This part where he only had the slides in class. Also the list thing.
how do NSAIDs affect the kidneys?
NSAIDs-- cause dec in prostaglandins-- prostaglandins regulate GFR-- dec GFR (vasoconstriction of renal artery)-- dec perfusion. ALSO have an affect on tubular cells bc they accumulate in them--> tubular damage.
3 things that cause crystalluria
ethylene glycol, sulfonamides, melamine (obstruction--> dec GFR)
3 diff mechanisms by which GFR is affected
afferent constriction, obstructing cast, leakage of filtrate.
diff drugs affect diff places in kidney
explain how a blockage in tubules affects GFR
inc pressure in tubules, backs up, now pressure is basically same as arteries, dec filtration bc loss of pressure gradient.
damage in kidney when GFR goes... (up or down?)
horrible pic of all diff mechanisms by which GFR goes down
what is the mechanisms by which a prox tubular cell (could be distal too but less common- remember melamine is distal) is damaged by a toxin?
initial loss of polarity and loss of integrity of tight junctions so big gaps in cells then...start to see degradation of cells bc of loss of tight junction AND direct toxic effects. leads to membrane damage--> necrosis-->apoptosi. so then you see a clinical pt and take a urine sample and look at sediment-- see tubular cells bc apotosis-->sloughing--> end up in urine. Can also lead to tubular obstruction (which dec GFR)
if talking about cell death/apoptosis, then actually talking about inflammation. inflammation can be due to damage to cells or can occur bc of ischemia. Pic of ischemia and explanation
bc of a lack of O2, probs starts in BVs (gaps in tight junctions of BVs first) Gaps in tight junctions of BVs-- easier and easier for cells to leak out of those gaps into the interstitium, so lots of WBCs move out of blood vessels into interstitium. and then they move into lumen of tubules and into urine. macrophages will try to get rid of as many of the dead cells as possible. But the WBCs produce cytokines and chemokines (and if there are too many, this leads to a deleterious effect in the kidney cells as well).
Renal side effects of common drugs--> 3 that affect prox tubules?
Aminoglycosides, Amphotericin B, Cisplatin
renal side effects of common drugs--> 4 that affect distal tubules?
why do Ags affect the nervous system, the kidney and ear specifically?
This is bc they bind to phospholipids, go into cell, and inc lysosomes
AGs are substrates for what transporters? how does continuous exposure of these transports to AGs affect them?
Substrates for OAT1 and OAT3; down- regulation of OAT expression following continuing exposure. And remember that OATs transport out of the system- so if you see downregulation of these, then there is a less efficient elimination of aminoglycosides.
what is reabsorption of AGs like? what is secretion like?
Time-dependent passive reabsorption; active secretion
what kinda killing do AGs do as abxs?
concentration dependant killing.
what is the Doze regimen for AGs, and what implication does this have for the kidneys?
6.6 mg/kg... look at graph and see what range you are in, and if you look at GGT ratio (Gamma-glutamyl transferase) you see it goes up around 1-3dose of AGs-- so the prob with aminoglycosides is conc-dependant.
whats the prob with trying to tx AG tox?
cant really wash them out bc elimination is transport dependant
what are the mult factors that Aminoglycoside tox depends on?
Duration of treatment, Cumulative dose, Average daily dose, Peak and trough serum concentrations, Concurrent diuretic use, Underlying disease status, Previous exposure to aminoglycosides
In AG tox, Peak and trough serum concentrations (esp trough) are esp important. Explain how that works
Trough conc needs to be low enough to give the transport systems a break. And remember that extended exposure leads to a downregulation of the OTA transporters, so there must be in that dosing interval a time where we don't necessarily use those OATs (if continuous pressure throughout the dosing interval, then we see downregulation of the transporters). ((basically dose in a way where it isnt too high or too frequent so the concentration goes up and down along the dosing interval so the OATs arent always exposed and then downregulated)
explain this pic-- the pic is about the mechanisms and cell signalling pathways which lead to gentamycin (a AG) tox
Gentamycin binds to phospholipids, then pinocytosis which brings aminoglycosides into the cell (internalization either by itself or binding to phospholipids and then pincytosis to get it in). There are ALSO gentamycin transporters. So it gets into cell and first thing you see is an inc in lysosomes in the cell (first signals of AG toxicosis). He said dont memorize all of this, just know important things: binding to phospholipids, which is why we particularly see tox in kidney/ear/nerves (high in phospholipid content) and phospholipids aid in internalization of the gentamicin, and the OATs also play a role in tox
Hypertension and progressive kidney failure in cats
what are two causes which lead to high levels of blood pressure? how do these cause this?
Melengestrol acetate and Long-term glucocorticoids treatment, which leads to inhibition of an enzyme (Inihibtion of 11-β-hydroxy-steroid dehydrogenase)
Inihibtion of 11-β-hydroxy-steroid dehydrogenase has what effect?
causes AMES: Apparent Mineralocorticoid Excess Syndrome ( can be seen in humans when they eat a lot of liquorice)
AMES: Apparent Mineralocorticoid Excess Syndrome is caused by what, and leads to what problems?
caused by Inihibtion of 11-β-hydroxy-steroid dehydrogenase which is inhibited by things like Long-term glucocorticoids treatment and Melengestrol acetate. It leads to Hypertensive retinopathy (BP > 160-180 mmHg), cardiomyopathy, and Chronic renal insuffciency
If you want to do enforced diuresis to help with renal tox, what is a limiting factor of this tx?
only in patients with maintained renal function!!!
what are two different ways to provide enforced duiresis?
Furosemide (nephrotoxic in high concentrations) - infusions (saline, electrolytes)
how will modulating urinary pH help with renal tox?
change in pH--> ion trapping--> excreted out with urine
So if you have a basic toxin, how will you wanna change renal pH, and with what?
want to ionize the basic toxin so it will be trapped in urine, so you want an ACIDIC urine, you acidift urine with ammonium chloride
If you have a acidic toxin, how will you wanna change the renal pH, and with that?
want to ionize the acidic toxin so it will be trapped in urine, so you want an BASIC urine, so can give sodium bicarbonate, sodium citrate
what is a problem which can some with trying to mess with the urinary pH?
can consider hemodialysis or peritoneal dialysis
peritoneal cavity full of fluid works as buffer, attracts some of the toxins, and then re-aspirate fluid you put in there. (flush peritoneal system)
Other renal toxins---> which heavy metals are toxic? (6)
Cd and Hg; Pb, As, Li and Cu
other renal toxins--> which mycotoxins (2)
OTA and citrinin
what plant-derived acid can cause renal tox?
Aristolochic acid (found this out with weight loss meds)
which rodentacide can cause renal tox?
pic where diff toxins affect diff sites
Main general clinical signs/symptoms with Acute renal function impairment?
nausea and vomiting, acetonemia, dehydration, polyuria (owner’s report!), uremia and gastric bleeding
Main general clinical signs/symptoms with Chronic renal failure?
hypertension (RAAS activation, retention of Na and H 2 O)), hypocalcemia, anemia (decreased erythropeitin-EPO).
what is GGT, what does it mean if its in the urine?
brush border enzyme- gives you an idea of prox tubular damage-- and ratio of GGT:creatinine in the urine is a very specific marker for damage to the kidney, esp prox tubular damage (where brush borders are)
what do AP (alkaline phosphatase) and LDH tell us?
what two particular heavy metals are specifically bad for the kidney?
Cadmium and inorganic arsenic (more on this later)
which two plants are super bad for kidneys, and in who specifically?
Lillies and Dieffenbachia (horrible for cats!) (kumar will cover this)
Risk of drug-induced nephrotoxicity super high with what 6 drugs?
cisplatin, amphotericin B, polymyxin B, cyclosporin, NSAIDs and aminoglycosides
Basic mechanisms resulting in renal damage are: Accumulation of chemicals and drugs in the proximal tubular cells-- what does this cause to happen in the cells, and what is it mediated by? what should you know about this method?
leads to concentration dependent radical formation and lipid peroxidation. It is .Mediated by diﬀerent renal transporters (OAT/OCT) and effux transporters, and Both transport protein families are easily saturated
Bioactivation of drugs and toxins by the β-lyase pathway in individuals happens when? results?
results in TOXIC substances, because limited activity of N-acetyltransferases (which would not cause toxic substances) (dogs and polymorphisms in humans causes varied activity of N-acetyltransferase)
.Release of metallothionein bound metal ions happens where, why, and which metal especially?
esp cadmium, in prox tubule cells, release due to pH change in kidney
Injury and mechanical obstruction following crystal formation: which 3 substances (and what kinda crystals)