Renal diseases and pharmacokinetics

Question 1

Kidney diseases and its progression

Answer 1

AKI - acute kidney injury

can progress to acute kidney disease (AKD)

that can progress to chronic kidney disease (CKD) which is longer than 90d

that can then progress to end-stage renal disease (ESRD) which requires renal replacement therapy.

As you progress the ratio of adaptive (resolution - clears debris and restores tubular epithelial layer) to maladaptive repair shifts towards maladaptive repair - this favours development of fibrosis and delayed resolution of the pathology

Risk factors include the severity of Aki, age, sez, albuminuria, hypoalbuminaemia, hypertension, obesity, diabetes

Question 2

AKI

Answer 2

rapid loss of kidney function. see sudden onset of renal impairment - GFR falls within hours or days.

can range from mild dysfunction to the need for renal replacement.

Causes can be prerenal (80%), intrinsic (infrarenal) or post renal

Prerenal factors include low renal perfusion or dehydration. can be caused by diuretics, ACEIs, AT1R antagonists, metformin and NSAIDs

Question 3

CKD

Answer 3

long term progressive irreversible loss of nephrons through disease, damage, or ageing. Can be stage 1-5 depending on severity. stage 5 is kidney failure. stages are based primarily on GFR.

CKD is clinical defined by the presence of kidney damage, a GFR of < 60mL/min/1.73m^2, and if it is persisting for > 3 months

Found in 13-14% of adults, and increases with age.

Sees anaemia, hyperphosphataemia, hypocalcaemia, and reduced renal size and cortical thickness. These are differences compared to AKI.

Can be caused by diabetes (causes 40% of ESRD), hypertension (25% of ESRD), obesity, renal vascular disorders (atherosclerosis, or nephrosclerosis), lupus, glomerularnephritis (15% of ESRD) infections such as tuberculosis, NSAIDs, heavy metals, kidney stones, polycystic kidney disease, etc…

Often asymptomatic up until stage 3. then see nausea, weight loss, itching, confusion, shortness of breath, weakness, altered urine output

Question 4

Effects of deteriorating kidney function

Answer 4

Can lead to proteinuria and haematuria due to altered glomerular filter integrity

Decreased excretion of creatinine, uraemia toxins, salt/water, acid, potassium and phosphate. can lead to hyperkalaemia, metabolic acidosis and hypertension

Also leads to decreased biosynthesis of EPO (involved in RBC synthesis) and the activation of vit D (leads to hypocalcaemia)

Question 5

Renal replacement therapies

Answer 5

Haemo- and peritoneal dialysis can be done to artificially filter the blood. releases uraemia symptoms

Kidney transplants are the therapy of choice for ESRD

Can be used for drug removal too. this is affected by PPB (poor if highly PPB), MW (poor for large MW), and solubility of the drug. less good at removal of lipophilic drugs.

Question 6

Effects of renal disease on PK

Answer 6

Renal disease can lead to increase gastric pH altering absorption. altered urinary pH may also alter excretion of acids/bases

Drugs may accumulate in the blood.

Some drugs may lose efficacy if they targeted tubular secretion and reabsorption, e.g., diuretics, nitrofurantoin.

Oedema may increase Vd of highly soluble drugs such as gentamicin

Uraemia may also decrease hepatic metabolism and BBB integrity.

Dose adjustments are needed in ACEIs, diuretics, B-blockers, metformin, insulin, antimicrobials (e.g., penicillin), NSAIDs, opioids, anticonvulsants (gabapentin, pregabalin), lithium, DOACs, methotrexate