given with caution prior to dialysis

What agent increases postdialysis BP and improves symptoms?

midodrine (oral alpha-1 adrenergic agonist)

• 2.5-10mg prior to dialysis

What are the ADR of midodrine?

• scalp paresthetsias

• heartburn

• flushing

• headache

• neck pain

• weakness

What are commonly prescribed drugs that are not renally cleared and do not need renal dose adjustment?

• PPIs

• statins

• corticosteroids

• CCBs

• acetaminophen

How does molecular weight/size affect drug removal during dialysis?

smaller → removed

How does Vd affect drug removal during dialysis?

large Vd → less likely to be removed

• >2 L/kg → poorly removed

How does protein-binding affect drug removal during dialysis?

highly protein-bound → less likely

How does membrane affect drug removal during dialysis?

high-flux (large pore size) & high efficiency (large surface area) HD filters → remove more that conventional/low-flux

How does blood flow rate affect drug removal during dialysis?

higher dialysis blood flow rate → greater removal over given time interval

Which type of dialysis is more effective at removing drugs?

HD

If no “dialysis” dose is available, what should be assumed?

GFR <15

When should a dose generally be given?

after dialysis

What should be done when dosing for dialysis?

• consult a reference

• document in EMR for continuity of care