W26 Nephrotoxicity (MH) Flashcards
What is nephrotoxicity?
- Rapid deterioration in kidney function as a result of medications and chemicals
- Adverse event caused by substances that caused damage to renal function
How can nephrotoxicity occur?
- Prescribed drugs, OTC, Herbal remedies/supplements Food products, Recreational drugs, Imaging agents
- Moulds and fungi, cancer therapeutics, and antibiotics, metals such as arsenic, lead, and mercury, as well as drugs of abuse
(alcohol too)
What is Nephrotoxicity dependent upon?
- Inherent nephrotoxicity of the compound
- Underlying patient susceptibility to kidney
injury - Metabolism and Excretion of compound
What are the Drug factors associated with increased risk for nephrotoxicity?
Inc kidney exposure to drug
Immune drug effects
Combinations of nephrotoxic drugs
Insoluble drug in urine (crystal formation)
Inc Drug concentrations within cells (transporter competition)
Intracellular drug accumulation
Drug-Uromodulin interaction (cast formation)
Direct drug nephrotoxicity
Drug Characteristics (Solubility, Structure, and Charge)
- Drugs and metabolites that are insoluble in the urine may cause acute crystalline nephropathy by precipitating in DCT
- Made worse by reduced urinary flow rates, urine pH (depending on drug pKa), excessive drug dosing, and rapid infusion rates.
-methotrexate, acyclovir, indinavir/atazanavir, sulfadiazine, vitamin C, foscarnet, oral sodium-phosphate, and triamterene. - Osmotic nephropathy drugs used for intravascular volume repletion accumulate within phagolysosomes of PCT cells. Because of their structure, these molecules cannot be metabolised and ultimately cause lysosomal dysfunction and cell swelling.
-dextran, hydroxyethyl starch, sucrose with intravenous immunoglobulin - Drugs with a positive charge e.g. polycationic aminoglycosides, are attracted to the negatively charged PCT membrane phospholipids which facilitates drug binding to the megalin/cubilin receptor complex
-aminoglycoside nephrotoxicity is in part related to their cationic charge—neomycin has higher cationic charge and is more nephrotoxic than amikacin, which has a lower cationic charge.
Nephrotoxicity
-Which Drug factors contribute to nephrotoxicity?
- Prolonged dosing periods and nephrotoxic drug exposure
- Potent direct nephrotoxic drug effects
- Combinations of toxins/drugs promoting enhanced nephrotoxicity
- Competition between endogenous and exogenous toxins for transporters, increasing drug accumulation within the tubular cell
- Insoluble drug and/or metabolite with intratubular crystal precipitation
- Drug that accumulates in lysosome due to lack of enzymes to metabolize the drug
What are the kidney factors in nephrotoxicity?
- High rate of blood delivery to the kidneys (approximately 25% of cardiac output)
- Increased drug concentrations within the kidney medulla and interstitium
- Biotransformation of drugs to nephrotoxic metabolites and reactive oxygen species
- High metabolic rate of tubular cells (i.e., loop of Henle) within a hypoxic environment
- Proximal tubular uptake of drugs
- Apical drug uptake via endocytosis or pinocytosis with drug accumulation
- Basolateral drug transport via hOAT ore hOCT with drug accumulation
- Reduced drug efflux via apical transporters with drug accumulation
What are the patient factors of nephrotoxicity?
- Female sex (Dec GFR)
- Old age (>65 yr of age) (Dec GFR)
- Race
- Nephrotic syndrome
- Cirrhosis/obstructive jaundice (nephrotoxic
bile acids) - AKI
- CKD
- True or effective volume depletion (kidney
hypoperfusion) - Decreased GFR
- Enhanced proximal tubular toxin reabsorption
- Sluggish distal tubular urine flow rates
- Metabolic perturbations
- Hypokalemia, hypomagnesemia, hypercalcemia
- Alkaline or acid urine pH
- Immune response genes increasing allergic drug response
- Pharmacogenetics favoring drug toxicity
- Gene mutations in hepatic and kidney P450 system
- Gene mutations in kidney transporters and transport proteins
Standard indicators (and Biomarkers) of nephrotoxicity
Signs and symptoms:
* Glomerular filtration rate (GFR)
* blood urea nitrogen
* urine output
* serum creatinine
* Electrolyte imbalance
↑K+, ↓Na+, ↓Ca2+
* ↓ elimination (azotemia, uremia)
* Fluid retention
Diagnosis:
* Urine: electrolytes, osmolality, proteinuria,
haematuria
* Blood: pH, electrolytes, [protein], urea nitrogen, creatinine
* Ultrasound / CT
- N-acetyl-glucosaminidase (NAG)
- Glutathione-s-transferase (GST)
- Gamma-glutamyl transpeptidase (GGT)
- Alanine aminopeptidase (AAP)
- Lactate dehydrogenase (LDH)
- Kidney injury molecule 1 (KIM-1)
Despite advances current kidney injury biomarkers are inadequate.
……a more comprehensive understanding of the
biochemical pathways that leads to
nephrotoxicity is necessary for the detection,
monitoring, and treatment of nephrotoxicity and
its clinical manifestations
What are 3 main causes of impaired kidney function?
AKI: acute decline divided by cause dependent upon where injury occurs
CKD: >3 months; any aetiology = major clinical manifestation of nephrotoxicity.
Polycystic Kidney disease: An inherited condition characterised by cysts on both kidneys
What are other causes of impaired kidney function?
- Hypertension
↑bp – hypertrophy/sclerosis of renal arterioles
– hypoperfusion, less O2 ischaemic injury –
↑macrophages which release growth factors
↑ EC matrix leading to glomerulosclerosis and
loss of function - Diabetic nephropathy
↑ [glucose] – glycosylation on efferent arteriole
(non-enzymatic) leading to glomerulosclerosis and loss of function - Glomerulonephritis
- Rheumatoid arthritis
- HIV nephropathy
- Long term medication use (NSAIDs)
- Polycystic kidney disease
Autosomal dominant polycystic kidney disease
(ADPKD)
- An inherited condition (Kidney are larger than usual due to the gradual growth of masses of cysts in both kidneys)
- ADPKD is caused by a genetic fault that disrupts the normal development of some of the cells in the kidneys and causes cysts to grow
- Faults in 1 of 2 different genes are known to cause ADPKD.
- PKD1, which accounts for around 78% of cases
- PKD2, which accounts for around 15% of cases
- Both types of ADPKD have the same symptoms, but they tend to be more severe in PKD1
- It’s estimated up to 1 in every 1000 to 2500 people in the UK has ADPKD. This means there could be between 30,000 and 70,000 people in the UK with the condition.
Autosomal recessive polycystic kidney
disease (ARPKD)
- rarer type of kidney disease that can only be inherited if both parents carry the faulty gene
- problems usually start much earlier, during childhood
What are the Symptoms for both types of PKD?
- abdominal pain
- hypertension
- blood in the urine (haematuria), which may not always be noticeable to the naked eye
- upper urinary tract infections (UTIs)
- kidney stones
- Kidney function may gradually deteriorate until so much is lost that kidney failure occurs
Examples of Urological conditions Vs Kidney conditions?
Urological:
* UTI
* Lower UTI
* Urinary incontinence
* Bladder cancer
* Penile and testicular cancer
* Prostate cancer
* Renal cancer
Kidney:
* Acute kidney injury
* Chronic kidney disease
* Polycystic kidney disease
* Renal stones
* Renal cancer
* Kidney infection
