Clinical Renal and Hepatic Disease Flashcards
What are the different types of tests to diagnose liver disease?
Medical history
Blood tests
Imaging
Liver biopsy- local anaesthetic
Name the blood tests used for diagnosis of liver disease:
LFTs
Electrolytes
FBC- end stage causes bone marrow suppression
Viral screens- see if its hepatitis/ viral cause
Blood clotting- prothrombin time
Name the imaging tests used for diagnosis of liver disease:
Ultrasound
CT scan
MRI
Name the main LFTs used for liver disease diagnosis:
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Describe the role of AST in the liver:
Role in gluconeogenesis
Catalyses reversible conversion of aspartate and alpha ketoglutarate to oxaloacetate and glutamate
Found in hepatocytes, but also other tissues including heart, brain and skeletal muscle
What is the reference range for AST?
5-40IU/L
Describe the role of ALT in the liver:
Also role in gluconeogenesis
Catalyses reversible transfer of an amino group from L-alanine to alpha ketoglutarate resulting in pyruvate and L-glutamate
More specific to liver
What is the reference range for ALT?
5-30IU/L
What do the levels of AST and ALT mean?
Very high levels in acute viral/toxic hepatitis
High levels in cholestatic jaundice/ cirrhosis
Ratio of AST/ATL useful in diagnosing different types of liver disease e.g AST/ALT more than 2 possibly due to alcohol injury, most other liver injuries ratio is less than 1
Name the non-main LFTs used for liver disease diagnosis:
Gamma glutamyl transferase (GGT)
Alkaline phosphatase (ALP)
What is useful about the GGT test?
Can be used as a use of alcohol consumption/ abuse
Levels drop after 3-6 weeks
Describe the role of GGT in the liver:
Catalyses transfer of gamma glutaryl moiety of glutathione to an a.a, peptide or water (forming glutamate)
Also in kidneys, pancreas and prostate
What is the reference range of GGT?
5-45IU/L
What do the levels of GGT mean?
Very high levels in biliary obstruction, lower increased levels in chronic alcohol or drug toxicity, hepatitis, cirrhosis or cholestasis
Describe the role of ALP in the liver:
Removes phosphate groups from nucleotides, proteins and alkaloids
Also in bone marrow, intestinal wall, renal tubules and placenta
What is the reference range of ALP?
20-100IU/L
What do the levels of ALP mean?
Very high levels in biliary obstruction
Describe the bilirubin test in blood tests for liver disease:
Reference range 0-17µmol/L
Jaundice occurs at more than 35µmol/L
Increases reflects depth of jaundice and useful for monitoring disease progression
Can measure total levels or difference conjugated/ unconjugated bilirubin
What is the difference between conjugated and unconjugated bilirubin?
Conjugated from the liver
Unconjugated from RBC/heme breakdown
Describe the plasma protein and albumin test in blood test for liver disease:
Reference ranges 60-80g/dL total protein
35-50g/dL albumin
Albumin is synthesised solely in the liver
Half life for plasma albumin is 20-26 days
Less than 20g/dL changes plasma protein pressure, leading to oedema
Why is the half life of albumin useful in determining?
As the half life is 20-26 days (long), a reduction can indicate long term damage due to extended half life which can’t be decreased immediately
What is the prothrombin time?
Reference range 10-15 secs
Increase PT when lack of clotting factors
PT depends on factor II,VII and X and will increase if these factors aren’t produced
If hepatocellular damage, liver can’t produce clotting factor as its unresponsive to vit K
If cholestasis increase in PT due to deficiency in bile salts responsible for vit K absorption so responsive to vit K
What is the treatment for cholestasis when PT is increased?
IV 10mg Vitamin K for 3 days
Describe the urea and ammonia test in blood tests for liver disease:
Reference range for urea: 2.5-7.8 mol/L
Reference range for ammonia: 16-60(M), 11-51(F) µmol/L
Urea decreases in liver disease
Ammonia increases in liver disease, hepative encephalopathy- due to failure of liver to convert ammonia to urea
What effects can liver disease result in?
Drug clearance
Biotransformation
Pharmacokinetics
What can liver disease cause alterations in?
Intestinal absorption
Plasma protein binding
Hepatic extraction ratio
Liver blood flow
Portal systemic shunting
Biliary excretion
Enterohepatic circulation
Renal clearance
Describe phase I metabolism and drugs metabolised there:
Oxidation e.g azathioprine
Reduction e.g halothane
Hydrolysis e.g atropine, pethidine
Describe phase II metabolism and drugs metabolised there:
Glucuronidation e.g paracetamol, morphine
Sulphonation e.g steroids
Acetylation e.g hydralazine, phenelzine
Methylation e.g nicotine
What is the extraction ratio?
Rate of drug removed by liver, depends on both the capacity to metabolise but also blood flow through the liver
Can be high or low
Name and describe drugs with a high extraction ratio:
Clearance depends on hepatic blood flow
Likely to require a larger decrease in dose
Chlomethiazole, lignocaine, morphine, propranolol, verapamil, metoprolol, pethidine
First pass metabolism, ER close to 1
Name and describe drugs with a low extraction ratio:
Clearance depends on metabolising capacity of the liver
Chloropropamide, phenytoin, diazepam, warfarin, atenolol, furosemide, prednisolone, lorazepam
ER close to 0
Name drugs and conditions which are Cyp450 inhibitors:
Cimetidine, ciprofloxacin, ethromycin, COCs, ketoconazole
CCF, cirrhosis, viral infections
Name drugs and conditions which are Cyp450 inducers:
Phenytoin, carbamazepine, phenobarbiton, primedonne, rifampicin
Smokers, heavy drinkers
Increase in GGT levels
Describe the pharmacodynamics in liver disease:
Increase sensitivity to drugs which:
-affect clotting/ bleeding, due to LD decrease clotting factor
-affect CNS, increase risk of hepatic encephalopathy
-diurects
-constipation
How can diuretics cause liver disease complications?
Hypervoleamia, decreases in K+, leads to increased risk of hepatic encephalopathy
How can consitpation cause liver disease complications?
Increase risk of hepatic encephalopathy as N waste products in GIT for increased period of time so increased risk of absorption
What is the treatment/ management for cirrhosis and end stage liver disease?
Low protein diet
Low Na+ and diuretics to minimise water retention
Draining of ascites fluid by paracentesis
Surgery to treat portal hypertension and decrease risk of bleeding
Medicines depending on disease and complications
Transplant
What are the lifestyle modifications in liver disease?
Lose weight and stop alcohol
What are the minor symptoms in acute alcohol withdrawal?
CNS hyperactivity resulting in insomnia
Tremulousness
Mild anxiety
GI upset
Headache
Diaphoresis (excessive sweating)
Palpitations
Resolves within 24-48 hrs
What are more severe symptoms in acute alcohol withdrawal, normally in chronic alcoholism?
Seizures- convulsions usually occur within 12-48 hrs of last drink
If untreated can lead to delerium tremens (DTs)
Alcoholic hallucinations- resolve within 24-48 hrs
Fluid and electrolyte abnormalities
Describe DTs in acute alcohol withdrawal?
DTs develop in 48-96hrs after last drink, results in hallucinations, disorientation, tachycardia, hypertension, hypothermia, agitation and diaphoresis, can be fatal
What is the treatment for acute alcohol withdrawal?
Symptom control and supportive care
Benzodiazepines
IV fluids
Nutritional supplementation
Frequent clinical assessment
Describe the use of benzodiazepines in acute alcohol withdrawal:
Control psychomotor agitation and prevent more severity
e.g chlordiazepoxide, oxazepam, decreasing regimen over 9 days
Lowest possible dose given to suppress symptoms without sedation
Seizures- IV lorazepam
Ideally don’t send home with supply as causes respiratory depression and dependence especially with alcohol
Describe the treatments for cholestatic pruritis:
Cholestryamine- first line:
ion exchange resin, binds to bile salts in the gut stop it being absorbed
Anti-histmaines:
non- sedating to avoid encephalopathy
Calamine lotion/ menthol in aqueous cream
How does ascties occur?
Earliest and most common complication of chronic LD- 50% within 10 yrs
Activation of RAS due to decrease in renal blood flow due to disordered liver anatomy
Increase in levels of aldosterone so fluid retention and also liver metabolises aldosterone so increase fluid
Chronic LD, decrease in albumin, decrease in osmotic pressure in plasma so fluid accumulation in abdomen
What is the treatment for ascites?
Diuretics
Bed rest
Na+ and fluid restriction
Paracentesis- physical draining of fluid
Aim for weight loss: 0.5-0.75kg decrease per day (up to 1-1.5kg per day if also peripheral oedema) -therapeutic monitoring
What are the consequences if the weight loss is too much in ascites?
Hypovolaemia - risk of encephalopathy
Hyponautramia
Hypokalaemia
Toxic monitoring
What are the diuretic treatments in ascites?
1st line= spironolactone as its an aldosterone antagonist
Add on= furosemide (loop) if no weight loss/ peripheral oedema
What is the initial treatment for Wernicke-Korsakoff syndrome?
IV Pabrinex (IV vit B/C preparations)
Infusion over 30 mins
2 pairs of ampoules TDS for 3-5 days
Need facilities for treating prophylaxis as potential serious allergic reaction
What is the additional treatment for Wernicke-Korsakoff syndrome?
Oral thiamine for treatment or prophylaxis
100mg TDS (regimen can vary)
Administered at same time as IV and then continue for 3-6 months after abstinence
What is the treatment for hepatic encephalopathy?
Lactulose
Rifaximin- add on when lactulose not working
Phosphate enemas- when lactulose CI
Avoid precipitating factors
Describe the use of lactulose in hepatic encephalopathy:
30-50ml TDS
Adjust to aim for 2-3 soft stools a day (therapeutic)
Disaccharide molecule, breaks down to form lactic acetic and formic acid so decreases pH of intestine, from 7 to 5, ionisation of N compounds to decreases absorption, alters intestinal flora (decreases ammonia producing bacteria), speeds up gut transit, less time for N and ammonia to sit in gut and be absorbed into system
What are the toxic monitoring parameters of lactose in hepatic encephalopathy?
Avoid diarrhoea casing dehydration and hypovolaemia
Describe the use of rifaximin in hepatic encephalopathy:
Semi-synthetic derivative of rifamycin
Decreases production/ absorption of gut ammonia
What are precipitating factors of hepatic encephalopathy?
Avoid dehydration
Hypokalaemia
GI haemorrhage
CNS drugs
High dietary protein
Constipation
What is the treatment for portal hypertension?
Aim to decrease portal BP and resting HR by 25%
Propranolol low dose and increase cautiously as undergoes 1st pass metabolism
Other vasodilators e.g nitrates
What is the treatment for bleeding oesophageal varices?
Resuscitation and correct hypovolaemia (blood transfusions, IV fluids)
Vasoactive therapy
Endoscope (camera down oesophagus)
-sclerotherapy (e.g ethanol amine to stop bleeding)
-ligation/banding
-balloon tamponade
-TIPS (transjugular intrahepatic porto systemic stent shunt)
Describe vasoactive therapy for the treatment of bleeding oesophageal varicies:
IV e.g vasopressin, terlipressin, octreotide
Started as soon as haemorrhage is suspected
Describe the treatment for prothrombin time:
PT is greater than 18seconds
Phytomenadione IV (vit K)- may not work if pt has severe liver disease
Avoid NSAIDs/ warfarin
Describe drug induced hepatotoxicity:
Over 900 drugs, toxins and herbs cause liver injury
Drugs cause:
-20-40% of all liver failure
-2-5% of hospitalised jaundice
-10% acute hepatitis cases
What are risk factors for drug induced hepatotoxicity?
Age e.g sodium valproate CI under 3
Sex- females 2x more likely
Alcohol ingestion
Pre-existing liver disease
Genetic facts
Other co-morbidities e.g HIV
Drug formualtion
What is the pathophysiologic mechanism for drug induced hepatotoxicity?
Disruption of the hepatocyte
Disruption of the transport proteins
Cytolytic T cell activation
Apoptosis of hepatocytes
Mitochondrial disruption
Bile duct injury
What are the two types of ADR?
ADR type A- intrinsic or predictable
ADR type B- idiosyncratic or unpredictable
Describe ADR type A reactions:
Reproducible injury in animals
Injury is dose related
Due to drug or metabolite
80% of all ADRs
e.g paracetamol or carbon tetrachloride
Describe ADR type B reactions:
Hypersensitivity or immunoallergenic response e.g phenytoin with fever, rash, eosinophilia
e.g chlorpromazine, halothane
OR
metabolic, idiosyncratic, indirect metabolite or offending drug
What are the LFT signs of drug induced hepatoxicity?
Many drugs can cause inconsequential rises in LFTs, if up to 2x upper limit then doesn’t require medicine
Liver damage has occurred when:
-ALT increased to more than 2x upper limit
-increased conjugated bilirubin more than 2x upper limit
-combined increased ALP and total bilirubin with one more 2x upper limit
What is the management for drug induced hepatotoxicity?
Drug withdrawal
Antidote if appropriate
Corticosteroids- evidence controversial, if LFTs still deteriorating 3 weeks after, or if hepatotoxicity remained 6 months after discontinuation
Supportive therapy
Yellow card report- serious report
What is the prevention for drug induced hepatotoxicity?
LFT monitoring
Patient eduction
-signs of liver damage e.g abdominal discomfort, malaise, nasuea
-OTC paracetamol, health/herbal remedies
What is the dosage of paracetamol that causes hepatotoxicity?
Accounts for more than 50% of acute liver failure
More than 15g leads to fatal hepatic necrosis
More than 7.5g risk of severe liver damage
More than 5g requires hospital admission and observation
What is the diagnosis for paracetamol toxicity?
Serum paracetamol concentration
What are the different phases in paracetamol hepatotoxicity?
Phase 1,2,3,4
What is phase 1 of paracetamol hepatotoxicity?
0.5-24 hours after ingestion
Asymptomatic or anorexia, N&V, malaise
What is phase 2 of paracetamol hepatotoxicity?
If left untreated
18-72 hours after ingestion
Right upper quadrant abdominal pain and tenderness, anorexia, N&V, possibly oliguria (decrease in urine)
What is phase 3 of paracetamol hepatotoxicity?
If left untreated
Hepatic phase 72-96 hours after ingestion
Continued symptoms, hepatic necrosis may be seen as jaundice, coagulopathy, hypoglycaemia, hepatic encephalopathy, possible acute RF, death from multi organ failure
What is phase 4 of paracetamol hepatotoxicity?
If left untreated
Recovery 4 days- 3 weeks
Complete resolution if survive phase 3 and complete resolution of organ failure
Describe the major route of paracetamol metabolism:
95% into paracetamol conjugates by glucuronide sulphates, then excretion in the urine
Describe the minor route of paracetamol metabolism in normal doses:
5% via Cyp450 metabolism
Into N-acetyl P benzoquinoneimine (NAPQI)- toxic
Normal doses, glutathione conjugates into non- toxic products and excretion in the urine
Describe the minor route of paracetamol metabolism in over doses:
5% via Cyp450 metabolism
Into N-acetyl P benzoquinoneimine (NAPQI)- toxic
In overdoses, glutathione stores become depleted, allowing NAPQI to accumulate and bind directly to hepatocytes causing cell damage= hepatotoxicity
Name the different treatments for paracetamol overdose:
N acetyl cysteine IV
Methionine oral, both replenish glutathione stores
Activated charcoal of gastric lavage within ONE hour
Describe N acetyl cysteine as a treatment for paracetamol overdose:
IV first line
Given during first 8 hours of overodse
Possible effective up to and beyond 24 hours, effectiveness decreases after 12 hours
Dosing depends on plasma paracetamol conc and time after ingestion
A= normal treatment line
B= enhanced risk line, for patients on enzyme inducers, alcoholics, malnourished, HIV
Name the systems of the renal system:
Aorta
Inferior vena cava
Left kidney- both found at the back of the abdominal cavity just below the ribcage
Right kidney- slightly lower due to presence of liver
Ureter
Bladder
Urethra
Describe the nephron:
1 million nephrons per kidney
What is eGFR?
eGFR, measuring renal function, looking at filtration rate from capillaries of glomerulus to Bowman’s capsule
Volume of fluid that filters into the Bowman’s capsule per unit time
Name the 4 functions of the kidney:
Excretory
Endocrine
Regulatory
Metabolism
Describe the excretory function of the kidney:
Excretes waste products and drugs
For certain drugs need to assess the extent of renal impairment
Make adjustments to dose/ drug choice
Avoid nephrotoxics
Describe the endocrine function of the kidney:
Erythropoietin production- stimulates RBC production in bone marrow
Renin production- BP control
PG production
Describe the regulatory function of the kidney:
Control fluid volume and composition
Regulate BP
Regulate blood pH
Describe the metabolism function in the kidney:
Vit D metabolism
Name the 2 different types of tests to assess renal function:
Plasma (blood)- more routinely
Urine
Name plasma tests for assessing renal function:
Creatinine (by product of protein metabolism)
Urea
eGFR
Name the urine tests for assessing renal function:
-Albumin:creatinine ratio (ACR)
-Osmolality- high particle conc= high osmolality
-Specific gravity- solute conc, higher gravity= more solutes- proteinuria/ microalbumina
-Haematuria- blood in urine
-Mid- stream urine (for UTI)
Describe creatinine as a test for renal function:
Freely excreted by the kidneys
Any level of renal impairment will cause increase in creatinine due to build up in the body as they kidneys are supposed to be excreting it out
Other factors can cause creatinine to rise, so rather than creatinine alone, can use creatinine clearance
Describe creatinine clearance (CrCl) as a test for renal function:
GFR roughly equal to CrCl
24 hour urine collection
CrCl (ml/min) = (urine Cr (µmol/L) x volume (ml))/ (plasma Cr (µmol/L) x time)
What are the problems with using CrCl using urine collection and what is the outcome?
Time delays and suspect accuracy of urine collection depending on where it is taken place
In practice use the Cockcroft and Gault equation
What is the Cockcroft and Gault equation:
CrCl (ml/min) = ((140-age) x weight x F)/ plasma Cr (µmol/L)
F= 1.23 males
F*= 1.04 females
What are the limitations of the Cockcroft and Gault equation?
Assumes average population data
Unsuitable for children and pregnancy
Renal function must be stable (plasma Cr stable)
What is the traditionally normal levels of Cr and CrCl?
Cr= 55-125 µmol/L
CrCl= 120 ml/min
Name 2 ways how eGFR can be calculated:
MDRD- Modification of Diet in Renal Disease equation
CKD-EPI- Chronic Kidney Disease Epidemiology Collaboration Formula
Describe the MDRD test to calculate eGFR:
4 variables used
Serum Cr
Age
Sex
Ethnic origin
Less accurate when more than 60ml/min/1.73m2 and overestimates for elderly
Describe the CKD-EPI test to calculate eGFR:
Most recommended
Same limitations as CrCl
Online calculator
Local laboratory calculations
Describe the race adjustments in eGFR equations:
Practice varies in x1.159 for Black ethnic groups as creatinine production is higher in black ethnic origin
Only found this to be advantageous in America so NICE has removed this recommendation
Name the different stages of renal impairment:
Stage 1(G1)- normal GFR
Stage 2 (G2)- mild impairment
Stage 3A (G3A)- mild to moderate
Stage 3B (G3b)- moderate to severe
Stage 4 (G4)- severe impairment
Stage 5 (G5)- established/ end stage
What is the eGFR value for stage 1 renal impairment?
More than 90
What is the eGFR value for stage 2 renal impairment?
60-89
What is the eGFR value for stage 3A renal impairment?
45-59
What is the eGFR value for stage 3B renal impairment?
30-44
What is the eGFR value for stage 4 renal impairment?
15-29
What is the eGFR value for stage 5 renal impairment?
Less than 15
What is the unit for eGFR and why?
ml/min/1.73m2
This is the normalised BSA
How would you calculate the GFR absolute?
Can use it to individualise someones GFR
= eGFR x (individual BSA/1.73)
Describe urea as a test for renal function:
Nitrogenous breakdown product of protein metabolism
Freely excreted by the kidney so a raise in blood levels suggest impairment
What is the normal and uraemia range of urea?
More than 15mmol/L= uraemia
Normal 1.7-6.7mmol/L
What are the symptoms of uraemia?
N&V
Puritis
What can blood urea levels also be increased by?
Dehydration
Muscle injury
Infection
Haemorrhage
Excess protein intake
So test should never be used alone
Describe the osmolality test for renal function:
Darker urine, more concentrated
Describe proteinuria test for renal function:
Albumin is a protein which is meant to be in the blood and not in the urine, so testing the urine for albumin is a predictor of renal disease development and adverse outcomes
How would you calculate the albumin: creatinine ratio (ACR):
Divide albumin (mg) by creatinine (g)
What is the ACR value showing renal failure in non-diabetics?
More than 70mg/mmol
What is the ACR value showing renal failure in diabetics?
More than 2.5mg/mmol in males
More than 3.5mg/mmol in females
Due to increased risk of developing renal disease
What is ACR used for?
To predict renal disease development and risk of adverse outcomes e.g CKD progression, AKI events and general mortality
What is the general classification of CKD?
Decreased GFR and increased ACR
Describe absorption of drugs in renal disease:
Uraemia decrease drug absorption via: D&V, GI, oedema
Reduced Ca absorption- due to less vit D activation
Hyperphosphatemia- kidney impairment struggles to excrete phosphate- phosphate binder treatment decreases some drug absorption
Describe distribution of drugs in renal disease:
Changes in distribution due to fluid accumulation so affect distribution of particularly water soluble drugs
Less protein binding
Less tissue binding
Describe how less protein binding affects the distribution of drugs in renal disease?
Phenytoin due to hypoalbuminemia and urea competition- less albumin for phenytoin to bind to
Increased levels, urea competes for protein binding sites so increased free phenytoin in blood
Describe how less tissue binding affects the distribution of drugs in renal disease?
Digoxin increases conc
Urea will compete with digoxin for tissue binding sites
Describe metabolism of drugs in renal disease:
Less vit D metabolised (less calcitriol production)
Less Ca absorption from gut and kidneys
Less insulin metabolism (T1D insulin requirements may be affected in RD)
Less elimination of pharmacologically active metabolites
Describe examples of active metabolites that aren’t eliminated as much due to renal disease:
Nor-pethidine- lead to CNS excitation and epileptic seizures
Morphine metabolites- can accumulate causing toxicity issues
Switch to alternative opioid e.g oxycodone which is less renally excreted
Describe excretion of drugs in renal disease:
Less excretion, need to modify doses of drugs which are renally excreted
Lower dose and/or increase dose interval- drug dependent
NO adjustment needed to loading doses
Describe ideal types of drugs in renal impairment:
Wide therapeutic index
Eliminated by the liver
Not affected by changes in fluid balance, tissue or protein binding
Not nephrotoxic
Describe the nephrotoxicity of a drug in renal disease:
Ideally not nephrotoxic but in some cases can be essential to use nephrotoxic e.g co-morbidity or long term renoprotective benefit e.g ACEi/ARB
Monitor RF and toxicity
In end stage renal failure- no further renal function damage can occur or decline- so not worried about nephrotoxic drugs but do need to monitor for toxic accumulation levels and side effects from this
What should occur in obese or severely underweight patients when calculating CrCl?
Use IBW for obese patients if BMI is over 30
If ABW is smaller than IBW, use ABW
What should occur if a patient has got a borderline CrCl?
Need to look at trends of their renal function- if its increasing can possible go for one above
Antibiotics- normally treat with higher dose to treat infection
What are the 3 classifications (causes) of renal disease?
Pre-renal (before the kidneys)
Intrinsic damage (damage to kidney itself)
Post-renal (after the kidneys in the urinary tract)
What is pre-renal failure?
Reduced renal perfusion, lack of blood supply to the kidney
Name and describe examples of causes of pre-renal failure:
Hypovolaemia (burns, dehydration, haemorrhage)
Decreased CO- due to HF,MI, so decreased blood flow to kidneys
Infection
Liver disease- chronic- lack of blood flow through the liver so lack of blood supply ongoing to the kidneys
Medications- ACEi, NSAIDs, ciclosporin, tacrolimus, diuretics, laxative abuse, D&V SEs
Describe the physiological state of the afferent arteriole in the glomerulus:
PGs dilate the afferent arteriole to glomerular capillaries and increase blood supply to them
Can leave the Bowman’s capsule and cause increased hydrostatic pressure and GFR to get blood into the nephron
Describe the physiological state of the efferent arterioles in the glomerulus:
Angiotensin II constricts the efferent arteriole
Hard for blood in the capillaries to get out
Describe the state of the afferent arterioles when NSAIDs are present:
NSAIDs inhibit PGs so they constrict the afferent arteriole
Potential kidney damage, decreases renal perfusion
Decrease hydrostatic pressure and GFR
Describe the state of the efferent arterioles when ACEi/ARBs are present?
ACEi/ARBs inhibit RAS so dilate the efferent arteriole
Renoprotective long term as preventing damage from high pressure
What is intrinsic renal failure?
Damage to renal tissue
Can be 2º from pre-renal failure and prolonged decreased perfusion
Name and describe examples of causes of intrinsic renal failure?
Glomerular (e.g diabetic nephropathy, glomerulonephritis- immune mediated insults)
Tubular (e.g interstitial nephritis, acute tubular necrosis)
Renovascular (e.g hypertension)
Infection
Nephrotoxicity-NSAIDs
Metabolic (e.g hypercalcamia, hyperuricaemia)
Congenital
What is acute tubular necrosis?
Necrosis of the kidney tissue from lack of perfusion and oxygen delivery
What are two ways how nephrotoxicity can occur?
Hypersensitivity reactions (unpredictable)
Directly toxic (more predictable)
Describe hypersensitivity reactions of drugs causing nephrotoxicity:
Glomerulonephritis- phenytoin, penicillins
Interstitial damage- penicillins, cephalosporin, allopurinol, azathioprine
Describe directly toxic drugs causing nephrotoxicity:
Cautioned/ CI in renal damage stages
Aminoglycosides (e.g gentamicin), amphotericin, ciclosporin
Can occur from a single dose
What is post renal failure
Obstructions to urinary flow after the kidney- back pressure into kidneys which cause damage/ scarring
Name and describe examples of causes of post renal failure:
Stones blocking ureter (e.g calcium oxalate)
Structural (e.g tumour, stricture)
Nephrotoxicity (e.g cytotoxic meds, high dose sulphonamides)
Outside UT (e.g ovarian tumour, prostatitis, BPH)
How can high dose sulphonamides cause post renal failure?
Depositions in urinary tract and block urinary flow- urate crystal deposition
How can BPH cause post renal failure?
Pressure on urethra and restrict urinary flow
May insert catheter if in acute urinary retention
Name types of drugs causing pre-renal failure:
Lactulose overdose
HF
Liver disease
Lisinopril
Name types of drugs causing intrinsic renal failure:
Gentamicin
Acute tubular necrosis
Uncontrolled hypertension
Name types of drugs causing post-renal failure:
MTX
BPH
Ovarian tumour
How can infection and NSAIDs fit in to the different types of causes of renal failure?
They fit into both pre-renal and intrinsic damage
In the majority they will cause pre-renal failure through a decrease in renal perfusion
In some circumstances they can cause intrinsic
What are the 3 classifications (reversibility) of renal disease?
AKI (Acute Kidney Injury)- reversible
CKD (Chronic Kidney Disease)- irreversible
ESRF (End Stage Renal Failure)- irreversible
Can a patient with CKD get AKI?
Yes
A patient with pre-existing CKD can have an acute drop in their renal function
What is AKI?
Rapid decline (hrs/days) in someones usual level of renal function which will continue to deteriorate (multiple organ failure/ death) and has up to 90% mortality rate if left untreated
Describe the restoration of the kidneys in AKI:
Usually, not always reversible
Complete restoration- kidney function back to where it was
Partial restoration- eGFR/CrCl may not be the same as before
Describe the prevalence of AKI:
400-600pts/ million of the population/ year have AKI
Up to 200pts/ million of the population/ year have AKI require dialysis
Name and describe the 3 potential factors for the diagnosis of AKI:
Serum creatinine rises by ≥26.5µmol/L within 48hrs OR
Serum creatinine rises by ≥1.5 fold from their baseline value, which is known or presumed to have occurred within the last 7 days OR
Urine output is <0.5ml/kg/hr for 6 hrs
What are the different stages in AKI?
Stage 1
Stage 2
Stage 3
What is the value for stage 1 AKI?
1.5 to 1.9x increase from baseline creatinine
What is the value for stage 2 AKI?
2.0 to 2.9x increase from baseline creatinine
What is the value for stage 3 AKI?
3.0 or more x increase from baseline creatinine
What are the risk factors for AKI?
Diabetes
CKD
Previous AKI
Hepatic disease
CCF or Peripheral Vascular Disease (PVD)
More than 65 years old
What are the causes of AKI?
Most common is pre-renal
Decreases perfusion due to low blood volume and reduced circulation
Hypotension/ sepsis/ infection/ dehydration
What are the medications that can cause AKI?
Triple whammy:
-ACEi -Diuretics -NSAIDs
Avoid nephrotoxics in those at risk e.g NSAIDs in elderly
Monitor renal function for those taking high risk drugs/ with high risk co-morbidities
Review meds
Educate pt on sick day rules
What are the AKI signs and symptoms for volume depletion?
Dehydration signs- initial
Thirst
A lot of fluid loss
Oliguria- loss of fluid
Dry mucosa (clinically dry in mouth/nasal passages)
Reduced skin elasticity
Tachycardia
Hypotension
Decreased JVP
What are the AKI signs and symptoms if left untreated?
Volume overload
Increase orthopnoea (SOB lying down) and Paroxysmal Nocturnal Dyspnoea (PND)- pts waking up coughing due to fluid when lying down
Oedema- ankles and lungs
SoA
Pulmonary oedema and crackles
What are the different steps in AKI management?
- Identify the cause
- Restore and maintain renal function (volume status and BP)
- Other treatments
Describe the first step in AKI management:
Identify the cause
Urine/ blood tests
Medication history:
-review and hold medication known to exacerbate AKI (ACEi/diuretics)
-adjust doses of other medication to prevent harm (metformin/ DOACs)
Remember, restarting long term medications post AKI is just ad important as holding them short term
How can ACEi/ ARBs be protective long term in kidney disease?
Preventing angiotensin II mediated of the efferent arteriole= vasodilation= decrease in hydrostatic pressure and GFR
Protective long term, prevent sustained vasoconstriction which leads to stenosis of the efferent arterioles and loss of nephron function- preventing a hypertensive cycle where there is sustained vasoconstriction
Why would you hold ACEi/ARBs in AKI?
ACEi/ARBs decreases hydrostatic pressure which is a protective effect
However in a hypovolaemic state (AKI), reduction of hydrostatic pressure worsens AKI
Describe how you would treat volume depletion in the second step of AKI management:
Aggressive, early fluid resuscitation to mimic the nature of fluid loss i.e blood, sodium chloride- to restore perfusion and oxygen delivery
Monitor input and output of fluid
Hypovolaemic- positive fluid balance to hydrate the pt and increase renal perfusion
Dialysis can be used in around 1’/3 of pts to maintain renal function while treating the underlying cause (rapidly rising Cr/urea, severe hyperkalaemia, metabolic acidosis)
Name treatments that would be used in the second step in AKI management for fluid overload:
Loop diuretics
Dopamine
Describe loop diuretics for fluid overload patients in AKI:
Only if no issue with renal perfusion- caution to avoid dehydration
Diuresis, decrease in tubular cell metabolic demands, increase in renal blood flow
High doses 1-2g IV over 24 hrs- furosemide
4mg/min max rate (if higher, risk of ototoxicity)
Describe dopamine for fluid overload patients in AKI:
More common in ICU
Low dose 2mcg/kg/min= renal vasodilation through DA1r increase perfusion and urine output
Higher dosing (more than 5mcg/kg/min) can cause vasoconstriction
What are the potassium levels which indicate hyperkalaemia in AKI patients?
≥ 6.5mmol/L K+= muscle weakness, ECG changes, VF, Cardiac arrest
>6mmol/L should be treated urgently in AKI
What are the levels and treatment for non AKI patients with hyperkalaemia?
≥6.5 should always be treated
Protect the heart with calcium gluconate 10% IV (antagonises K+ at cardiomyocyte membranes)
Shift K into cells- rapid acting insulin in glucose over 15 mins to stim Na/K transporter
Nebulised salbutamol- lower serum K levels by stimulating take up into cells
What is the treatment for moderate K+ 6-6.4mmol/L with no ECG changes?
Insulin glucose infusion
Check pre-treatment blood glucose level
Give 10 IU of actrapid insulin in 50ml of 50% glucose (25g) via large IV access over 15-30 mins
If pre treatment BG less than 7 mmol/L give 10% glucose at 50ml/hr for 5 hrs (25g)
Monitor BG levels
Consider salbutamol 10-20mg nebulised
What is the treatment for severe K+ ≥6.5mmol/L with ECG changes?
Emergency help
30ml 10% Ca gluconate IV
Use large IV access and administer over 10 mins
Administer over 30 mins if on digoxin
Do not administer with NaHCO3
Repeat ECG- consider further dose 5-10 mins after if ECG changes present
Then the insulin regimen like moderate K+ level and then salbutamol
What is CKD?
Worsening, progressive and irreversible loss of kidney function
Can lead to end stage kidney failure- permanent damage/ loss of function
What is the definition of CKD?
UK Kidney Association (UKKA) defines CKD as a pt with abnormalities of kidney function or structure present for more than 3 months
The definition includes all individuals with markers of kidney damage or those with an eGFR of less than 60ml/min/1.73m2 on at least 2 occasions 90 days apart
What are the causes of CKD?
AKI- irreversible intrinsic damage
Hypertension- vessel thickening and narrowing leads to less blood flow (RAS system worsens and can cause glomerulosclerosis- stenosis of efferent)
Diabetes- nephropathy leading to fibrosis, membrane thickening and sclerosis
Glomerulopathies/ vasculitis/ polycystic kidney disease
How can glomerulopathies cause CKD?
Filtration to be impaired/ altered
How can vasculitis cause CKD?
BV inflammation
Leads to kidney sclerosis
Hardening of the kidney tissue
So blood flow will be directed to nephrons still working, leading to hyper filtration in nephrons (good short term)
But increase pressure can cause sclerosis and damage of more nephrons
How can polycystic kidney disease cause CKD?
Hereditary disorder
If burst can lead to damage and scarring
What are the complications of CKD?
Water and electrolyte balance
Hypertension
Acid/ base balance
Muscle dysfunction
Renal bone disease
Uraemia
Anaemia
In the early stages of CKD, how is the kidney unable to regulate water/ electrolytes?
Polyuria/ nocturia
Osmotic effect of urea (>40mmol/L)
Loss of ability to concentrate urine
In CKD progression, how is the kidney unable to regulate water/ electrolytes?
Kindeys fail to excrete Na+ and water- fluid retention
Peripheral and pulmonary oedema
Ascites
80% have volume dependent hypertension
What are the main complications in CKD when the kidney is unable to regulate water/ electrolytes?
Hyperkalaemia- kidneys inability to excrete, risk of CA, VF
Acidosis- inability to remove H+ ions= decrease in bicarbonate ions
What is the first line treatment in CKD when the kidneys can’t regulate water?
Fluid restriction- turn off the tap
Not yet on dialysis and still pass urine, restriction at a min of 1L/day
If patients on haemodialysis and not passing urine, restriction may be a lot less, around 500ml/ day
Na+ restriction- dietary measures
Monitor daily weights at home and BP
What is the second line treatment in CKD when kidneys can’t regulate water?
If fluid restriction doesn’t work, move onto diuretics- take the plug out
Diuretics- loop diuretics first line (furosemide up to 2g daily), bumetanide better absorbed if a lot of fluid accumulation in the abdomen
Metolazone (atypical thiazide)- cautious addition as very strong diuretic, closely monitor, stop when dialysis start- most pts
What is the target level of potassium in pre-dialysis patients?
4.0-6.0mmol/L
What is the first line treatment in patients with hyperkalaemia in CKD?
Calcium resonium (potassium binder)- binds to K+ in the GIT
Releases Ca2+ in exchange and constipation SE- prescribed lactulose alongside it
What is the second line treatment in pts with hyperkalaemia in CKD?
Sodium zirconium cyclosilicate and Patiromer calcium approved by NICE for acute and chronic hyperkalaemia meeting certain criteria
What are the benefits of the second line treatment for hyperkalaemia in CKD?
Allow CKD pts to stay on ACEi/ARBs for longer or at higher doses
Better adherence
What is the treatment for acidosis in CKD?
Sodium bicarbonate PO 500mg TDS
Can be uptitrated
What is the level in CKD that a patient has uraemia?
More than 15mmol/L
What is the main treatment for uraemia in CKD?
Effective treatment requires dialysis
What are the symptoms of uraemia in CKD?
Anorexia
N&V
Constipation
Foul taste
Pruritis
Skin discolouration
What are off label use medications for uraemia in CKD?
Anti-histamines
SSRIs
Gabapentinoids
What is a NICE approved treatment for prutitis in uraemia in CKD?
Jan 2024
Difelikefalin in HD pts
Why does muscle dysfunction occur in CKD?
Due to nutritional deficiencies and electrolyte disturbances + on dialysis
What are the symptoms of muscle dysfunction in CKD?
Cramps and restlessness legs especially at night
What is the non-pharmacological treatment of muscle dysfunction in CKD?
Lifestyle measures- as drugs that are used have debatable efficacy or can be addictive
e.g check caffeine levels
Check iron levels
What is the drug treatment of muscle dysfunction in CKD?
Quinine 300mg ON (cramps)- efficacy debated and trail recommended, should be reviewed within 2-4 weeks
Ropinirole 250mcg ON (restless legs) -dopamine agonist
Why is there hypertension in CKD?
Circulatory volume expansion due to Na and H2O retention
Leads to artery stenosis= renin release= HTN increase and increase rate of renal function decline
What can be a negative outcome of HTN in CKD?
Proteinuria
Sustained HTN can lead to protein in the urine
>2g in 24 hr= glomerular disease
>5g in 24 hrs= severe disease (nephrotic syndrome)
State and describe the blood pressure targets for patents with CKD:
Targets decided on protein level
Proteinuria low (ACR<70 or PCR<100) BP <140/90
Proteinuria high (ACR>70 or PCR>100) BP <130/80
What are the patient characteristics where you should follow the normal NICE HTN guidelines?
Pts have CKD, HTN and ACR of 30mg/mmol or less
What are the patient characteristics where you should not follow the normal NICE HTN guidelines?
CKD, HTN and ACR of more than 30mg/mmol
Or have diabetes and ACR is 3mg/mmol or more
What is the treatment for HTN for CKD patients when not following the normal NICE guidelines?
ACEi/ARB started and optimised
ACEi/ARB may also be offered to CKD patients who do not have existing HTN or diabetes if ACR is more than 70mg/mmol or more
What are the monitoring requirements for ACEi/ARBs?
Monitor K+ prior to treatment and 1-2 wks after initiation/dose change
-potassium binder may be required if hyperkalaemia on repeat sample
Monitor creatinine, 1-2 wks after initiation/ dose change
-in ESRF don’t need to worry about creatinine
What is the CI of ACEi/ARBs and why?
In renal artery stenosis
Atherosclerosis in renal arteries supplying blood to kidney= decreased GFR
RAS system constricts the efferent arteriole to maintain pressure and perfusion
RAS blockers (ACEi/ARBs) block this compensatory mechanism, causing further renal impairment
Describe CCBs in CKD for hypertension:
Ankle oedema SE, particularly in nifedipine
Describe diuretics in CKD for hypertension:
Not usually for HTN, mainly oedema
-thiazide diuretics (except metolazone) ineffective CrCl <25ml/min
-K+ sparing diuretics increase hyperkalaemia risk egg spironlactone
Describe B blockers in CKD for hypertension:
Cardioselective e.g metoprolol (cleared by liver), low dose and titrate
Can also be seen on bisoprolol and atenolol
Describe a blockers in CKD for hypertension:
Doxazosin, cleared via liver
Describe vasodilators in CKD for hypertension:
E.g hydrazalazine
SEs of reflection tachycardia (use with B blockers), fluid retention (use with diuretics) and minoxidil causes excess hair growth
Describe the MoA of SGLT2i:
Renal protective effect- slows the mechanism of CKD and prevent adverse outcomes
Mechanism unknown:
proposed via inhibiting sodium reabsorption (as inhibits glucose reabsorption) which activates adenosine as sodium is kept in nephron and activate ‘macular denier’ in DT= gentle vasoconstriction of the afferent arteriole (tubulogolmerular feedback)
Prevents prologued high hydrostatic pressure and damage in the glomerulus
Describe the use of SGLT2i in CKD:
Dapagliflozin is the only licensed one in CKD
Add on to optimised standard including highest tolerated ACEi or ARB unless CI
eGFR 25-75ml/min/1.73m2 at the start of treatment WITH T2D or urine ACR of at least 22.66mg/mmol
What’re the warnings/ counselling points for SGLT2i?
Sick day rules
MHRA warning- DKA that can be euglycemic (normal BG) so need to monitor ketones
MHRA warning- Fournier’s gangrene- genital necrosis infection as urinating glucose rich for bacteria, keep area clean/dry and report signs of genital infection
What are the main causes of renal bone disease (RBD)?
Particularly in CKD stages 4 and 5
-hyperphosphatemia
-low vit D
-hypocalcaemia
Describe hyperphosphatemia in RBD:
Less excretion of phosphate by the kidney so build up in the blood
Symptoms include pruritis
Describe low vitamin D in RBD:
Less activation of vit D
Cholecalciferol (inactive) from sunlight/ gut converted to calcitriol by hydroxylation in 25 position in liver and 1 alpha position in the kidney- 2nd step impaired- so defective bone mineralisation and osteomalacia (bone softening)
Describe hypocalcaemia in RBD:
Main cause is less activated vit D- vit D main role is to absorb Ca from GIT and kidneys, less activated vit D leads to less absorption of Ca in the blood
Secondary point is more phosphate in the blood means more sequestering of Ca as Caphosphate in bones
How can RBD cause issues of the parathyroid gland?
Metabolism of Ca and P is controlled by PTH
PTGs detect low level of Ca and in response releases PTH
PTG works got stimulate an increase in Ca in blood, the main 2 routes of how it does this is the kidney and the bone
As the kidney doesn’t work, the only route is via the bone which just doesn’t work so causes PTG to work really hard and become enlarged, leads to 2º hyperparathyroidism
How is Ca released from the bone?
Increase bone turnover to release Ca in the blood stream
Increase level of Ca in the blood leads to weakening of the bone architecture (osteitis)
Osteopenia and osteoporosis are common
Increase fracture risk
Bone hardening (osteosclerosis)
What is the treatment of hyperphosphatemia in RBD?
Diet- decrease phosphate intake
Phosphate binders e.g Calcium acetate (1st line), Sevlamer (2nd line), lanthanum
Bind with phosphate in the gut (take with/before meal and dose according to meal size)
What are the problems with phosphate binders in RBD?
Need to check adherence before changing
They are large tablets which many need to taken at once
Come with GI SEs
What are the treatments of hypocalcaemia and low vit D?
Vit D3 analogue e.g Calcitriol (activated)
Alfacalcidol (activated in liver)
Can’t give Cholecalciferol as needs to be activated by the kidney
What are the treatments for hyperparathyroidism?
Effective management of Ca and phosphate
Cinacalcet- lowers PTH levels by increasing sensitivity of Ca receptors (calcimimetic)
Paricalcitiol- IV vit D analogue (expensive, not seen often)
Parathyroidectomy- last resort
What are the targets for PTH in RBD?
> 2x and <4x upper limit of normal
What are the targets for phosphate in RBD?
1.1-1.5mmol/L
1.1-1.7 mmol/L if on dialysis
What is the corrected Ca levels in RBD?
2.2-2.6 mmol/L
What is renal anaemia in CKD?
Common in CKD stage 3 onwards
Erythropoietin (low levels)
Low levels of iron also
What is erythropoietin?
Hormone synthesised in kidney, synthesis triggered by low level of oxygen in tissue so causes RBC proliferation in bone marrow leading to more oxygen transport
Describe what low erythropoietin levels in CKD can cause:
Decrease in RBC proliferation in bone marrow leading to anaemia
What are the symptoms of low erythropoietin?
Fatigue
Breathlessness
Angina (underlying ischaemic HD)
What is the first line treatment for low erythropoietin in CKD?
Recombinant human erythropoietin by injection (IV/SC) AKA Epoinjections
-epoetin alfa (Eprex), Darbepoetin (Aranesp), Epoetin beta (NeoRecrmon)
What are the SEs of the first line treatment for low erythropoietin in CKD?
HTN
Pre red cell aplasia (Eprex only)
What is the second line treatment for low erythropoietin in CKD?
HIF stabilisers
Roxadustat
Involved in gene expression in erythropoiesis to increase Hb production and improve iron response
Hb target: 100-120g/L
What treatment in renal aneamia needs to be sorted first and why?
Erythropoietin produces RBCs which need iron, so iron stores need to increase before Epo injection
What is the target ferritin range in CKD?
200-500mcg/L
Max 800mcg/L and min more than 100mcg/L
What is the treatment for iron anaemia in CKD?
PO iron may be sufficient for pre-dialysis patients
Most patients will need IV replacements e.g Ferinject, Venter is serum ferritin under 200mcg/L
What is one major thing to avoid in iron anaemic patients in CKD?
Avoid blood transfusions- particularly if they are a candidate for renal transplantation in the future as there is an increased chance of rejection
What are the vitamins complications of CKD?
All water soluble vitamins tend to get removed
Need replacement
Renavit- contains water soluble vitamins along with dietary advice
Particularly need on dialysis as removes water soluble vitamins
Describe the use of the Hep B vaccination in CKD:
5 yearly booster for all CKD patients with blood manipulation, particularly HD (monitored yearly for Abs)
Doses are doubled at 3x 40mcg dose
When do we initiate dialysis?
In ESRF average eGFR 7ml/min
-becomes unmanageable by other interventions
Joint decision between MDT and patient, pt choice as may not be suitable e.g elderly as too frail
Patient needs to understand that it wont be curative and life lengthening
What are the symptoms of dialysis?
Extreme fatigue/ lethargy
N&V
Itching
Drowsy
Bone pain
Inability to urinate
WEIGHT LOSS
What are the dialysis principles?
Mimicking natural processes occurring in the kidney:
1. mimicking ultra filtration in the glomerulus
2. mimicking the reabsorption in the proximal/ distal convoluted tubule and the LoH
Describe the first step in dialysis principles:
Ultra filtration
Remove fluid build up- hydrostatic pressure generation or generating an osmotic gradient
Waste product removal- diffusion from high to low conc across a semi-permeable membrane
Describe the second step in dialysis principles:
Reabsorption/ conservation of wanted molecules
Editing the dialyse fluid use- the fluid running next to blood supply, its composition is tailored to the pts biochemistry so can make sure the patient is getting/ keeping what they need
Give a brief description of haemodialysis (HD):
Take blood from the body into a separate machine which has an artificial kidney inside
Artificial kidney made up of hollow fibres creating a semi-permeable membrane for diffusion to occur
Pump in the machine generates the hydrostatic pressure, generates the osmotic movement
Give a brief description of peritoneal dialysis:
Using the patients own peritoneum membrane to mimic the glomerular basement membrane, creates hydrostatic pressure which helps the osmotic movement
The peritoneum membrane is blood rich, fill the peritoneal space with dialysate fluid to allow exchanges to occur
Describe the process of HD:
Use a filter (dialyzer) to clean the blood
Arterial blood is taken from the body, first the patient is anti coagulated with heparin
Blood is then passed through the dialyzer, a countercurrent dialysate fluid to bathe the blood and maximise the conc gradient
The cleaned blood is then returned to the body via a vein and the dialysate fluid is discarded
Describe the structure of the ‘artificial kidney’ in HD:
Plastic tube with hundreds of hollow fibres creating the semi-permeable membrane
The pts blood flows through inside it and the fluid bathes it around
Name and describe the gold standard way of accessing the blood in HD:
Surgical arteriovenous fistula
-placed 6-8 wks before dialysis starts, so can mature, pressure in artery joins into vein so enlarges
-placed under general/local anaesthesia, radial or brachial artery
-join thin walled artery to a thin walled vein together to create two large vessels
What are the advantages of surgical arteriovenous fistula compared to other methods?
Lasts a lot longer
Lower risk of infection and clotting
Describe an alternative way of accessing the blood in HD:
Need direct access to the blood stream with strong flow
Temporary catheter (emergent access) into the internal jugular vein/ femoral vein
Infection/thrombosis risk
What is dialysis adequacy?
How well toxins and waste products are being removed from the patients blood
How can you increase dialysis adequacy?
Increase blood flow rate
Increase size/ SA of dialyser
Longer on dialysis/ more frequent
What are the monitor requirements when a patient is on dialysis?
Need to assess weight before and after dialysis- assessing fluid removal as too much fluid removal can cause dizziness/ hypertension
Fluid accumulation between sessions, no more than 1.5kg gain and each pt has tailored ‘dry weight’ - weight gain causes risk of pulmonary oedema and acute hospital admission for cardiac failure
What is the time scale for dialysis and why?
Work up to 3-5 hours to prevent disequilibrium syndrome: headaches, N&V, convulsions due to large urea removal
Usually 4 hrs 3x a week
Describe the process of peritoneal dialysis:
Using peritoneal membrane
Lines internal organs creating an abdominal space, rich in blood supply
Peritoneal space can have small amount of fluid in it, but generally empty space
Dialysate fluid ran into the peritoneal cavity by gravity, fluid then drained out under gravity, when full new bag is put in (30 mins to change bags)
Fluid will dwell in the peritoneal space for a certain amount of time allowing the conc gradient to take effect
High glucose conc used so the fluid moves out and osmosis into dialysate fluid
What are the advantages and disatvantages of peritoneal dialysis?
Patients can do this at home
Need 4 changes every day- continuous ambulatory peritoneal dialysis CAPD
Describe the way of accessing the peritoneal membrane in peritoneal dialysis:
Use indwelling Tenckhoff catheter
Inserted under general/ local anaesthetic
Through the abdominal wall and sits in the peritoneal space
Cuffs and stitched on either side of the abdominal wall to hold in place- scar tissue will form and become water tight over time
When inserted a prophylaxis antibiotic dose is given to minimise infection
Generally not given for a few weeks
Clean technique needed when changing catheter
Name the 2 types of peritoneal dialysis:
Continuous Ambulatory Peritoneal Dialysis (CAPD)
Automated peritoneal dialysis
Describe automated peritoneal dialysis:
Exhanges carried out via a machine over night over 8-10 hrs
1-3L of fluid that will dwell in the peritoneal cavity for 1-3 hrs at a time then replaced
More frequent and shorter duel times so improved dialysis adequacy
Decrease peritonitis incidence
What are the advantages of peritoneal dialysis?
Decrease anaemia as less loss of blood at needling site
Less aggressive so doesn’t leave patient fatigued as HD
Better for cardiac stability gently rate of fluid removal
Can be done at home, more independent
Dietary and fluid restrictions not as strict
What are the disadvantages of peritoneal dialysis?
Risk of PD peritonitis
Membrane can become fibroses and inefficient
Risks of hyperglycaemia due to using high glucose content solutions
Requires a lot of equipment and good technique
Less clearance of smaller molecules e.g urea, creatinine
What is the signs and treatment for PD peritonitis?
Cloudy bag- should normally be clear
Give IV vancomycin- via port via catheter (+ve)
PO ciprofloxacin (-ve)
Targets both gram -ve and gram +ve
What is the dietary requirements when on dialysis?
Healthy diet- low fat and salt, high fibre
Low potassium- in chocolate, potatoes, caffeine
Low phosphate
High protein diet in CAPD- can lose protein through CAPD fluid
What is the fluid restriction requirements in HD?
More strict
Urine output + 500ml a day
What is the fluid restriction requirements in PD?
Urine output + 750ml a day
Includes anything that is a liquid at room temperature e.g ice cream
What is a counselling point if a patient feels thirsty and are fluid restricted?
Suck on an ice cube, spit out the water
What are the medication considerations when a patient is on dialysis?
Fluid management- stop diuretics unless residual function to pass urine
Acid/ base balance- stop sodium bicarbonate
HTN- monitor pre/post dialysis like to decrease after dialysis but still needed
Renal bone disease- remain on treatment
Erethypoetin- risk of blood loss increases in dialysis so still required and usually given with IV iron on dialysis
What are drug factors that are more likely to be removed during dialysis?
Low molecular weight e.g metronidazole (mw=71) removed, vancomycin (1448) not removed, gentamicin (543) partially removed
Low plasma protein binding
Low volume of distribution
High water solubility
High renal clearance in usual kidney function
What are dialysis factors which are more likely to cause drugs to be removed during dialysis?
Membrane type (HD)
Duration of dialysis- longer
Fluid composition, conc and volume (osmotic conc gradient in PD)
Peritoneum pathology (PD)
Blood flow rate (HD)- high (increased rate, increased pressure)
Name the different types of solid organ transplants:
Heart
Lung
Liver
Simultaneous Pancreas and Kidney transplant (SPK)
Pancreas
Kidney
Bowel
Multi-visceral- intestine, liver, spleen, stomach
Where can organ donation come from?
Deceased donor
Living donor (kidney and liver)
-altruistic, unknown person
-directed, to someone you know
Which patients can’t be a donor of organs?
Transmissible Spongiform Encephalopathy CJD
Ebola
Active cancer
HIV patients (sometimes)- can act as donates to other HIV pts
What are reasons why you would be on a waiting list in SOT?
Exclusion criteria- other diseases that meant life expectancy less than 2 years, other reasons
Donor- recipient blood group need to match
HLA- compatability need to match
What are the aims of SOT?
Increase life expectancy
Increase QoL
Decrease financial implications
What is the issue and resolution of SOT?
Recipient immune responses
Solution is to use immunosuppression
What are the aims of using immunosuppression?
Prevent graft rejection (acute or chronic)
Induction of tolerance to transplanted organ
What are the risks of using immunosuppression?
SEs
Infections
Malignancy
Post transplant lymphoproliferative disease
Name the different types of grafts?
Xenografts
Autografts
Isografts
Allografts
Describe xenografts:
Between different species- greatest immune response= rejection
Describe autografts:
From one part of the body to another on the same individual= no rejection
Describe isografts:
Grafts between genetically identical individuals= no rejection
Describe allografts:
Between members of the same species= varied response
Dependent on the degree of histocompatibility of donor and recipient (but also type of organ)
Name and describe the antigens responsible for rejection:
Histocompatibility antigens (products of the histocompatibility genes)
The Loci of the genes eliciting the most vigorous rejection are those of the Major Histocompatibility Complex-MHC
In humans this is called the human leukocyte antigen- HLA
Where is MHC I located and its function?
Normally expressed on all nucleated cells and present antigenic peptides from inside the cell to CD8 T cells
Where is MHC II located and its function?
Only expressed on professional antigen presenting cells, activated macrophages and B cells and present extracellular antigens to CD4 T cells
What is the type of immune responses in transplants?
Involve adaptive (both cellular and humour response) and innate mechanisms
Name the types of T cell recognition in foreign grafts:
Signal 1
Signal 2
Signal 3
Describe signal 1 in T cell recognition:
Interaction between the T cell receptor and the antigen presented by the MHC
Describe signal 2 in T cell recognition:
Co-stim receptor/ ligand interaction between the T cell and APC i.e CD28 of T cell and APC cell surface ligand B7-1 or B7-2 (aka CD80/86)
Another co-stim interaction is CD40 with its ligand
Causes activation of 3 signal transduction pathways:
-calcium- calcineurin pathway
-mitogen activated protein (MAP) kinase pathway
-protein kinase C-nuclear factor kappa B
Responsible for TF activation
Describe signal 3 in T cell recognition:
Growth signals activating the cell cycle
-activation of the phosphoinositide-3-kinase (DI-3K) pathway and molecular-target- of rapamycin (mTOR)
What are the ways that we can minimise/ control the hosts immune response in transplant?
HLA compatibility
Immunosuppression
What type of genes are MHC I encoded by?
Partly encoded by:
HLA-A loci
HLA-B loci
HLA-C loci
What type of genes are MHC II encoded by?
HLA-DP region
HLA-DC region
HLA-DR region
What are the strongest determinants in matching the MHC encoding genes?
HLA-DR
HLA-B
HLA-A
More than 1250 alleles determine these antigens
What are the benefits of having good HLA compatibility?
Better graft function
Fewer episodes of rejection
Longer graft survival
Possibility of decreased immunosuppression (potential for decreased infection and malignancy risk)
Decreased risk of sensitisation increased issues with further transplants if required
What are the 2 phases of immunosuppression?
Induction
Maintenance
Name the immunosuppressive drugs used at induction:
Higher level due to highest risk of infection
Corticosteroids
Basiliximab
Alemtuzumab
Antithymocyte globulin (ATG)
Bottom 3 are more specific agents, decrease rate of graft rejection but extremely expensive- given intraoperatively and after surgery
Name the immunosuppressive drugs used at maintenance:
Lower degree of immunosuppression
Ciclosporin/ tacrolimus (calciuneurin inhibitors)
Azathioprine/ mycophenolate (anti proliferative drugs)
Corticosteroids
Balatacept
Sirolimus (mTORi)
Describe how Basiliximab works at induction:
Chimeric (human/murine) MAB against the IL-2r (CD25 T cells must be activated for this to be expressed)
Inhibits differentiation and proliferation but is minimally T cell depleting- doesn’t decrease ones already there
What are the monitoring requirements/ pre meds for Basiliximab?
Minimal adverse effects (no pre/med specialist monitoring)
When is Basiliximab given at induction?
Given at induction and 3-4 days post surgery
Describe how Alemtuzumab works at induction:
Used to treat episodes of rejection- can delay maintenance onset
Humanised, rat IgG MAB directed against CD52 cell surface antigen causing cell lysis and prolonged depletion (also inhibits most monocytes, macrophages and NK cells)
What are the monitoring requirements/ pre meds for Alemtuzumab?
Associated with first dose reaction, neutropenia, anaemia, pancytopenia (rare)
Autoimmunity (haemolytic anaemia, thrombocytopenia, hyperthyroidism)
Describe how Antithymocyte globulin works:
IgG from horses or rabbits inoculated with human thymocytes
Blocks a large number of T cell membrane proteins (including CD2,CD3,CD45) causing altered function, lysis and prologues T cell depletion
What are the monitoring requirements for Antithymocyte globulin?
Cell lysis responsible for cytokine release syndrome- fever, chills, hypotension, rash, dyspnea
Develops soon after admin and can last several hours
Associated with thrombocytopenia, leukopenia, occasional serum sickness (type III hypersensitivity)
Normally can continue medication and support patients recovery
What are the pre meds for Antithymocyte globulin?
Paracetamol
Chlorphenamine
IV Corticosteroids
What is used for?
Used to treat episodes of rejection (monitor every 15 mins)
Used much less in induction, more in maintenance
What are the doses of Antithymocyte globulin?
If obese need to use IBW
What are the SEs of corticosteroids?
Adrenal suppression
Hypertension
Diabetes
Osteoporosis
Cushings
GI
Weight gain
Hyperlipidaemia
Infection
Describe how Ciclosporin works in maintenance therapy:
It is a metabolite of fungal, Tolypocladium inflate
Binds to cyclophillin (immunophilin) to form a complex
Complex inhibits calcineurin phosphatase (enzyme) suppressing T cell activation by inhibiting cytokine production (primarily IL-2)
What are the monitoring requirements for ciclosporin?
Concentration related to adverse effects- therapeutic level- 100-300ng/ml
Nephrotoxicity- monitor eGFR
Hypertension, hyperlipideamia, gingival hyperplasia, hirtuism, tremor
May also induce: haemolytic uraemia syndrome, DM (5%)
What is the dosing and prescribing regime of ciclosporin?
BD daily dosing regime
Prescribed by brand only
What are the interactions of ciclosporin?
Metabolised by the Cyp450 enzyme- no grapefruit juice
Inducer decreases ciclosporin conc
Inhibitor will increase ciclosporin conc
Describe how Tacrolimus works in maintenance therapy?
Macrolide antibiotic derived from Streptomyces tsukubaensis
Binds to FK506- binding protein 12 (an immunophillin) to inhibit calcineurin and T cell activation (binds a different intracellular protein to a ciclosporin but has subsequent MoA)
More potent than ciclosporin
What are the monitoring requirements for Tacrolimus?
Similar SEs to ciclosporin (nephrotoxicity and haemolytic uremic syndrome) but lower incidence of HTN, hyperlipidaemia, hirtuism and gum hyperplasia and higher incidence of DM and neurotoxicity
Therapeutic levels- 5-15ng/ml
Also metabolised by the Cyp450
What is the dosing and prescribing regime of Tacrolimus?
OD or BD depending on brand and transplant
Liver- BD- Adoport
Kidney- OD- Advagraf MR
Other brand is Prograf
When is the best time to take tacrolimus?
Best absorption on an empty stomach as food decreases bioavailability
Describe the different bioavailability for different formulations in ciclosporin:
Oral dose ciclosporin is around 3x the IV dose
Describe the different bioavailability for different formulations in tacrolimus:
Oral dose tacrolimus is around 3-5x the IV dose
How does Azathioprine work in maintenance therapy?
Metabolised to 6-MP is converted to thioguanine nucleotides which interfere with DNA synthesis
Another metabolite can also inhibit purine synthesis
Inhibiting proliferation of T and B cells
What are the monitoring requirements for azathioprine?
Haematological (dose dependent mylosupression can occur with over 50% of patients developing leukopenia- reversed by reducing/ stopping the drugs)
Thrombocytopenia (reversed by reducing/ stopping the drug)
N&V- alleviated when given with food or in divided doses
Close FBC required
TMPT levels
What is the dosing regime for azathioprine?
OD dosing
What is a major interaction with azathioprine?
Allopurinol
Need to decrease azathioprine dose by 1/4
How does mycophenolate work in maintenance therapy?
Mycophenolic acid (MPA) is the active component of mycophenolate mofetil (MMF)
MPA blocks inosine monophosphate dehydrogenase, the enzyme required for de novo synthesis of guanosine monophosphate nucleotides
This blocks purine synthesis preventing T and B cell proliferation
What are the benefits of mycophenolate over azathioprine as an antiproliferative?
More potent than azathioprine with greater decrease in acute rejection
What are the monitoring requirements for mycophenolate?
Haematological- neutropenia, leukopenia, mild anaemia (monitor FBC)
GI SEs- diarrhoea can be dose limiting (Enteric coated MPA (Myfortic) may improve SEs)
What is the dosing regime for mycophenolate?
BD dosing
What are the important drug interactions of mycophenolate?
Antacids, iron, rifampicin- decreases MMF level
Acyclovir, gancylovir- increases MMF level
When is Sirolimus used in maintenance therapy?
Used as an alternative to calcineurin inhibitor and antiproliferatives or in combo with calcineurin inhibitors
Describe how sirolimus works in maintenance therapy:
Formally known as rapamycin, sirolimus is a drug that inhibits the mammalian target of rapamycin (mTOR)
Sirlimus firstly binds the immunophillin FKB12 forming a complex that inhibits mTOR
mTOR is a serine/ threonine protein kinase involved in regulation of cell growth, proliferation and of protein synthesis and ribosome biogenesis
Blockage of mTOR inhibits the cellular proliferation response to a variety of cytokines including IL-2
What is the therapeutic drug levels of sirolimus?
12-20ng/ml trough level
What are the SEs/ monitoring requirements for Sirolimus?
Less nephrotoxic than CNI but can have some glomerular effects and see proteinuria
Less likely to cause DM
Risk of life threatening pneumonitis (resolves after treatment withdrawal)
Impaired wound healing (mTOR inhibition of fibroblast response to fibroblast GF) so not used immediately post transplant
Hyperlipidaemia, thrombocytopenia, HTN
When should sirolimus be administered?
Consistently, with or without food
What are the types of interactions with sirolimus?
Metabolised by the CYP450 enzymes so numerous
Describe how Balatacept works as a drug used in maintenance therapy:
Selective T cell co-stim blocker
Binds to CD80 or CD86 receptor on the APC preventing CD28 of T cell from binding
What is the dosing of Balatacept?
Divided into 2 phases
-initial phase- IV day 1 and 5 and at the end of weeks 2,4,8 and 12
-maintenance phase- IV end of week 16 and every 4 weeks thereafter
What is the risk/ SEs when taking Balatacept?
Risk of post transplant lymphoproliferative disease- associated with B cell infected with EBV, increase in proliferation
When is Balatacept used?
Used as an alternative to CNI
Comparison studies have shown equivalent patient and graft survival but a higher incidence of acute rejection
What is the combination therapy of immunosuppression for an intestinal transplant?
Alemtuzumab SC (with prior pre med)- induction
Methylprednisolone IV (then to oral)- plan to reduce to stop- induction
Prograf (immediate release tacrolimus)
Then starting (after)- azathioprine OR mycophenolate
What is the combination therapy of immunosuppression for a renal transplant?
Pre-med/induction- mycophenolate, methylprednisolone IV, IV basiliximab- as soon as pt return to ward (OR alemtuzumab if intermediate/high risk of immunologic risk)
(second dose of basiliximab required around day 4)
Prednisolone- 20mg OD (dose decrease to stop)- 1 day post
Mycophenolate mofetil (after basiliximab) 750mg BD
What are factors that can put a patient at high immunologic risk?
Previous transplant
Receiving blood mismatch
Previous rejection
What are the other risks to consider in renal transplants apart from immunosuppression?
Risk of infection
Transplant renal vein thrombosis and DVT prophylaxis
Gastric mucosal protection
Pain
What infections are at risk on patients on immunosuppressants following a kidney transplant?
Pneumocystis Jiroveci (PCP)- fungal infection
Fungal infection
Tuberculosis
Cytomegalovirus
Describe the symptoms and treatment for PCP in a kidney transplant:
Fever, cough, difficulty breathing, chills, fatigue, can cause loss of the graft and fatal
6 months prophylaxis co-trimoxazole
What is the treatment for fungal infections in a kidney transplant?
Candidia
Nysatin solution for 4 weeks after transplant
Describe the treatment for TB in a kidney transplant:
If the patient is considered at risk- carrier of latent TB- look at environment
Treat with prophylaxis isoniazid, pyridexime
Describe the symptoms of cytomegalovirus and how can a patient get it?
Passed with contact of bodily fluids with active virus
Widespread asymptomatic in immunocompetent patients- but are sero positive with CMV antibodies
In immunocompromised can cause end organ damage
Patients that are CMV IgG seropositive (R+) recipient positive- causes reactivation or receive an organ form a seropositive donor (D+)
What is the prophylaxis for CMV in kidney transplant patients?
Valganciclovir prophylaxis for all at risk for 3-6 months
What is the treatment for DVT in a kidney transplant?
LMWH- doses change on weight/ RF
Initially LMWH doesn’t work as good in a kidney transplant
CrCl <20ml/min, dose of 1500IU dalteparin
CrCl >20ml/min, dose of 5000IU dalteparin
What is the treatment for gastric mucosal protection in a kidney transplant?
PPI
Omeprazole 20mg OD
What is the pain treatment in a kidney transplant?
Paracetamol
Fentanyl, PCA (patient controlled analgesia)
How can the use if immunosuppression cause malignancy?
Skin cancer
Lymphoproliferative disease
Due to decreased immunosurveillance, decreased management of cancer causing infections
