Transplant and Renal Failure Pharm Flashcards
Many people die waiting for a kidney transplant. What comorbid conditions accompany ESRD?
Advanced age (many are just old), high incidence of diabetes, CAD, peripheral vascular disease, COPD and cancer. *plus, for a 40-year old life expectancy on dialysis is 8 years
Is kidney transplantation better no matter what compared to dialysis?
Yes, but only in the long-term survival rate. It’s MORE risky in the short term (surgery, infection, immunosuporession, etc)
*also, it’s cheaper for society and gives a better quality of life when it works
What do the terms SCD, DCD, ECD mean in the context of kidney trasplantation?
SCD = standard criteria (donor was brain dead so all organs were perfused until the surgery)
- DCD = donation after cardiac death (increases warm ischemia time and risk of delayed function after transplant)
- ECD = extended criteria donor (donor is older, associated with a higher rate of failure within 2 years, reserved for those who will likely die on dialysis)
What is the standard immunosuppressive treatment for transplant patients?
Triple therapy: calcineruin inhibitor, proliferation signal inhibitor (shuts down purine de novo synthesis which shuts down clonal proliferation), prednisone
What are the calcineurin inhibitor examples?
cyclosporine, tacrolimus
What are the proliferation inhibitor examples?
- MMF = mycophenolate mofetile
* mTOR inhibitors = sirolimus, everolimus
How should AKI in the setting of a transplant kidney be approached?
Much the same as in any AKI, starting with pre, renal, or post as the first question.
*you need to add in the nephrotoxicity of the immunosuppression and the graft vs. host complications and more infectious possibilities too
What are the added “pre-renal” AKI causes in transplant patients?
- volume depletion from post op fluid shifts and blood loss
- thrombosis of the transplanted renal artery or vein (surgical emergency)
- calcineruin inhibitor effects on efferent arteriole
What are the added “post-renal” causes of AKI in transplant patients?
- transplant ureter obstruction due to fluid collection like lymphocele and hematoma (surgical drainage)
- urine leak - ureter to bladder anastomoses breakdown, seen by rising creatinine in serum (needs surgical repair)
What are the added AKI causes in “renal” for transplant patients?
- recurrence of primary renal disease
- infection - UTI and pyelonoephritis, CMV infection and interstitial nephritis (treated with ganciclovir), BK virus nephropathy and interstitial nephritis and fibrosis
- rejection
What’s the stepwise approach to kidney trasplant patient AKI?
1) History and physical - focus on hemodynamic events and findings
2) imaging and lab assessment - ultrasound for obstruction, calcineurin inhibitor levels, urinalysis for infection, viral culture or PCR, antibodies for rejection
3) renal transplant biopsy - when you just gotta know
At what stage of CKD do renally eliminated drugs need dosage reduction?
Under 30ml/min, or once moderate GFR reduction has taken place
What is the main concern in both cases of increased and decreased volume of distribution in CKD?
increased - might be due to plasma protein loss in a case where the drug normally is very plasma protein bound. This would result in MORE FREE DRUG WHICH IS THE WORRY
*decreased- digoxin is the best example where CKD results in less tissue binding overall so MORE FREE DURG WHICH IS THE WORRY
How is the maintenance dose calculated and how is it affected in CKD?
MD/tau = CP-ss*CL
MD = maintenance dose
tau = mg/hr or the time interval you use to give doses
Cp-ss = mg/L and is the concentration of the drug in the plasma at steady state
CL = L/hr and that’s kidney clearance
*obviously it’s clearance that will go down in CKD thus the MD must go down to achieve same Cp-ss
*remember decreasing CL will increase 1/2 life of the drug in question
What besides clearance is the kidney involved in concerning the maintenance dose?
MD/tau = CP-ss*CL
- Kidney has some phase I CYP450 reactions (20% or so)
- kidney also contributes to phase II of metabolism (conjugation with glucouronide, sulfate, glutathione)
- in diabetic patients without CKD, renal metabolism is 30% of insulin removal. this metabolism decreases markedly in CKD and you must reduce insulin dose drastically in later stages of CKD
What must be done in CKD management of diabetes patients concerning insulin dosing?
- metabolism is messed up in CKD
- *in diabetic patients without CKD, renal metabolism is 30% of insulin removal. this metabolism decreases markedly in CKD and you must reduce insulin dose drastically in later stages of CKD
What is the number you need to get to determine renal clearance of drugs and thus renal dosing?
eGFR.
- this is the only readily estimatable/measurable commodity in CKD
- use this to estimate CKD stage and whether or not to renally dose
- use the cockroft-Gault formula (used creatinine clearance)
- CL-cr(ml/min) = [(140-age)(ABW)]/(S-cr*72)
- ABW = actual body weight (not ideal body weight)
- S-cr is mg/dL
What is the cockroft-Gault formula?What is it used for?
- use the cockroft-Gault formula to estimate GFR (using creatinine clearance)
- allows you to stage CKD and renally dose if appropriate
- CL-cr(ml/min) = [(140-age)(ABW)]/(S-cr*72)
- ABW = actual body weight (not ideal body weight)
- S-cr is mg/dL
- REMEMBER THAT FEMALES NEED TO HAVE ANSWER MULTIPLIED BY 0.85*
Though dosing adjustments are drug specific and largely arbitrarily defined, what are the general rules for when dosing adjustments should start in CKD?
Stage one and two, no changes necessary
- Stage 3-5, yes there are dosing reductions that need be implemented
- not recommended until GFR falls below 50ml/min/1.73m2
Which drugs decrease arteriolar resistance and what does that do?
- decreasing arteriolar resistance (afferent arteriole) will increase GFR (increases flow to glomerulus thus increases P-gc)
- Nitric oxide, PGE2/PGI2, dopamine, caffeine (adenosine antagonist)
What do *Nitric oxide, PGE2/PGI2, dopamine, caffeine (adenosine antagonist) all have in common (kidney)
Dilate afferent arteriole, reduce arteriolar resitance, increase GFR
What drugs increase afferent arteriolar resistance and what does that do?
- increasing arteriolar resistance means constricting the afferent arteriole
- Angiotensin 2 (though much less than efferent)
- Norepinephrine (sympathetic innervation)
- Adenosine
- NSAIDs (through inhibition of PGE2/PGI2)
What drugs increase efferent arteriole resistance and what does that do
- constriction of efferent arteriole will increase GFR by increasing P-gc
- Angiotensin 2 is the MAIN efferent constrictor
- Norepinephrine (sympathetic nervous system)
What drugs dilate the efferent arteriole and what does that do?
This decreases GFR by decreasing arteriolar resistance and decreasing P-gc
*ACEIs
*ARBs
both of these will inhibit the effect of Angiotensin 2 which is the main efferent constrictor
How can dopamine be renal protective?
It increases RBF (renal blood flow) in cases of hypovolemia or AKI due to low flow
How does progressive CKD affect your prescription of thiazide diuretic?
Thiazides are the first line treatment for hypertension.
- In CKD though, as GFR is below 30, need a loop diuretic
- as GFR falls, less drug gets to target and they are just plain less effective
What might happen considering diuretic efficacy in CKD?
Diuretic resistance can occur in later CKD stages.
*can be overcome by combination diuretic therapy, targeting different sites along the nephron
What three things if present can be treated to slow the progression of CKD?
diabetes, hypertension and hyperlipidemias
- the lecture focused on treatment for stage 3 or 4 CKD patients
- no need to dose change in stage 1 or 2
How does diabetes management (pharm) change in CKD?
Oral hypglycemics = glyburide (1/2 life prolonged), Glipizide (no adjustments necessary), Thiazolidinediones (no adjustments necessary), Metformin (DON’T USE if Scr is over 1.5)
Insulin = 1/2 life is prolonged so be careful and decrease dose in later stages of CKD
What diabetes medication should not be used in CKD?
Metformin (DON’T USE if Scr is over 1.5)
*in CKD, Scr will be over 1.5 if in stage 3,4
How does the (pharm) treatment of hypertension change in CKD?
Diuretics = thiazides (lose effectiveness in later stages), Avoid potassium sparing diuretics, later stages use furosemide
ACEIs/ARBs = use them throughout CKD but monitor for hyperkalemia and Scr elevations. May CAUSE AKI in hypovolemic patients
Beta-Blockers = Atenolol (1/2 life prolonged in CKD so decrease dose), Metoprolol, carvedilol (no adjustments)
Other drugs don’t need to be changed (alpha-blockers, CCBs, Clonidine, Vasodilators)
How does the (pharm) treatment of hyperlipidemia change in CKD?
- HMG CoA reductase inhibitors (no adjustments)
- fibrates (in stage 5 CKD, use Gemfibrozil)
- Niacin (no adjustments)
- Ezetimibe (no adustments)
How do you treat the anemia that coincides with CKD by directly influencing blood cell production?
- Epoetin and Darbepoetin
- glycoproteins prepared with recombinant DNA tech that mimics EPO
- given SC every week (epo) or 1-2 weeks (darbepoetin)
- only adverse effect is hypertension
What’s up with iron supplements in CKD?
- iron supplements/treatment - designed to combat the iron deficiency anemia that is associated with CKD
- supplement is oral iron salts
- treatment is IV iron sucrose
- side-effects are constipation, nausea, abd cramping
- can cause drug interactions with calcium and drugs that increase gastric pH (antacids, PPIs)
What’s up with renal osteodystrophy in CKD?
- bad kidney function means high phosphate levels as excretion goes down
- elevated phosphate levels leads to decreased calcium levels
- decreased calcium will stimulate PTH release
- compounded by the problem with vitamin D and thus less calcium resorbed in gut
How do you (pharm) treat renal osteodystrophy?
Posphate binding agents and Vitamin D compounds and calcimimetics
What can you do about the elevated phosphate levels in CKD?
Renal Osteodystrophy
- Phosphate binders = calcium acetate or non-elemental agents (help reduce metabolic acidosis)
- bind dietary phosphate to make it insoluble and fecally eliminated
- has GI side effects
What can you do about the altered vitamin D levels in CKD?
Renal Osteodystrophy
*calcitriol (already 1,25-dihydroxy vitamin D form, already active)
*indirectly suppresses PTH secretion through helping GI calcium absorption
*side effects =
hypercalcemia and hyperphosphatemia
*cholestyramine coadministration reduces absorption
How can you fight the vitamin D problems and renal osteodystropy in hypercalcemic patients?
Giving vitamin D would increase their already over-abundant calcium levels
- Cinacalcet
- binds to calcium-sensing receptors on PTH cells which reduces PTH secretion directly
- GI side effects and possible hypocalcemia
- POTENT inhibitor of CYP2D6 (so very much potential drug-drug interactions)
What is the pharmacotherapy for hyperkalemia associated with CKD?
Acute and symptomatic therapy = hemodialysis is definitive, temporizing therapies include IV calcium gluconate (stabilize the heart), insulin + glucose (shift), sodium bicarb (shift), nebulized albuterol (shift)
chronic and asymptomatic therapy = sodium polystyrene sulfonate
- resin that uses ion exchange mechanism to take up potassium and release sodium in intestine
- oral and rectal
- side effects of constipation, fecal compaction, nausea, vomiting
What’s up with hyperkalemia in CKD?
- failing kidney can’t excrete sufficient potassium.
- most common in stage 5 or ESRD
- drugs that can CAUSE hyperkalemia = ptassium sparing diuretics, ACEIs, ARBs, Digoxin toxicity
