renology and urology - wk 5 Flashcards
what conditions can cause problems with respiratory removal of Co2 effecting acid-base balance
Causing acidosis via hypoventilation
- Lung disease eg COPD
- Airway obstruction
- Opioid overdose/ head injury
Causing alkalosis via hyperventilation
- Panic attack
- Reaction to pain
- Respiratory disorders eg asthma
what metabolic issues can cause acidosis
- Over-production of acid
o lactic acidosis from inadequate oxygen supply to tissue
Eg Hypovalaemia, anaemia,
o Ketoacidosis due to inadequate cellular supply of oxygen
Eg type 1 diabetes, starvation, alcohol intoxication - Impaired excretion (from global loss of kidney function
o Eg AKI, end-stage CKD
o Renal tubular acidosis – bad filtration of H+ - Unusual losses of bicarbonate
o Lost from bowel following severe diarrhoea
o Formation of fistula in small bowel
o Renal tubular acidosis
what metabolic issues can cause alkalosis
- Loss of hydrogen ions o Eg following protaractive vomiting o Severe hypokalaemia o Hyperaldosteronism - Unusual indigestion of bicarbonate o Eg overdose of sodium bicarbonate
what are the 4 questions you should consider when interpreting blood gases
1) Is patient adequately oxygenated? (pO2, FIO2, [Hb}
a. Even is pO2 good, low Hb could mean not enough O2 delivered to tissues
2) What is there pH or H+ - normal, or acidaemia/alkalaemia
3) Is there a pCo2 disturbance?
4) Is there a [HCO£-] disturbance?
whats base excess
- The concentration of H+ per L of blood, required to return H+ to references range at a ref range pCO2 (~5.3kPa)
- Negative in metabolic acidosis
- Positive in metabolic alkalosis
- Ref. range -3 -> 3 mmol/L
whats standard bicarbonate
- What the HCO3 would be if pCO2 were ref range (~5.3pKa)
- So should be in reference range for a purely respiratory disorder
o Ref range 21-29 mmol/L - Should be the same as the actual bicarbonate conc. In a metabolic disorder
- Mixed metabolic and resp = significant difference with actual bicarb
whats the anion gap
Can be useful to narrow differentials of metabolic acidosis
Anion gap = difference between most abundant [cations] and [anions]
= [Na+] – [Cl-] - [HCO3-]
Ref. range anion gap; 6-18 mmol/L
- Elevated in certain types of metabolic acidosis
- Value depends on what HCO3- ions are replaced with.
o No change – replaced with Cl- ions (hyperchloremic acidosis)
o Elevated – replaced with anions corresponding to lactate, keto-acids et
what are the systemic effects of metabolic acidosis
Cardiovascular
- Negative inotropic effect (if severe)
Oxygen delivery
- Acutely – H+ causes R-shift of oxyHb dissociation curve (facilitates Os delivery)
- After several hours H+ reduces 2,3 DPG causing L-shift of curve (impairs O2 delivery)
Nervous system
- Impaired consciousness (little correlation with H+)
Potassium homeostasis
- Leakage from cells causing high plasma (k+), may also be lost renally
- If above sustained, total body K+ may be depleted
Bone
- If chronic acidosis get buffering by bone
- Leads to decalcification
what are the systemic effects of respiratory acidosis
Hypercapnia (high CO2)
- SOB – although drive impaired in chronic retention
- Neurological – anxiety, coma, headache, extensor plantars, myoclonus
- Cardiovascular – systemic vasodilation
Independent to acidosis, often also effects of
- Underlying pathology
- Hypoxia caused by that pathology eg SOB, drowsy, cyanosis
what are the systemic effects of respiratory alkalosis
Acute hypocapnia
- Cerebral vasoconstriction – light-headedness, confusion, syncope, fits
- Fall in ionised calcium – peioral, peripheral paraesthesia
Cardiovascular
- Increased heart rate, vasoconstriction (possibly chest tightness/ angina in those with background of CAD)
what are the systemic effects of metabolic alkalosis
Not usually significant - May cause shift of K+ into cells Beware effect of IV sodium bicarb in CKD - Metabolic acidosis common in CKD - Acute fall in acidity may reduce solubility of calcium salts and increase risk of systemic calcification
define acute kidney injury
- Increase in serum creatinine by >26.5 umols/L in 48 hrs
- Increase in serum creatinine by >1.5x baseline creatinine within last 7 days
- Urine volume <0.5ml/kg/hr for 6 hours
define pre-renal AKI and state some causes
- Reduced real or ‘effective’ blood volume
Causes…
o Hypovolaemia eg bleeding, 3rd space fluid losses, over-enthusiastic diuretic therapy
o Hypotension eg septic/ cardiogenic shock, liver failure
o Reduced renal blood supply secondary to severe renovascular disease (ACE inhibitors eg), dissection of abdominal aorta, renal stenosis
define renal AKI and state some cause
- Glomerulus, tubules and interstitium
casues
- Tubulointerstitial (tubules and the bit ‘in between’)
- Glomerulus
- Blood vessels
define post-renal AKI and state some causes
- Obstruction – multiple levels (eg ureter, bladder etc)
Causes
o Note that bilateral obstruction or obstruction of a single kidney (transplant) Is required in order to result in AKI
o Prostate – hypertrophy(common), cancer
o Bladder lesions – tumour
o Ureter – calculi, tumour, extrinsic compression (retroperitoneal fibrosis, tumour)
why is myeloma an important cause of AKI
- B cells can precipitate in the nephron forming ‘casts’
- If this happens in many nephrons in the kidney = widespread intratubular obstruction and AKI
- Urgent so Treated with chemotherapy for malignancy
what is the commonest cause of renal AKI and explain it
Commonest cause is ACUTE TUBULAR INJURY
- Tubular toxins eg gentamicin, cisplatinum, NSAIDs, radio-contrast dye
- Severe prolonged hypotension (sepsis, MI)
Renal hypoperfusion eg elderly patient on ACE inhibitor, diuretic who has D&V
o Become unwell with diarrhoea/ vomiting
o Combo limits perfusion to kidneys
o So develop acute tubular injury - AKI
Initial oliguria then may exhibit polyureic recovery phase (watch electrolytes)
what are some tubulointerstitial causes of AKI (renal)
- Acute allergic interstitial nephritis
- DRUG-RELATED eg PPIs (omeprazole), antibiotics, diuretics, NSAIDs
- May have an eosinophilia (no rash)
- Often have little symptoms and no obvious reaction
- But if diagnosed and drug stopped respond well to steroids
- To the right all the red cells are eosinophils
what are some glomerular causes of AKI (renal)
Rapidly progressive glomerulonephritis (RPGN); immune aetiology and characterised by ‘glomerular crescents’
- Rarer
- In tissue section we see crescents aka mass of inflammatory cells outside of glomerulus in bowman’s space
- Caused by different conditions
- In cross section looks like crescent – becomes bigger and bigger encircling glomerulus
- Glomerulus on the right is doomed – will become small and scarred with little functions
vascular causes of AKI
Haemolytic uraemic syndrome (HUS)
- Haemolysis, damage to blood vessels, kidney failure, uraemia
Caused by
- E coli (shiga toxin toxic to particular vascular beds – kidney vasculature vv vulnerable – thrombosis in the kidney)
- Familial cases (genetic aetiology) – mutations, normally require second illness eg hypotension, pregnancy etc
Leads to capillary loops full of fibrin
what should we ask about in a clinical history of a patient with suspected AKI
- Renal history – pre-existing renal disease, diabetes, family history
- Urine volume - ?acute oliguria (low urine volume)
- Drug history – new drugs, nephrotoxic drugs (NSAIDs, ACEI, antibiotics)
- Systemic symptoms – diarrhoea, rashes etc
what areas are important in clinical examination of a patient with suspected AKI
- Fluid status (jugular venous pressure, BP) dehydrated
- Evidence of infections
- Rash, joint pathology
- Arterial bruits, underlying renovascular disease
- Palpable bladder (obstruction)
- Check drug chart
what investigations should be undergone in an AKI patient
- Urine dipstick – simple BUT important (blood, protein in urine = infection/ immune disease eg lupus/ vasculitis)
- Urine culture
- Renal ultrasound – if obstructed – decompressed
- Renal biopsy (AKI and normal sozied kidney
- Angiography +- intervention (if you think it’s a vascular issue)
what blood tests are important in someone with AKI
- FBC, blood film, clotting screen
- Biochemistry including Ca2+, (PO4)2-, LFTs and albumin
- Creatinine kinase (damage to muscles from long lie/ drugs – release muscle components into blood because myoglobin coming from muscles is toxic to kidneys)
- Blood cultures
- Virology and serology eg Hep B, ASOT
what does widespread muscle damage lead to
The urine of someone with rhabdomyolysis aka widespread muscle damage will be dark red
- Could also be someone with malaria
- CK will be very high – 100,000-200,000!!!!
what is the general treatment of AKI
- Optimise fluid balance and circulation
- Stop exacerbating factors eg nephrotoxic drugs (check drug chart)
- Appropriate prescribing (check BNF, discuss with pharmacist) eg opiates accumulate AKI
- Supportive treatment eg dialysis, nutrition
what are specific treatments to target specified causes of AKI
- Obstruction – drain renal tract (catheter etc)
- Sepsis – effective antibiotics
- RPGN eg SLE – immunosuppression
- Goodpasture’s syndrome – plasma exchange
- Compartment syndrome – fasciotomy
when should an AKI patient be put on dialysis
Severe uraemia - No prospect of immediate improvement - Uraemic encephalopathy or seizures - Uraemic pericarditis Hyperkalaemia unresponsive to medical treatment (>6.5)
also if…
- Fluid overload, especially pulmonary oedema, resistant to treatment with diuretics/ fluid restriction
- Severe acidosis (results in myocardial depression and hypotension)
whats the difference between intermittent and continuous haemodialysis
- Intermittent for ~3 hrs a day or every second day
o Requires someone to tolerate treatments
o Challenging to cardiovascular patients - Continuous dialysis
o Much more gentle
o Better for very sick patients
give a brief overview of what cells are part of the innate and adaptive immune systems
Innate immune system - Macrophages - Neutrophils - Complement and natural antibodies (IgM) Adaptive immune system - Dendritic cells (antigen presentation) - T cells (helper and cytotoxic T cells) - Natural killer cells (NK) – cytotoxic - B cells (antibody generation and memory)
what is the major histocompatibility complex (MHC)
- MHC in humans called histocompatibility Locus Antigen (HLA)
- These molecules imprint ‘individuality’ on cells and are pivotal in the generation of immune responses
- HLA genes are polymorphic i.e., there are many different variations possible at each gene locus
describe class I and class II MHC molecules
Class I molecules – HLA-A , -B, -C
- Expressed by most somatic cells of body
- Used to present peptides from internally processed proteins
Class II molecules – HLA-DP, -DQ, -DR
- Expressed by Antigen Presenting Cells (DCs etc) that constantly ‘sample’ their microenvironment
- Used to present antigenic peptides derived from digested material (including pathogens, abnormal or foreign cells)
explain the role of HLA Class I molecules
HLA CLASS I MOLECULES – HLA-A, -B, -C
- If class 1HLA molecule is associated with virus-derived protein, then the cell is recognised as infected
- Infected cell will be killed by cytotoxic T cells
explain the role of HLA Class II molecules
HLA CLASS II MOLECULES – HLA-DP, -DQ and -DR
- Used by antigen presenting cells (DCs)
- To present antigenic peptides derived from material digested or processed
- Cell surface expression of a peptide derived from a pathogen or foreign cell will stimulate a T cell immune response
- How immune responses are initiated
explain the t cell receptor and costimulation mechanism
- Don’t want immune response kicking off randomly
- So other molecules must be engaged before signal is strong enough to engage T cells and make sure they’re activated
- These accessory molecules are also used to target for immunosuppression in patients
- So not a simple T cell receptor, instead it’s a range of receptors that must be brought together to = activation
When they are activated T-cells are very effective assassins
- When find abnormal cell has range of kill mechanisms
o Tumour necrosis factor induce cell death
o Fas ligand induces cell death
o Perforin and Gz B punch holes in membrane = cell death
how does the immune system react to transplant organs
- Dendritic cell finds abnormal pathogen/ cell from transplant
- Presents this antigen to initiate T cell responses which are antigen specific
- Facilitated by production of IL-2 which is an interleukin required for proliferation of T cells
- Clonal expansion = army of T cells unique to attacking the organ cells
- After infection eradicated these cells die through activation induced cell death
- BUT LEFT WITH MEMORY
what are the key principles of transplant immunology
- Rejection of Tx is directed at specific proteins called antigens
- Rejection is donor specific
- Rejection may be both cell or antibody mediated
- Rejection exhibits ‘memory’ ie a 2nd similar Tx is rejected MORE RAPIDLY and this results from the rapid generation of cytotoxic antibodies that recognise the Tx
how is HLA profiling used in kidney transplant in relation to mismatch
HLA profiling is used to allocate kidneys but less important for other organs such as liver (less immunological)
- Is all HLA-A, -B and -DR loci are the same then it is a 0-0-0 mismatch
- If they are all different it’s a 2-2-2 mismatch
- Transplant lasts longer is there’s less mismatch
what immunosuppression treatments are used during transplantation
Corticosteroids
- Kill lymphocytes
- Interfere with T cell activation and gene transcription
- Powerful anti-inflammatory agents
Calcineurin inhibitors (CNI) – Tacrolimus
- Inhibit T cell activation by interfering with intracellular signalling pathways
Anti-proliferative agents – mycophenolate mofetil (MMF)
- Inhibit clonal expansion of T cells
Various Monoclonal and polyclonal antibodies
Directed against…
- IL-2 receptor blockers (IL-2 stimulates clonal expansion of T cells)
- T cells (cytotoxic complement fixing Abs)
- Co-stimulator molecules
what are important factors of patient history when thinking about transplant
- Age important (biological and chronological)
- Primary cause of renal failure eg polycystic kidneys versus conditions which can recur in a transplant (eg aHUS, FSGS)
- Comorbid disease eg cardiovascular disease (IHD, PVD), diabetes etc
- History of infections
- History of tumours (need tumour free period)
- Urological disease (eg bladder dysfunction)
explain the assay used to assess immunological x-match
take cells from serum of recipient and cells from the donor
add source of complement
if antibody binds to an antigen then lytic process happens – holes punched in membrane and cell dies
if you add a vital dye this enters the cells that are getting holes punched in them and you can see the dye colour in the interior of the cell
if the donor has antibodies the cells will become green
so if cells = green this signals a positive cross match meaning the kidney transplant can’t go ahead
explain production of HLA antibodies ie sensitisation and give some possible reasons for this
- if a person is exposed to a foreign HLA molecule, they can produce HLA antibodies against this eg if patient is A1, A24 they may be exposed to A31 and generate this antibody
- approx.. 30% of patients on renal waiting list have anti-HLA antibodies
- the ‘specificity’ of these antibodies has to be defined
Highly sensitised patients exhibit high levels of cytotoxic Abs to many HLA antigens that may be derived from – - previous transfusions (WBC filtered but some white blood cells can get through)
- pregnancies (foetuses’ antigens)
- previous transplantation
describe the steps of the luminex HLA antibody detection test
LUMINEX HLA ANTIBODY DETECTION
- 100 different colour coded polystyrene beads in a single well
- Each bead population coated with selected class I or class II antigens or pool of antigens for screening purposes
Procedure
1- Microbeads coated with HLA antigen incubated with patient serum
2- Wash beads
3- Incubate with PE conjugated anti-human IgG
4- Wash beads
5- Run beads on LabScan 100TM – assign assay reactivity and antibody specifities
- So you mix beads with patient serum and if there’s antibodies for the antigen on the beads they will bind.
- you can pick up the antibodies binding to the beads by adding anti-human immunoglobulin which binds to the antibody on the bead and gives a fluorescent signal
- gives you this graph
- at the left the patient has high antibodies for these antigens so want to give patient a kidney with antibodies on the right side of the graph as they don’t have antigens against these ones
whats hyperacute rejection
- occurs when Tx carries antigens to which the recipient is already sensitised
- cytotoxic antibodies bind endothelial cells and induces complement activation, platelet aggregation and intravascular thrombus formation
- the Tx is often destroyed ‘on the operating table’
what are some features of acute rejection and what conditions must be excluded upon these features after transplantation
Features
- rise in creatinine (often only indication if immunosuppression potent)
- reduced UO
- tender transplant
- fever
Exclude
- dehydration (clinical exam, BP)
- renal obstruction (US)
- vascular catastrophe (doppler)
- drug toxicity (tacrolimus levels – as its nephrotoxic)
antibody mediated rejection signs histologically
- when antibody binds to epithelium it’s not there vv long
- but activates compliment forming C4d =.an antibody footprint
- you can stain kidney and look for this
- associated with inflammation = capillaritis
how do we treat acute rejection
- high dose methyl prednisolone (anti-inflammatory, kills lymphocyte etc)
- Change to more potent immunosuppressive agent or an increased dose
- “anti-T cell” antibody (increased risk of infection, tumours)
- Plasma exchange (severe acute Ab mediated rejection)
what are features of chronic rejection and what conditions must be excluded upon these features
Features
- Progressive renal dysfunction
- Interstitial fibrosis and vascular disease on renal biopsy
Need to exclude
- Recurrent disease (membranous, MCGN)
- Obstruction (US)
- Renal artery stenosis (doppler of renal artery +- MRI angiography)
what are the mechanisms behind chronic rejection
- Increased HLA mismatch (1-2-1 vs 0-0-1)
- Previous acute rejection
- Poor drug compliance (low tacrolimus levels)
- Prolonger cold ischaemia time in kidney prior to surgery (CIT of living donor «_space;cadaveric donor)
what are some factors promoting graft failure in transplantation
- Delayed graft function
- Cytomegalovirus (CMV) infection
- Age of donor and ‘donor disease’
- Poor blood pressure control
- Proteinuria
management of chronic rejection
- No specific treatment available
- Most patients will eventually require dialysis and potentially further Tx
- Optimise immunosuppression
- Proactive treatment BP, lipids, proteinuria etc
what are infective risks of immunosuppression
Bacteria
- Urinary tract infection, chest infection
- Prophylactic cotrimoxazole
Viral
- CMV, herpes virus, parvo virus, BK virus (causes renal dysfunction)
- Prophylactic valganciclovir if recipient CMV -ve and donor CMV +ve
- TB (may require prophylactic treatment)
what are tumour risks of immunosuppresion
Tumours
- Incidence of all cancers increased
- Skin cancers common (UV block, avoid sun, monitor skin)
- Post Tx lymphoproliferative Disorder (PTLD) – secondary to infection with Epstein Barr Virus (reduce immunosuppression, may need chemotherapy)
what are side effects of immunosuppressive drugs
Calcineurin inhibitors are nephrotoxic
- Plasma levels of tacrolimus are measured regularly
Increased risk of diabetes (steroid and tacrolimus)
Hypertension (steroids and CNI)
Osteoporosis (steroids)
whats central pontine myelinolysis
Devastating / fatal condition associated with rapid correction of hyponatraemia
- Related to water fluxes into and out of brain
- Commoner in alcoholism and malnutrition and young women
- Associated with the pons in the brain
whats the main cause of hypernatraemia
- Hypovolaemia is almost always the case (concentration)
- The list of potential causes is vv similar to that of hyponatraemia
- The difference is the sodium: water balance
explain diabetes insipidus as a cause of hypernatraemia
- Diuresis continues unabated
- Free water loss occurs
- Sodium is concentrated
- Hypernatremia occurs
- No/ failed feedback mechanism
what are the 2 types of diabetes insipidus
Cranial/central DI – non/ reduced synthesis ADH
Eg – pituitary tumour, head injury, meningitis, genetic, idiopathic
Nephrogenic – reduced tubular response
Eg – inherited (receptors don’t work/ not there), drugs (lithium carbonate – treatment for bipolar defective disorder SE it blocks receptors on tubular cells for ADH)
what’s the treatment for hypernatraemia stemming from diabetes insipidus
- Can be very difficult
- Hydration tends to simply cause polyuria
- Synthetic ADH (DDAVP) exists
o Works in central/ cranial DI
o Supranormal doses might work in nephrogenic DI - NSAIDs might help
what’s a hydronephrotic kidney
- Renal pelvis is larger darker area because it’s fluid filled
- Pressure builds up = dilated pelvis
- As back pressure builds up over time there’s dilatation of ureter and renal pelvis over time
- The longer it persists the worse the damage to the kidney
- If reversed early no long-term consequences
- But if persists = renal damage and CKD
