The kidneys and renal disease Flashcards
Kidney functions
The kidney is involved in excretion of metabolic waste, including urea, creatinine (muscle breakdown), uric acid (breakdown of nucleic acids), end products of haemoglobin breakdown and hormone metabolites, as well as foreign substances, including drugs, pesticides and food additives.
The kidney also controls:
- Water and electrolytes (K+, Na+, Cl-)
- Arterial blood pressure
- Acid-base balance (H+, HCO3-)
Endocrine functions include the synthesis of erythropoietin (EPO), renin and 1,25-dihydroxyvitamin D3 (calcitriol).
- EPO is the only true hormone produced by the kidney
- Calcitriol is activated vitamin D
The kidney is also involved in glucose synthesis (gluconeogenesis) during prolonged fasting.
Kidney failure results in a disruption of these homeostatic functions, causing severe abnormalities in body fluid volumes and composition.
Anatomy of the kidneys
The kidneys are two paired, bean-shaped organs.
They lie in the back of the abdominal cavity and on either side of the vertebral column. The right kidney sits slightly lower due to the large right lobe of the liver.
The kidney is surrounded by a tough protective fibrous renal capsule and also by visceral fat.
The medial side of the kidney contains a ‘notch’ (hilum) from which renal artery, renal vein, nerves, pelvis and ureter pass through.
The kidney is made up of the outer ‘grainy’ cortex and an inner medulla.
The medulla is divided into multiple cone-shaped masses called pyramids.
The nephrons are the functional units of the kidney.
Nephrons
Each kidney is composed of about 1 million nephrons. After age 40, there is a natural loss of 1% of nephrons per year.
The nephron consists of vascular and tubular components.
Vascular components:
- Afferent arterioles deliver blood to the glomerular capillaries. This is where filtration occurs. The glomerulus is surrounded by the tubular component known as the Bowman’s capsule, and together these form the renal corpuscle.
- Glomerular capillaries rejoin to form efferent arterioles. Unfiltered blood leaves the glomerulus.
- Efferent arterioles subdivide into peritubular capillaries, which supply blood all around the kidney, surrounding nephrons.
Tubular components include the Bowman’s capsule, proximal convoluted tubule, loop of Henle, distal convoluted tubule and collecting duct.
The collecting duct goes from the cortex into the medulla and empties its contents into the ureter. Up to 8 nephrons can feed into a single collecting duct.
Urine formation involves 3 basic renal processes which modify urine composition and volume. These include filtration, reabsorption and secretion.
Excretion = filtration - reabsorption + secretion
Drugs extracted unchanged in urine
Some drugs that are extracted largely unchanged in urine include:
- 100-75% - furosemide, gentamicin, methotrexate, atenolol, digoxin
- 75-50% - benzylpenicillin, cimetidine, oxytetracycline, neostigmine
- 50% - metronidazole, trimethoprim, tubocurarine
Renal elimination is the main factor which determines the duration of action of these drugs.
Special care should be taken in individuals whose renal function may be impaired.
If the same dose is given to someone with impaired kidney function, the rate of elimination will be reduced, meaning that plasma concentration will be higher, which can result in adverse effects and toxicity.
Renal corpuscle
The renal corpuscle is the blood-filtering unit of the kidney, composed of the glomerulus and Bowman’s capsule.
The barrier to compound movement consists of endothelial cells with fenestrations lining the capillary lumen, the basement membrane (dense ECM layer), and podocytes with processes (pedicels) making up the Bowman’s capsule endothelium, and these are connected by tight junctions.
To be filtered, a substance must pass through all of these layers.
Filtration is dependent on MW; the renal corpuscle acts as a molecular sieve, only allowing compounds <60kDa through.
Electrical charge also influences filtration; all 3 layers are negatively charged, so negatively charged molecules will be repelled.
Renal elimination - Filtration
The first step of renal elimination is filtration, which forms the ultrafiltrate.
This contains inorganic ions such as K+, Na+, Cl-, Ca2+, PO43-, H+, HCO3-, as well as organic molecules such as glucose, amino acids and urea.
There are no RBCs, WBCs or platelets and virtually no protein - a tiny amount of albumin may be present as it is small enough to pass through the pores, but its negative charge limits filtration.
To be filtered into the Bowman’s capsule, the drug must have a low MW, be free/unbound, water soluble and have a low Vd (largely contained to blood plasma).
Binding to plasma proteins retards the rate of filtration as it increases the molecular weight and plasma proteins are negatively charged.
Warfarin is 98% protein bound, so only 2% can be filtered.
Renal elimination - Reabsorption and Secretion
Reabsorption involves movement from the tubule to the blood. The substance must cross the luminal membrane, cytosol, basolateral membrane, interstitial fluid and finally the capillary wall. This is transcellular transport.
Some molecules can pass through tight junctions. This is paracellular transport.
Secretion is movement in the opposite direction.
The molecules need to be transported through an aqueous environment and membranes.
Ionisable molecules can undergo changes in secretion or reabsorption if the pH of the environment changes.
Na+, Cl-, K+, HCO3-, glucose, water, urea and amino acids are reabsorbed into the blood from the proximal convoluted tubule. Reabsorption involves active and passive transport processes.
Organic acids and bases are secreted into the PCT.
Lipophilic drugs have high tubular permeability and so are passively reabsorbed, while polar drugs and metabolites are not reabsorbed and are therefore excreted.
Reabsorption increases the half-life of a drug.
pH partition effects: weak bases are more rapidly excreted in acidic urine (reverse applies to weak acids).
Urine is normally slightly acidic and so favours the excretion of basic drugs.
- The basic drug will become ionised in the urine and won’t be able to be reabsorbed, so it will therefore be excreted.
- Acidic drugs will be uncharged so they will be reabsorbed more.
In renal impairment, with decreased H+ excretion, urine can become more alkaline.
Therefore, the balance will switch and basic drugs will be reabsorbed more than acidic drugs.
Drugs bound to proteins are excreted by secretion, so this is a major route of renal drug elimination from blood.
- e.g. penicillin is 80% protein bound, almost completely removed by tubular secretion.
- When protein-bound, penicillin won’t be passively excreted, but active secretion can transport it into urine.
Secretion is mostly an active process.
- Organic anion (OA-) transport (e.g. bile salts, urate/uric acid)
-Organic cation (OA+) transport (e.g. adrenaline, NA, dopamine)
- Drugs include diuretics (OA-), penicillins (OA-), opioids (OA+)
Glomerular filtration rate
GFR can provide an estimate of how efficiently the kidney filters waste from blood.
It is an essential part of assessing patients with kidney disease by providing information on the severity and course of kidney disease and an approximate percentage of kidney function, which influences drug dosing.
3 main methods are used clinically to estimate GFR: creatinine clearance, the Cockcroft & Gault formula and the CKD-EPI (2009) formula for eGFR.
Creatinine clearance
Creatinine is used to estimate GFR as it is cleared from the body almost completely by glomerular filtration. A very small amount is secreted.
Creatinine is derived from the breakdown of creatine and creatine phosphate during energy production in the muscle.
As long as a person’s muscle mass does not change, production of creatinine is relatively constant.
When using creatinine to measure renal function, we need to consider:
- Skeletal muscle mass - generally higher in males
- Diet - meat consumption increases serum creatinine levels, patients asked not to eat meat at least 12 h before the test
- Age - ≥ 40y, natural loss of 1% each year
Clearance is defined as the volume of plasma that is completely cleared of a substance by the kidneys per unit of time.
We need to measure plasma creatinine levels and urine output collection over 24h, which can be inconvenient.
CrCl = (Ucr x flow rate) / Pcr
If you have good kidney function, plasma creatinine levels will be low and urine levels high. Plasma clearance will therefore be high.
Cockcroft & Gault equation
The Cockcroft & Gault equation takes into account the sex, age and weight of the patient to provide an estimate of creatinine clearance.
Estimated CrCl = [(140-age) x weight x constant] / serum creatinine
- The constant is 1.23 in males and 1.04 in females
This is the preferred method for estimating renal function for patients aged ≥ 75y OR for extremes of muscle mass/weight (with adjustment)
Estimated GFR (eGFR)
Estimated GFR (eGFR) is done using a well-validated formula, the chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula, which is based on serum creatinine, sex and age.
see ‘The Kidney’ notes
Units are in mL/min/1.73m2 (m2 refers to body surface area of an average adult - 5’7’’ and 65 kg)
The CKD-EPI formula is the NICE recommended method for estimating GFR and calculating drug doses in most patients with renal impairment.
CKD-EPI is adjusted for body surface area (BSA) and utilises serum creatinine, age, and sex as variables.
The modification of diet in renal disease (MDRD) formula was previously widely used.
CKD-EPI is more accurate than MDRD for eGFR > 60mL/min/1.73m2 (normal GFR is >90)
Also, MDRD overestimates eGFR for the elderly
The CKD-EPI equation should NOT be used in acute kidney injury or for children, malnourished patients, in pregnancy, in oedema or extremes of muscle mass (e.g. amputee, body builder, muscle-wasting disease), as these patients will not have the average body surface area.
In patients aged ≥ 75y, it has the potential to overestimate renal function
In patients with reduced muscle mass it will lead to overestimation of GFR
In patients with increased muscle mass it will lead to underestimation of the GFR
For children, you should use the Modified Bedside Schwartz formula.
Chronic kidney disease in adults
Prognosis in CKD can be predicted based on GFR and urinary albumin:creatinine ratio (ACR).
A decreased GFR and an increased ACR is associated with an increased risk of adverse outcomes.
- Normally, there is very little plasma protein in urine.
- In kidney disease, the renal corpuscle becomes leaky, causing the appearance of protein in urine, known as proteinuria.
In end stage renal disease, the patient requires dialysis or a renal transplant.
There is an increased risk of developing cardiovascular problems including heart attack and stroke.
Renal disease and pharmacokinetics
The progression of kidney disease from acute kidney injury (AKI) to end stage renal disease (ESRD) involves maladaptive repair.
- Adaptive repair involves clearing debris, proliferation to restoring the tubular epithelial cell layer and resolution of pathology/inflammation.
- Maladaptive repair involves the development of fibrosis as tissues become scarred, and delayed resolution of pathology/inflammation.
Acute KD lasts less than 3 months. After this period, it is called chronic KD.
ESRD requires renal replacement therapy (RRT)
Risk factors in progression include: severity/ frequency of AKI, age, sex (males have a more rapid progression), pre-existing CKD, albuminuria, hypoalbuminemia, hypertension, obesity, diabetes mellitus.
Acute kidney injury (AKI)
AKI involves a rapid loss of kidney function. There is a sudden onset of renal impairment, seen as a fall of GFR within hours to days. There is a well-defined cause of injury.
AKI can range from mild renal dysfunction to the need for RRTs, which are dialysis and kidney transplant.
The possible outcomes are: recovery, AKD with recovery, CKD, ESRD or death.
AKI can be due to prerenal, intrinsic or postrenal causes.
Pre-renal AKI can be caused by low renal perfusion or dehydration, especially in the elderly. This accounts for 80% of all AKI instances. Medicines which can impact on hydration, such as diuretics, antihypertensives and laxatives, can cause prerenal AKI.
Intrinsic or intrarenal AKI is damage to any parts of the nephron, such as the glomerulus or any parts of the tubular segment.
Postrenal damage includes kidney stones, obstruction within the ureter or problems within the bladder, including bladder cancer.
Drugs that exacerbate AKI
In treatment of AKI you should withhold drugs which can exacerbate AKI or are unsafe to use. There are 2 acronyms you can use to remember these.
DAMN:
- Diuretics
- ACE inhibitors, AIIRAs
- Metformin
- NSAIDs
CANADA:
- Contrast media - used in CT scans
- ACE inhibitors
- NSAIDs
- Diuretics
- AIIRAs
Dose adjustment is guided by clinical judgement and drug monitoring.
Chronic kidney disease (CKD)
CKD is long-term, progressive, irreversible loss of nephrons, either through disease/damage or ageing. There is a deterioration of kidney funcion.
It is clinically defined as the presence of kidney damage OR eGFR < 60 mL/min/1.73m2 (45-59% of normal function) persisting for ≥ 3 months irrespective of cause.
There are different stages depending on severity. Kidney failure is when function is <15%.
Prevalence is 13-14% adults (age ≥ 16)
In the UK, 6% of adults (age ≥ 16) are living with advanced CKD (Stages 3-5).
In middle age, more men have CKD, but after 75 years the ratio evens out.
Altered glomerular filter integrity can lead to the presence of protein and RBCs in urine, causing proteinuria (hypoproteinaemia) and haematuria.
There is decreased excretion of creatinine, uremic toxins, salt/water, acid, potassium and phosphate. This leads to increased serum creatinine and therefore decreased eGFR, uremia, hypertension, oedema, metabolic acidosis, hyperkalemia and hypophosphataemia.
In advanced CKD, there is decreased biosynthesis of EPO and activation of vitamin D, resulting in anemia and hypocalcaemia causing osteodystrophy (essentially osteoporosis).
Stages 1-3 of CDK often have no symptoms (asymptomatic).
Later stages can cause: nausea, vomiting, loss of appetite, weight loss, itching, confusion, seizures, oedema (leading to ankle swelling and pulmonary oedema manifesting as shortness of breath), weakness, fatigue, and altered urine output.
CKD vs AKI
Long duration of symptoms
Absence of acute illness
Anaemia
Hyperphosphataemia and hypocalcaemia (but similar laboratory findings may complicate AKI)
Reduced renal size and cortical thickness on renal ultrasound (but renal size is typically preserved in patients with diabetes)
Causes of CKD
Diabetes mellitus, hypertension, obesity
Renal vascular disorders: atherosclerosis, nephrosclerosis
Immunological disorders: SLE, glomerulonephritis
Infections: pyelonephritis (a type of UTI), tuberculosis
Nephrotoxins (NSAIDs, heavy metals)
UT obstruction (kidney stones, hypertrophy of prostate)
Polycystic kidney disease
Renal replacement therapies (RRTs)
Long-term dialysis for ESRD can be performed in the form of haemodialysis or peritoneal dialysis.
This is performed to relieve uraemic symptoms and detoxify.
Kidney transplantation (cadaveric or living donor transplantation) is however the therapy of choice for ESRD.
Renal disease and pharmacokinetics
Absorption can be altered by different factors in renal disease, such as nausea and vomiting with uremia and increases in gastric pH.
Glomerular blood flow and filtration are decreased, so creatinine and many drugs and their metabolites accumulate in the blood, leading to increased concentrations that can cause ADRs/toxicity.
Tubular secretion and reabsorption are decreased, so drugs like diuretics and nitrofurantoin (antibiotic for UTIs) do not gain access to their site of action.
- These drugs need to be secreted into the nephron to exert therapeutic effects.
Altered urinary pH may alter the excretion of acid/base drugs. In CKD, the urine becomes more alkaline, so acidic drugs won’t be reabsorbed as much as they become ionised in urine.
Renal bioactivation and metabolism, e.g. of vitamin D3 and insulin, are decreased.
- There is a decrease of insulin metabolism in CKD. In diabetes patients, this can result in them having plasma concentrations that are too high, resulting in hypoglycemia.
Protein binding is decreased due to hypoalbuminemia and uraemia leading to decreased albumin affinity. This can affect the volume of distribution, increasing it and therefore increasing target interaction. However, the rate of clearance can also increase as plasma proteins normally provide a protective element, so half-life can decrease.
Oedema may increase the Vd of highly soluble drugs (e.g. gentamicin) and dehydration can increase plasma concentration of drugs.
Non-renal clearance is also altered as uremia can decrease hepatic metabolism.
Uremia also impairs BBB integrity increasing CNS side-effects/toxicity of drugs. Therefore, drug effects are altered.
With elevated risk of high [drug] and associated side-effects, dose adjustment may be required in patients with renal impairment.
Drug removal by RRT
Factors affecting removal of drug from the blood by RRT include:
- Protein binding – highly protein bound drugs are not generally removed by RRT as they cannot be drawn out by dialysis
- Molecular weight – very large molecules are less likely to be removed than smaller ones
- Water solubility – dialysis solution is aqueous so water-soluble drugs enter into solution preferentially. Lipid-soluble drugs tend to have bigger Vd so concentrations in plasma are comparatively small and less drug is removed.
- Flow rate, and the chemistry and surface area of the membrane
Therefore the same factors that affect regular renal elimination of drugs, as well as the properties of the dialysis machine used, affect drug removal by RRT.
Drugs requiring dose adjustment in kidney disease
Antihypertensives: ACE inhibitors, diuretics, ꞵ-blockers
Antihyperglycemic agents: Metformin, insulin - impaired insulin breakdown results in hypoglycaemia risk
Antimicrobials: penicillins, cephalosporins, macrolides, antifungals, aminoglycosides
NSAIDs and opioids (morphine, tramadol, codeine, pethidine)
CNS drugs: anticonvulsants (lamotrigine, topiramate, gabapentin, pregabalin), lithium
Anticoagulants: DOACs, LMWHs
DMARDs (Methotrexate)
Summary of drug action in kidney disease
Dose alteration of renally-cleared drugs can be achieved by reduction in dose, extension of dosing interval, or use of an alternative drug not extensively cleared by the kidneys.
Dosages should be adjusted based on the patient’s renal function (calculated as creatinine clearance or glomerular filtration rate).
Patients with renal impairment may be more sensitive to pharmacological effects or side-effects of certain drugs.
Be aware of drugs with active metabolites that can exaggerate pharmacological effects in patients with renal impairment.
Some drugs are less effective when renal function is reduced (e.g. thiazide-like diuretics).
