- Final common route of elimination for many drugs/metabolites is the kidney, through: glomerular filtration, active tubular secretion or passive tubular reabsorption.
- Water soluble drugs are excreted in the unchanged active form (gentamycin)
- Lipid soluble drugs like morphine, first undergo hepatic conjugation with a highly polarised endogenous substance (e.g. glucoronic acid) to aid renal excretion.
- Drugs can either be initiators of kidney disease or progress the disease
- Drug induced renal failure = aprox 20% ARF cases
- To function correctly kidneys require: normal renal blood flow (NSAIDs, COX2 inhibitors), functioning glomerulli and tubules (cyclosporin and tacrolimus) and a clear urinary outflow. Drugs can affect any one of these factors.
How drugs damage the kidney: interfere with either afferent (PG’s) or efferent (Angiotensin II) limb.
- NSAIDS cause vasoconstriction of the afferent limb and decrease renal perfusion, glomerular pressure and drop GFR.
- ACE-I dilates efferent limb, drop glomerular pressure and therefore GFR.
Pre-renal effects: COMPROMISED PERFUSION (from reduced CO or increased vasoconstriction)
- Volume depletion: loop diuretics, lithium, laxatices, NSAIDs
- Increased catabolism: (raised urea) from glucocorticoids, tetracyclins
- Vascular occlusion: oestrogen therapy, anticoagulant complications
- Altered renal haemodynamics: ACE-I, ARB’s, cyclosporin, tacrolimus.
Post-renal effects (=obstructive uropathy): ureteric fibrosis, renal calculi, blood clots
- Retroperitoneal fibrosis: Beta blockers, methyldopa, bromocryptine.
- Tubular blockage: uric acid, sulphonamides, chemptherapy, radio contrast, statins = rhabdomyolysis, increased vitamin D.
Allergic or immune damage: hypersensitivity, vasculitis, nephritis, glomerulonephritis.
- Acute interstitial nephritis with proteinurea, micro/macro haematuria, fever, rash, arthralgia, abnormal LFT’: allopurinol, carbomezapine, antibiotics, propanolol, NSAIDs
- Chronic interstitial nephritis: analgesics (paracetamol), caffeine
- Lupus erythematous syndrome: hydralazine and ioniazid
Direct nephrotoxicity: Acute tubular necrosis, interstitial damage or papillary necrosis.
- Acute tubular damage: aminoglycosides, cephlosporins, amphoteracin, NDAIDs, tacrolimus, ciclosporin.
- Plasma expanders: dectrose, mannitol
- Distal tubular damage: lithium, carbomezapine, SSRI’s.
Increase in creatinine without AKI: trimethoprim (inhibits tubular creatinine secretion).
- NSAIDs = increase uremic GI bleeding risk and complicate fluid overload
- ACE-I = may precipitate hyperkalemia on background elevated K+ levels
- Digoxin = has an increased sensitivity in ARF
- Increased sensitivity to CNS drugs = benzodiazepines
Old equation = cockroft and gault which made corrections for males and females. Determines mild, moderate or severe renal impairment.
New equation = eGFR which gives a stage of renal disease (1-5)
The stages are relevant to kidney DISEASE not kidney failure, and indicate when to start dialysis.
Serum creatinine can be used (is used in hospitals) but this is not as accurate.
Therapeutic drug monitoring (TDM) in: vancomycin, teicoplanin, gentamycin, phenytoin, lithium, ciclosporin, tacrolimus, digoxin, theophyline, aminophyline.