Drugs and the Kidney Flashcards
What mediates the tubular reabsorption of peptide-like drugs such as β-lactam antibiotics and ACEIs?
Peptide transporters (PEPT1, PEPT2) expressed on the apical membrane of renal epithelial cells keep in mind that must drugs enter the PT from the bloodstream on the BL and reabsorption is from the lumenal side is more rare
Describe the relationship between Pcr and GFR.
In healthy subjects, large declines in GFR are associated with relatively small increases in serum creatinine. Beyond drop of GFR of ~50%, further decrements are associated with larger increases in serum creatinine, whichmakes the marker more sensitive to change.
Drugs are implicated in up to __% of acute kidney injury in hospitalized patients.
25%.
Why do drugs cause so much toxicity in the kidneys?
High bloodflow means kidney easily exposed to drugsReabsorption of water along loop of Henlé concentrates drug; this magnifies toxicity
When would creatinine be low even if the kidneys weren’t functioning well?
in those (typically females) with low muscle mass, low creatinine levels can exist even in the presence of significant renal insufficiency
How do NSAIDs affect GFR?
inhibit prostaglandin induced afferent vasodilation
What does chronic use of NSAIDs lead to?
Hyponatremia 2° to increased fluid retention (ADH effect)Hyperkalemia & metabolic acidosisHyporeninemic hypoaldosteronism 2° to decreased RAAS activityHypertension
Why are aminoglycosides very nephrotoxic (10-25% of time)?
Their toxicity is directly related to charge (cationic). Proximal tubule accumulation results in cell death
How common is nephrotoxicity due to SMX-TMP?
~11%
What is seen in the kidneys with trimethoprim (TMP) administration?
increases measured serum creatinine w/o affecting GFR inhibits epithelial N+ channels in DCT resulting in hyperkalemia
What is seen in the kidneys with SMX administration?
injury 2° to acute interstitial nephritis (AIN)rarely, crystal nephropathy
How can you avoid the crystal nephropathy seen with SMX?
Hydrate and alkalinize urine
What are some other drugs causing AIN?
NSAIDs, including COX-2 inhibitors• Penicillins and cephalosporins• Rifampin• Diuretics, including furosemide and bumetanide, and thiazide-type diuretics• Ciprofloxacin • Cimetidine• Allopurinol• PPIs such as omeprazole and lansoprazole• Indinavir• 5-aminosalicylates (e.g., mesalamine)
When would AIN (typically) present after 1st exposure of a drug inducer?
10-14 days
When would AIN (typically) present after 1st exposure of a drug inducer?
3-5 days
How does AIN present?
Fever, rash (~50%), eosinophilia (>75%)• Urinalysis– WBC casts, hematuria, eosinophiluria, mild proteinuria, oliguria
Note on NSAID induced AIN
NSAIDs onset 2-3 m; NO eosinophilia/uria, fever or rash; proteinuria >3g/24 h
Are the effects of drug-induced AIN dose-related?
No, but definitely discontinue the offending agent
What are the three ‘parts’ of acute tubular necrosis (ATN)?
InitiationMaintenanceRecoveryATN is basically tubule damage/cell death result from acute ischemia
Where does the most intense ATN damage occur?
Most prominent damage in proximal tubules and in TALH
What happens during the ‘initiation’ stage of ATN?
– Hypo-perfusion plus casts and debris obstruct tubule lumen, causing back-leak of filtrate through the damaged epithelium– Na+/K+ ATPase pumps and integrins relocate to apicalmembrane– ATP is depleted – pump function fails and cells swell,accumulating Na+ and Ca2+– Lipid peroxidation and free radical damage occurs
What happens during the ‘maintanence’ stage of ATN?
Low level GFR stabilizes over 1-2 weeks
What happens during the ‘recovery’ stage of ATN?
Tubular epithelial cells are regeneratedabnormal renal function may lead to salt/H2O loss and volume depletion
What drugs can cause ATN?
-Contrast media-Aminoglycosides-Vanco-AmphoB-cisplatin-sulfa drugsCAVACS
How should ATN be treated?
Discontinue offending agent– Effects sometimes dose-related• Renal function should begin recovery in 1-2 weeks
How does AmphoB cause ATN?
AmB can create pores in the apical membrane of the PT which allows back flux of H+ into the cell, which inhibits urinary H+ excretion and, therefore, results in distal renal tubular acidosis, urinary concentration defect and electrolyte disturbances
What else does AmphoB do to the kidneys?
produces renal vasoconstriction
What is the standard of care when using AmB?
Volume expansion is standard of care
What is the role of VEGF in the kidneys?
maintenance of fenestrated glomerular epitheliumDisruption (by drug therapy) may result in HTN, proteinuria, and thrombotic microangiopathy
What role does EGF play in the kidneys?
Activation of EGFR by EGF and its tyrosine phosphorylation may directly activate TRPM6 and/or TRPM7 channel activity ormay regulate insertion or retrieval or TRPM6 present in intracellular vesicularcompartments which stimulates PT Mg++ reabsorption.
Where is the EGF made?
In the DCT. Because the DCT is so close to the PT, EGF generated by the DCT may activate EGFRs at the proximal tubule and therefore affect Mg2+ handling by this nephron segment, which reabsorbs 25% of filtered Mg2+.
What drugs block EGFR?
cetuximab, leading to Mg++ wasting
What disease does lithium accumulation in the kidneys lead to? How?
Accumulation of cytotoxic levels of lithium, via the apical epithelial Na+channel (ENaC) leads to inhibition of glycogen synthase kinase type 3βsignaling pathways, causing dysregulation of AQP-2 and development of NDI.
How would lithium toxicity be treated?
-stop usage-Enac blockers (amiloride, etc.)
What is the result of calcineurin inhibitor toxicity in the kidneys?
An acute, functional and dose-dependent decrease in renal blood flow and GFRChronic structural changes and dose-independentinterstitial fibrosis
What are the effects of cisplatin on the kidneys?
Exposure of tubular cells to cisplatin activatessignaling pathways that are cell death promoting (MAPK, p53, ROS, and so on) orcytoprotective (p21). Meanwhile, cisplatin induces TNF-alpha production in tubular cells
What does production of TNF-a stimulate?
Triggers a robust inflammatory response, further contributing to tubular cell injury anddeath. Cisplatin may also induce injury in renal vasculature, leading to ischemic tubular cell death and decreased GFR. Together, these events culminate in acute renal failure.
What are some diuretics that promote hyperkalemia?
K+ -sparing diuretics: amiloride, triamterene
What are some antibiotics that promote hyperkalemia?
Trimethoprim, Pentamidine
Other hyperkalemic inducing drugs by decreasing excretion?
-ACEIs/ARBSSpironolactone/Eplerenone-Cycosporine -Tacrolimus
How does Cyclosporine cause hyperkalemia?
Blocks Na+/K+-ATPase Activity in the Distal Nephron
What are some drugs that promote K+ cellular uptake?
-insulin-BB agonists
Hyperkalemia can also be induced by cell-lysis, where there are massive reservoirs. One place that contains a lot of intracellular K+ is skeletal muscle. What are some drugs that cause rhabdomyolysis induced hyerpkalemia?
lovastatincocaine
What are some drugs that promote excretion of K+?
-Diuretics-Foscarnet-Laxatives
What are some drugs that promote intracellular uptake K+?
-B2-agonists-dextrose-Insulin-levothyroxine-Theophylline
Other drugs that promote hypokalemia?
Caspofungin, Corticosteroids(mineralocorticoid activity), Itraconazole
What inhibits K+ release into the lumen in the thick ALH?
Mg++ binds and prevents its movement into the lumen
What are some causes of hypokalemia secondary to hypomagnesia?
Aminoglycosides, Ampotericin B, Cisplatin, Cyclosporine,Loop diuretics
Notes
Keep in mind that there are both BL and lumenal transporters for drugs and so accumulation of a drug in the PT (leading to toxicity) can be the result of increased influx through the BL or decreased efflux throughout the apical membrane
