Renal Disease Flashcards
where are the kidneys are situated
The kidneys are situated retro-peritoneally with the left kidney positioned slightly higher than the right.
Renal size
Renal size does relate to the size of the individual and therefore vary in length, but will generally range from length 11-14cm, width 5-6cm, depth 3-4cm.
Renal shrinkage is usually a characteristic of
Chronic Kidney Disease (CKD), with the kidneys being less than 8cm in length as a rule
The kidneys consist of the following cells and structures:
• Renal cortex • Renal medulla • Nephron - Renal corpuscle - glomerulus - glomerular (Bowman’s) capsule • Renal tubule -proximal convoluted tubule -loop of Henle -distal convoluted tubule • Collecting duct
Fundamentally kidneys act as a
The kidneys have a very complicated anatomy but fundamentally they act as a filter. They are very vascular organs receiving around 25% of the cardiac output which is one of the reasons why they are linked to cardiovascular disease e.g. hypertension, atherosclerosis
What is the nephron
The Nephron is the functional unit of the kidney and there are around 1 million nephrons in each kidney.
Excretion =
= filtration (Renal corpuscle) + secretion ( tubule) + reabsorption (tubule & collecting duct)
how much blood is filtered
Each day 170-180L of blood is filtered which approximates to a Glomerular Filtration Rate (GFR) of 120-130ml/min/1.73m2
- Reabsorption and concentration of urine also occurs to
produce a urine volume of 1 -2 litres/day.
Reabsorption is affected by
Reabsorption is affected by hormones, in particular
aldosterone and Anti-diuretic Hormone (ADH). Aldosterone is secreted by the adrenal cortex and acts on the distal tubule and collecting duct. ADH is secreted by the pituitary gland and acts on the collecting duct. Glucose, amino acids, sodium and water are reabsorbed in the proximal tubule and water is absorbed in the descending limb (which is impermeable to sodium). Sodium is absorbed in the ascending limb which is impermeable to water. This creates an interstitium hypertonicity (created by a countercurrent mechanism) which then leads to water being absorbed from the collecting duct. Urea is reabsorbed down a conc gradient which leads to concentrated urine.
Function of the Kidney
- Acts as a filter-regulation of fluid and electrolyte balance
- Removes waste products
- Removal of metabolic waste products
- Removal of foreign chemicals
- Balances body’s fluid content
- Regulates blood pressure
- Endocrine functions:
- Produces erythropoietin, essential for RBC production
- Produces Renin
- Activation of Vitamin D to 1,25dihydroxycholecalciferol to maintain healthy bones.
The kidneys balance
The kidneys balance the chemicals in the blood and produce hormones which control blood pressure and maintain healthy blood cells and bones, when kidneys fail these functions are impaired or cease. This reflects the medication you will see on a prescription for a patient with Chronic Kidney Disease (CKD).
renal failure can be described as
a decline in kidney function (glomerular filtration rate) resulting in an accumulation of waste products and other toxins. The GFR is kept fairly constant by regulatory mechanisms and the large extra capacity to function known as the “renal reserve”. An individual generally will have lost more than 50% of their kidney function before an increase in waste products e.g. urea and creatinine are observed.
A patient with renal failure can be
A patient with renal failure can be acutely unwell; this is usually in Acute Kidney Injury (AKI) or the onset may be more insidious; particularly in Chronic Kidney Disease (CKD). When kidneys fail to filter properly, waste accumulates in the blood and the body, and as the disease progresses, symptoms will become noticeable. Symptoms will vary from person to person.
Types of Renal Impairment
• Acute – Abrupt deterioration in renal function – Usually reversible • Chronic – Long-standing – Progressive • Acute on chronic – Abrupt deterioration on background of chronic renal impairment
Causes of Renal Impairment
• Pre‐renal – Decreased blood flow to the kidneys • Renal or intrinsic – Damage to or loss of nephrons • Post‐renal – Obstruction of filtrate along tubule / collecting duct / urinary system
All these cause a reduction in the GFR which leads to:
- Reduced ability to eliminate waste
- Reduced ability to regulate volume and composition of body fluid
- Increases in serum urea and/or creatinine
What is Chronic Kidney Disease?
At this stage of your studies you need to be aware that CKD is a chronic illness that can be caused by many factors which may include an existing co-morbidity e.g. Type 2 diabetes mellitus.
In general, it is non-reversible and can affect a range of body systems e.g. bone turnover, the cardiovascular system, haematological parameters.
what is acute kidney injury (AKI)
The term describes a rapid deterioration in renal function and is characterised by reduced urine output and increased serum creatinine. The cause of AKI can be pre-renal (eg, hypovolaemia), intrinsic (eg, acute interstitial nephritis) or post-renal (eg, urinary obstruction).
Diagnosing renal failure – investigations and laboratory tests
• Examination of urine
– Appearance, volume, chemical testing, microscopy
– Presence of blood, glucose, protein, micro-organisms
• Imaging – Abdominal X-ray, Ultrasound scan, CT, MRI
• Kidney Biopsy
• Blood tests
– Urea and creatinine
How is the GFR measured/estimated?
Serum creatinine – waste product of protein metabolism (mostly muscle)
Serum urea – nitrogenous waste products
Both urea and creatinine are crude measurements of renal function and should not be used alone as both urea and creatinine can be affected by many factors
Serum urea is affected by many factors: production
Increased by: • High protein diet • Increased catabolism • Surgery • Infection • Trauma • Corticosteroid therapy • Tetracyclines • Gastrointestinal bleeding • Cancer
Decreased by:
• Low-protein diet
• Reduced catabolism e.g. old age
• Liver failure
Serum creatinine
Can be affected by:
Non‐renal influences
• Gender and ethnicity: women have a lower serum creatinine than men. Individuals of African descent tend to have higher creatinine levels, people of Asian and Hispanic descent tend to have lower levels.
• Age: GFR declines with age. As a rule of thumb after the age of 40 an individual loses 10mL/minute per decade, so that at age 80, a normal GFR is 50-60 mL/minute.
• Body habitus: serum creatinine reflects body size, more specifically muscle mass. Obesity does not affect the serum creatinine or eGFR measurement but needs to be taken into account when using the Cockcroft and Gault formula.
• Muscle wasting, amputees: serum creatinine value is lower than expected given loss of muscle mass, and this must be taken into consideration when interpreting serum
creatinine and eGFR.
• Diet, hydration status, and medications: The GFR estimation calculations are not accurate in people on special diets (e.g. very high or low in protein). Altered hydration status will also affect serum creatinine, and thus the estimated GFR.
• Medications and medical conditions can alter creatinine levels or interfere with lab results: e.g. trimethoprim, amiloride, ascorbic acid; icterus
Drug handling in Renal Impairment - Absorption
Absorption - (not usually significant enough to justify altering doses)
• Nausea, vomiting and diarrhoea associated with uraemia, absorption becomes unpredictable
• may have GI oedema “soggy gut syndrome” e.g. in nephrotic syndrome in Congestive Cardiac Failure may need to change to IV diuretics
• Reduced GI motility and gastric emptying, especially if diabetic; can reduce time taken for the drug to be absorbed but does not generally affect the extent of
absorption.
• pH changes e.g. increased ammonia production in anaemia, patients with CKD may have the co administration of medications that increase the pH e.g.
phosphate binders, proton pump inhibitors, iron supplements
Drug handling in Renal Impairment - Distribution
Distribution
Changes to distribution may occur due to changes in fluid status
• Dehydration, oedema/ascites; salt and water overload or depletion affects
concentration of drug obtained
• Patients may be on diuretics, IV fluid, Renal Replacement Therapy (RRT) which will affect hydration status
• Important if small Vd (<50L) as Vd will be increased in uraemia, oedema or ascites and decreased in dehydration
• Lithium/aminoglycosides (also have a Narrow Therapeutic Index). When taking levels for TDM, the hydration status should be noted
• Reduced protein binding due to:
• Uraemia
• Malnourishment or protein loss (hypoalbuminaemia)
• Altered structural arrangement of albumin possibly reducing affinity or number of binding sites for drugs
• Important for highly protein-bound drugs (>80%); care with interpretation of TDM
• Reduced tissue binding
Drug handling in Renal Impairment - Volume of distribution (Vd)
- Considers lipid/water solubility and plasma/tissue binding of drug
- Drugs with low lipid solubility/high plasma binding tend to have low Vd
• Gentamicin - Drugs with high lipid solubility/high tissue binding have large Vd
• Digoxin
Drug handling in Renal Impairment - Metabolism
- Slower – higher adverse effects and toxicity where drugs are usually metabolised to inactive metabolites
- Consider if the drug’s metabolism is affected in uraemia? Some drugs can have a catabolic effect e.g. steroids
- Insulin 98% reabsorbed in tubules - 40% returned to venous blood, 60% metabolised. Metabolism is reduced therefore requirements in renal impairment are reduced
- Conversion of precursor to active metabolite reduced e.g. renal conversion of inactive cholecalciferol to active 1,25 dihydroxycholecalciferol
Drug handling in Renal Impairment - Elimination
- higher plasma levels of drugs renally cleared if drug is renally eliminated – this is the most important factor in whether to adjust doses or not
- metabolites of lipid soluble drugs may be water soluble and therefore toxic e.g. pethidine
Drug handling in Renal Impairment - Pharmacodynamic alterations
- patients with uraemia have increased risk of GI bleeds with irritant drugs e.g. NSAIDs
- increased risk of hyperkalaemia with potassium sparing diuretics
Considerations regarding medicines and patients with renal impairment
- How essential is it?
- If not needed don’t give, especially in AKI - Is there a better alternative?
- Can the drug reach its site of action?
- Will accumulation of drug or metabolites occur?
- Is the drug toxic to the kidney?
- Is there a parameter that can be monitored for efficacy and safety (e.g. clotting time)?
- Is the drug more likely to cause side effects or worsen the uraemic state e.g. NSAIDs
Note: adverse effects of drugs are more likely in patients with renal failure, especially in the elderly - Is the drug a sodium or potassium salt?
- Are there fluid restrictions to be considered?
Drug‐induced renal impairment
• Pre-Renal
– Hypovolaemia
• Loop diuretics e.g.furosemide
Lithium co-administered with furosemide leads to synergistic toxicity
• Excessive laxative use
– Reduction in cardiac output impairs renal perfusion e.g. beta blockers
– Reduction in renal blood flow e.g. ACE inhibitors
Drug‐induced renal impairment
• Renal
– Acute tubular necrosis (ATN) produced by direct nephrotoxicity – prolonged or excessive treatment with e.g. aminoglycosides, contrast media, vancomycin
– Acute tubulointerstitial nephritis (ATIN) often associated with proteinuria and haematuria and Chronic tubulointerstitial nephritis
(CTIN) e.g. NSAIDs, penicillins, furosemide, gentamicin
– Membranous glomerulonephritis immune mediated e.g.
penicillamine, gold, anti-TNF, allopurinol, NSAIDs, penicillins
Drug‐induced renal impairment
• Post Renal
– Ureteric fibrosis secondary to analgesic nephropathy
– Cytotoxic tumour lysis e.g. cytotoxics cause uric acid crystals deposition in renal tubules
– Crystalluria e.g. cisplatin, aciclovir, methotrexate
– Drugs causing obstruction e.g. ergotamine
In which condition are kidneys enlarged
An obvious exception to this is in adult polycystic kidney disease where the kidneys are usually enlarged (and clearly cystic on ultrasound).
Example of concomitant drug use
- Antihypertensives and a diuretic – can worsen hypovolaemia
- ACE Inhibitor plus a diuretic and an NSAID: all affect kidneys to lower BP, reduce renal perfusion and worsen dehydration
Cockcrof and Gault equation
estimated CrCl in mL/min = (140 - age) x weight (in kg) x constant / Serum creatinine (umol/L)
Constant = 1.23 in men and 1.04 in women
eGFR MDRD
GFR = 186 x serum Cr -1.154 x age -0.203 x 1.212 (if black) x 0.742 (if female)
It is less accurate than the CKD-EPI formula when eGFR is greater than 60 mL/min/1.73 m2. It also overestimates GFR in elderly patients
CKD - EPI
eGFR (ml/min/1.732) = 1.41 x min (Scr/ k, 1)a x max (Scr/ k,1) -1.209 x 0.993 age [x1.018 if female] [x 1.159 if black]
a = -0.329 in females and -0.411 in males k = 0.7 in females and 0.9 in males
Which drugs should be avoided in renal impairment
Nephrotoxic drugs should, if possible, be avoided in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when renal reserve is already reduced.
Also consider concomitant drug use For example:
- Antihypertensives and a diuretic – can worsen hypovolaemia
- ACE Inhibitor plus a diuretic and an NSAID: all affect kidneys to lower BP, reduce renal perfusion and worsen dehydration
Renal shrinkage may be absent in..
Shrinkage may be absent in diabetic nephropathy and infiltrative disease such as amyloidosis i.e. their kidneys may appear to be of normal size.
Measuring renal function
Glomerular filtration rate (GFR)This is the sum of all the nephron filtration rates; it is the best index of overall function and equates to percentage kidney function. The ideal substance to measure GFR needs to be:
- In constant production
- Completely filtered
- Not reabsorbed
- Not transported or secreted
- Easily detected in blood/urine
Serum urea is affected by many factors: elimination
Increased by:
• Elevated GFR e.g. pregnancy
Decreased by: • Glomerular disease • Reduced renal blood flow - hypotension - dehydration • Urinary obstruction • Tubulointerstitial nephritis
What other tests/investigations are available?
Direct GFR measurement:
Radionuclides e.g. 125 I-iothalamate
Cystatin C: Cystatin C is a relatively new test which can be used to estimate GFR as it is filtered completely by the kidneys
24 hour urine creatinine clearance (CrCl):
The serum creatinine level is obtained during a 24 hour period (P)
CrCl = U x V/P
U = Urinary creatinine concentration
V = Urine flow
This can be inaccurate if urine collection incomplete. Specialists still use this method in conjunction with prediction equations if additional confirmation is required. This is the most accurate method in clinical practice if undertaken accurately.
Examples of Monitoring
- Monitor renal function, drug efficacy, side effects, toxicity
- Measure serum drug levels if appropriate
How are drug doses adjusted?
- Dose remains the same but interval increased
Peaks higher as drug accumulated but more time given for serum concentration to reduce before next dose given - Dose is decreased but interval remains the same
Peaks lower as dose reduced therefore takes less time for serum concentration to reduce so next dose can be given as usual - Decrease dose and increase interval
Peaks lower and more time for serum concentration to reduce before next dose – can be used where narrow therapeutic window exists
Examples of drugs/ dose forms to be used with caution or are contra-indicated
• Opioids, gentamicin, vancomycin, metformin, statins, low molecular weight heparins (LMWHs), bisphosphonates
• Particular dosage forms e.g. Polyethylene glycol can be absorbed from open wounds and damaged skin and is excreted by the kidneys therefore polyethylene glycol based topical preparations should not be used in conditions where absorption of large quantities of
polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment.
Degrees of renal impairment defined using eGFR - Normal Stage 1
eGFR mL/minute/1.73m2
More than 90
Degrees of renal impairment defined using eGFR - Mild Stage 2
eGFR mL/minute/1.73m2
60-89
Degrees of renal impairment defined using eGFR - Moderate Stage 3
eGFR mL/minute/1.73m2
30-59
Degrees of renal impairment defined using eGFR - Severe Stage 4
eGFR mL/minute/1.73m2
15-29
Degrees of renal impairment defined using eGFR - Established renal failure Stage 5
eGFR mL/minute/1.73m2
Less than 15
Chronic kidney disease is present in which stage
Stage 3A eGFR: 45-59
Stage 3B eGFR: 30-44
which drugs should be avoided in renal impairment according to BNF
Nephrotoxic drugs
Do not routinely offer loop diuretics to treat acute kidney injury
Do not offer low-dose dopamine to treat acute kidney injury.
Detect acute kidney injury, in line with the (p)RIFLE[3], AKIN[4] or KDIGO[5] definitions, by using any of the following criteria:
- a rise in serum creatinine of 26 micromol/litre or greater within 48 hours
- a 50% or greater rise in serum creatinine known or presumed to have occurred within the past 7 days
- a fall in urine output to less than 0.5 ml/kg/hour for more than 6 hours in adults and more than 8 hours in children and young people
- a 25% or greater fall in eGFR in children and young people within the past 7 days.
LEVOTHYROXINE
- Type of medicine
- Require therapeutic drug monitoring
- Consider how it is metabolised.
- Identify whether to use the eGFR or CrCl for dose adjustments.
- Justify your answers in terms of the type and pharmacokinetics of the medicine
- Decide whether it should be administered or omitted in patients with acute kidney injury
- Naturally occurring
- Doesn’t require TDM
- excreted through the kidneys and metabolized through conjugation and glucuronidation and excreted directly into the bile and the gut where they undergo enterohepatic recirculation.
- eGFR
- Long half-life.
- Could omit
LITHIUM
- Type of medicine
- Require therapeutic drug monitoring
- Consider how it is metabolised.
- Identify whether to use the eGFR or CrCl for dose adjustments.
- Justify your answers in terms of the type and pharmacokinetics of the medicine
- Decide whether it should be administered or omitted in patients with acute kidney injury
- Narrow therapeutic index. Toxic in overdose. Nephrotoxic
- TDM required
- is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions
- CrCl
- Consider risk v benefit of stopping. Reinitiating. Reduce dose. Take levels. Signs of toxicity
- Omit low therapeutic index so its toxic
GENTAMICIN
- Type of medicine
- Require therapeutic drug monitoring
- Consider how it is metabolised.
- Identify whether to use the eGFR or CrCl for dose adjustments.
- Justify your answers in terms of the type and pharmacokinetics of the medicine
- Decide whether it should be administered or omitted in patients with acute kidney injury
-Narrow therapeutic Index. Toxic in overdose. Nephrotoxic.
- TDM required
- not metabolized in the body - is excreted unchanged in active form via the kidneys. Excreted primarily in urine by glomerular filtration; small amounts may be excreted in bile and breast milk
- CrCl
- Known to be nephrotoxic, ototoxic, narrow
therapeutic index. Consider the dosing regimen e.g. interval dosing, once daily dosing. See notes in the BNF. Risks v benefits, degree of AKI. Alternative to treat
infection. Take levels.
- Omit Y/N
METHOTREXATE
- Type of medicine
- Require therapeutic drug monitoring
- Consider how it is metabolised.
- Identify whether to use the eGFR or CrCl for dose adjustments.
- Justify your answers in terms of the type and pharmacokinetics of the medicine
- Decide whether it should be administered or omitted in patients with acute kidney injury
- Cytotoxic
- Doesn’t require TDM
- undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase.
- CrCl
- Once weekly dosing. What is it being used for? RA, psoriasis or as chemotherapy?
- Omit Y, But always to consider individual circumstances
DABIGATRAN
- Type of medicine
- Require therapeutic drug monitoring
- Consider how it is metabolised.
- Identify whether to use the eGFR or CrCl for dose adjustments.
- Justify your answers in terms of the type and pharmacokinetics of the medicine
- Decide whether it should be administered or omitted in patients with acute kidney injury
- Anticoagulant
- Doesn’t require TDM
- dabigatran etexilate is metabolized primarily by esterases
- CrCl
- Dose reduction needed. Newer medicine not so much experience with its use as other medicines. Antidotes? Alternative medicine? Depends on individual circumstances / indication, see BNF and SPC for full details. Need baseline U and Es and annual monitoring (See BNF).
- Omit Y/N
CKD can be caused by:
high blood pressure – over time, this can put strain on the small blood vessels in the kidneys and stop the kidneys working properly
diabetes – too much glucose in your blood can damage the tiny filters in the kidneys
high cholesterol – this can cause a build-up of fatty deposits in the blood vessels supplying your kidneys, which makes it harder for them to work properly
kidney infections/ kidney inflammation
cysts develop in the kidneys
blockages in the flow of urine – from recurrent kidney stones or an enlarged prostate
long-term, regular use of medicines such as lithium and (NSAIDs)
Naproxen 500mg tablets recommended dose for patients with RI
The lowest effective dose should be used for the shortest possible duration.
Avoid if possible or use with caution.
Avoid if eGFR less than 30 mL/minute/1.73 m2.
20-50 dose as in normal renal function, but avoid if possible
10-20 - dose as in normal renal function but avoid if possible
<10 dose as in normal renal function but only use if on dialysis
Co-amoxiclav 1.2g injection recommended dose for patients with RI
Adults : if eGFR 10–30 mL/minute/1.73 m 2, 1.2 g initially, then 600 mg every 12 hours; if eGFR less than 10 mL/minute/1.73 m 2, 1.2 g initially, then 600 mg every 24 hours.
Children: use normal initial dose and then use half normal dose every 12 hours if estimated glomerular filtration rate 10–30 mL/minute/1.73 m 2 ; use normal initial dose and then use half normal dose every 24 hours if estimated glomerular filtration rate less than 10 mL/minute/1.73 m 2 .
Risk of crystalluria with high doses (particularly during parenteral therapy).
30-50 dose as normal in normal renal function
10-30 IV 1.2g every 12 hours
<10 1.2g stat followed by 600mg every 8 hours or 1.2g every 12 hours
alginate preparation for indigestion
Alginates may contain sodium or other electrolytes. Aluminium may accumulate so Magnesium Trisilicate may be more appropriate than aluminium containing products, although caution is still needed.
relieve constipation
Ispaghula husk is low in sodium. Osmotics: macrogol 3350 with potassium chloride, sodium bicarbonate and sodium chloride. Care re-electrolytes.
loperamide to take on holiday
Consider should she take loperamide if it is an infection? Make sure it is diarrhoea and not overflow constipation (unlikely but contextualise last year’s GI learning). Rehydration: not rehydration sachets (electrolyte content). If on anti-hypertensives and diuretics, consider discontinuation if patient has diarrhoea
Which drugs may decrease end organ sensitivity in renal impairment
• May be decreased, this is of consequence when drugs exert their effect in the kidney e.g. thiazide diuretics
Which drugs may increase end organ sensitivity in renal impairment
• May be increased e.g. centrally acting drugs such as phenothiazines and opiates
loperamide to take on holiday
Consider should she take loperamide if it is an infection? Make sure it is diarrhoea and not overflow constipation (unlikely but contextualise last year’s GI learning). Rehydration: not rehydration sachets (electrolyte content). If on anti-hypertensives and diuretics, consider discontinuation if patient has diarrhoea
What mediciation should be avoided in cystitis
Avoid preparations containing potassium if on a low potassium diet
