Renal - Week 3 Flashcards
describe acid production in the body
• Cellular respiration
o Produces CO2 which reacts with water to form carbonic acid
• Metabolic processes
o Give rise to non-volatile acids: ketones, lactate etc
o ~60 mmol non-volatile acids per day
o In 14L this would make the body pH 2.3
describe how acid homeostasis is maintained
• Buffers (rapid)
o Bind to protons to reduce acidity
o Proteins e.g. Hb
o Bicarbonate
• Lungs (fast)
o Remove CO2
o Limited by HCO3 reserves
• Kidneys (slow)
o Excrete H into urine
o Recover HCO3
what happens in hypoventilation
- Increased CO2 respiratory acidosis
- Lung disease, airway obstruction, neurological problem leading to depressed breathing such as head injury or opiate overdose
what happens in hyperventilation
- Less CO2 respiratory alkalosis
* Panic attack in response to pain or asthma
how can you get metabolic acidosis
• Increased protons
o Over production of acid such as lactic acidosis (tissue hypoxia) or ketoacidosis (diabetes, starvation, alcohol)
o Impaired excretion
Acute kidney injury or CKD
• Losing bicarbonate
o Severe diarrhoea
o Fistula formation in small bowel
o renal tubular acidosis type II
how can you get metabolic alkalosis
• Unusual loss of protons o Vomiting o Severe hyperkalaemia o Hyperaldosteronism • Unusual ingestion of bicarbonate
what are the compensation mechanisms for each acid base disturbance
metabolic acidosis
- increased RR to lower CO2
- increased renal recovery of HCO3
metabolic alkalosis
- decreased RR to increase CO2
- decreased renal recovery of HCO3
- usually marginal
respiratory acidosis
- increased renal recovery of HCO3
respiratory alkalosis
- decreased renal recovery of HCO3
- usually marginal
how is HCO3 calculated
using the henderson-hasselbalch equation
CO2 + H2O H2CO3 H + HCO3
what is important to remember about arterial blood gases
Blood gases often performed on the radial artery – can damage artery
Need to be analysed asap and not sent by pneumatic tube – pressure
We only need H, pO2, pCO2 and HCO3
Base excess and HCO3 are calculated by the analyser
Base excess is the amount of H per L of blood, required to return the pH to reference range at pCO2 of 5.3kPa
Should only be deranged where a metabolic disorder is present
describe standardised bicarbonate
- What the HCO3 conc would be if pCO2 were reference range (5.3kPa)
- Std bicarb should only be deranged where a metabolic disorder is present
- Purely metabolic disorder - approx. equivalent to actual bicarb
- Mixed resp-meta disorder - significant difference to actual bicarb
what are the effects of metabolic acidosis
• Cardiovascular
o Negative inotropic effect (if severe)
• Oxygen delivery
o Acutely – H causes R-shift of oxyHb dissociation curve (facilitates oxygen delivery)
o After several hours – H reduces 2,3-DPG causing L-shift of curve (impairs O2 delivery)
• Nervous system
o Impaired consciousness
• Potassium homeostasis
o H leakage from cells causing high plasma K, may also be lost renally
o If above sustained, total body K can be depleted
• Bone
o If chronic, acidosis can get buffered by bone
o Leads to decalcification
describe the relationship between metabolic acidosis and anion gap
some causes have anion gap and some done
elevated o DKA o lactic acidosis o salicylate overdose o ethylene glycol, methanol poisoning o renal failure
normal
o severe diarrhoea
o high intestinal fitula output
o renal tubular acidosis
what are the effects of respiratory acidosis
hypercapnia -
o shortness of breath
o neurological - anxiety, coma, headache, myoclonus
o systemic vasodilation
o hypoxia
what are the effects of metabolic alkalosis
not usually significant
K moves into cells
beware effect of IV bicarbonate in CKD as metabolic acidosis is common in CKD - acute fall in acidity can reduce solubility of calcium salts and increase risk of systemic calcification
Remember the compensation for alkalosis is limited
what are the effects of respiratory alkalosis
acute hypocapnia
o cerebral vasoconstriction - light headedness, fits, confusion, syncope
o fall in ionised calcium -perioral, peripheral parasthesia
cardiovascular
o increased heart rate
o vasoconstriction - possible angina in those with coronary artery disease
Remember the compensation for alkalosis is limited
how can you get respiratory acidosis
acute o airway obstruction o cardio-resp arrest o infective exacerbation of COPD o pneumonia o neurological - opiate toxicity, guilllain barre syndrome, myasthenia gravis
chronic o COPD o obstructive - obesity o restrictive - pulmonary fibrosis o neurological - MND, myopathy
how can you get respiratory alkalosis
usually acute in nature o asthma, COPD. PE o pain, panic attack o iatrogenic o altitude sickness
o inappropriate stimulation of respiratory centre
• head injury
• raised ICP
• local tumour
• metabolic e.g. hepatic encephalopathy, poisoning
chronic
o pregnancy - mild resp alkalosis compensated by minor metabolic acidosis
what are the immune systems normal functions?
Recognition of ‘non-self’or ‘abnormal self’
Protection from pathogens (bacteria, viruses etc)
Surveillance for tumours
what are the components of the immune system
Innate immune system
Macrophages
Neutrophils
Complement & natural antibodies (IgM)
Adaptive immune system
Dendritic cells (antigen presentation) T cells (helper and cytotoxic T cells) Natural Killer (NK) cells - cytotoxic B cells (antibody generation & memory)
describe MHC (Major Histocompatibility Complex)
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 very polymorphic i.e. there are many different variations possible at each gene locus
Class I molecules: HLA-A, -B and -C
Expressed by most somatic cells of body
Used to present peptides from internally processed proteins
Class II: HLA-DP, -DQ and –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)
Class I: HLA-A, -B and -C
If Class 1 HLA molecule is associated with virus-derived protein then the cell is recognised as infected
Infected cell will be killed by cytotoxic T cells
Class II: HLA-DP, -DQ and –DR
Used by Antigen Presenting Cells (DCs etc) to present antigenic peptides derived from digested and processed material
Cell surface expression of a peptide derived from a pathogen or foreign cell will stimulate a T cell immune response
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’ i.e. a 2nd similar Tx is rejected MORE RAPIDLY and this results from the rapid generation of cytotoxic antibodies that recognise the Tx
describe HLA profiling
Performed using molecular biological and serological techniques
e.g. HLA-A1 and A3,
HLA-B44 and B44
HLA-DR7 and DR15
The HLA tissue types of all patients on the Kidney Transplant waiting list is held on a central UK database and the ‘best match’ chosen when kidneys become available
Used to allocate kidneys but less important for other organs such as liver (less immunogenic)
If all HLA-A, -B and –DR loci are the same the it is a 0-0-0 mismatch
If they are all different then it is a 2-2-2 mismatch
describe immunosuppressive treatment
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 signaling 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-stimulatory molecules
which organs are transplantable
Kidney Pancreas (complete organ or pancreatic islets) Liver Lung Heart Small Bowel Cornea Faces, arms etc
what needs to be assessed in patients needing a transplant
Age important (biological vs chronological!) - frailty
Primary cause of renal failure e.g. polycystic kidneys versus conditions which can recur in a Tx (e.g. aHUS, FSGS)
Comorbid disease e.g. cardiovascular disease (IHD, PVD), diabetes etc
History of infections
History of tumours (need tumour free period)
Urological disease e.g. bladder dysfunction
Additional investigations:
CARDIAC - exercise ECG, myocardial perfusion studies
Angiography (need decent vessels for the anastomosis)
Urodynamic studies
Tumour markers, imaging etc
what are the types of transplant?
Cadaveric Tx (commonest) e.g. subarachnoid haemorrhage • DCD = donated after cardiac death • DBD = donation after brain death Living related donor Tx • Sibling, spouse, altruistic Typically a kidney Tx
Live donation lasts longer than cadaveric
what are the criteria for a kidney Tx to go ahead?
Blood group (ABO) compatible (RIE now has an ABO incompatible programme)
Immunological ‘X-match negative’
• Take serum from the recipient and donor lymphocytes
• Add a complement e.g. vital dye which will enter killed cells and turn them a colour if they are matched to recipient antibodies
describe anti-HLA antibodies
If a person is exposed to a foreign HLA molecule, they can produce an HLA antibody against this e.g. patient is A1, A24 and with exposure to A31 generating an anti-A31 antibody
Approximately 30% patients on renal waiting list have anti-HLA antibodies
The ‘specificity’ of these antibodies has to be defined (e.g. A31, B8, DR3 etc)
Highly sensitised patients exhibit high levels of cytotoxic Abs to many HLA antigens that may be derived from:
• Previous transfusions (WBC filtered)
• Pregnancies
• Previous Transplantation
why do anti-HLA antibodies matter?
HLA antibody status requires careful consideration
- make a successful X-match less likely (long wait for Tx)
- can lead to antibody mediated rejection
- Consider desensitisation/antibody removal or paired exchange Tx
what types of rejection are there
Hyperacute rejection (should not happen)
Acute rejection
Chronic rejection
describe HLA antibody detection
put beads with selected class I or II antigens into a well
incubate this with patient serum
wash
incubate with PE conjugated anti-human IgG
wash
and then scan them.
you can derive a graph from this to show how many antibodies they have to certain molecules
describe hyperacute rejection
Occurs when the 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
Features: • Rise in creatinine (often only indication) • Reduced urine output • Tender transplant • Fever Exclude: • Dehydration (clinical examination, BP, weight) • Renal obstruction (ultrasound) • Vascular catastrophe (Doppler) • Drug toxicity (tacrolimus levels)
how do you 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)
describe chronic rejection and what do we need to exclude
Features:
• Progressive renal dysfunction
• Interstitial fibrosis and vascular disease on renal biopsy
Need to exclude:
• Recurrent disease (membranous, MCGN)
• Obstruction (ultrasound)
• Renal artery stenosis (Doppler of renal artery +/- MRI angiography)
what are the causes of chronic rejection
- Artery stenosis
- Recurrent crescentic nephritis
- Recurrent diabetic neuropathy
- Interstitial fibrosis
- Vasculopathy – can cause narrowed lumen of arteries
what is the pathogenesis of chronic rejection
Multifactorial: immune and non-immune mechanisms:
Increased HLA mismatch (1-2-1 vs 0-0-1)
Previous acute rejection
Poor drug compliance (low tacrolimus levels)
Prolonged cold ischaemia time of kidney prior to surgery (CIT of living donor «_space;cadaveric donor)
what are some factors promoting graft failure
Delayed graft function Cytomegalovirus (CMV) infection Age of donor and ‘donor disease’ Poor blood pressure control Proteinuria
how do you manage chronic rejection
No specific treatment available
Most patients will eventually require dialysis and potentially a further Tx
Optimise immunosuppression
Proactive treatment of BP, lipids, proteinuria etc
what are the infective risks of immunosuppression
Bacteria
urinary tract infection, chest infection
prophylactic cotrimoxazole
Viral
CMV, herpes virus, parvo virus, BK virus (causes renal dysfunction)
prophylactic valgancyclovir if recipent CMV –ve and donor CMV +ve
TB (may require prophylactic treatment)
what are the tumour risks of immunosuppression
Incidence of all cancers increased
Skin cancers common (UV block, avoid sun, skin surveillance)
Post Tx Lymphoproliferative Disorder (PTLD) – secondary to infection with Epstein Barr virus
(reduce immunosuppression, may need chemotherapy)
what are some side effects of immunosuppressive drugs
Calcineurin inhibitors are nephrotoxic! Plasma levels of tacrolimus are measured regularly
Increased risk of diabetes (steroids and tacrolimus)
Hypertension (steroids and CNI)
Osteoporosis (steroids)
What is AKI defined as?
any of the following:
- Increase in serum creatinine by > 26.5 μmols/L in 48 hours or,
- Increase in serum creatinine by > 1.5x baseline creatinine within last 7 days or
- Urine volume < 0.5ml/kg/hr for 6 hours
what percentage of hospital inpatients does AKI affect
7%
what are the concequences of AKI
- Increased length of stay in hospital
- Increased morbidity
- Increased hospital & post-discharge mortality
- Very costly (~£500 million/annum)
what are the differential diagnoses for pre-renal AKI
PRE-RENAL reduced real or ‘effective’ blood volume
- Hypovolaemia e.g. bleeding, 3rd space fluid losses, over-enthusiastic diuretic therapy!
- Hypotension e.g. septic/cardiogenic shock, liver failure
- Reduced renal blood supply secondary to severe renovascular disease (±ACEI), dissection of the abdominal aorta etc
what are the differential diagnoses for renal AKI
RENAL glomerulus, tubules and interstitium
• Acute tubular injury
– Commonest cause of AKI in hospitals and can complicate everything previously discussed!
– Tubular toxins, eg gentamicin, cisplatinum, NSAIDs, radio-contrast dye
– Severe prolonged hypotension (sepsis, MI)
– Renal hypoperfusion e.g. elderly patient on ACEI, diuretic who has D&V
– Initial oliguria then may exhibit polyuric recovery phase (watch electrolytes)
Tubulointerstitial causes Acute allergic interstitial nephritis DRUG-RELATED e.g. PPIs, (omeprazole) antibiotics, diuretics, NSAIDs May have an eosinophilia (no rash) Often respond well to steroids
Examples of cresentic RPGN (rapidly progressing glomerular nephritis)
Goodpasture’s syndrome: anti-GBM Ab
Wegener’s granulomatosis: PR3 Ab
Microscopic polyarteritis (MPA): MPO Ab
SLE: Anti-nuclear Ab (ANA), anti-dsDNA Abs
Vascular causes
Haemolytic uraemic syndrome (HUS)
E coli related (E coli O157)
Familial cases (genetic aetiology)
- Acute tubular injury - may follow severe hypotension
- Rhabdomyolysis - crush injury or low lie on the floor
- Contrast nephropathy
- Interstitial nephritis - drugs e.g. penicillin, NSAIDs
- Systemic vasculitis
- Myeloma - tumour of plasma cells
- Haemolytic uraemic syndrome - E. Coli O157 infection
what are the differential diagnoses for post-renal AKI
POST-RENAL obstruction – multiple levels (e.g. ureter, bladder etc)
- Note that bilateral obstruction OR obstruction of a single kidney (transplant) is required in order to result in AKI
Causes include:
Prostate – hypertrophy (common), cancer
Bladder lesions - tumour
Ureter - calculi, tumour, extrinsic compression (retroperitoneal fibrosis, tumour
Myeloma – proliferation of B cells in the bone marrow – these make a single antibody called a paraprotein which can precipitate and completely obstruct the lumen
Hydronephrosis – very dilated due to an obstruction
All patients with significant renal injury MUST have an ultrasound to exclude or demonstrate obstruction to the renal tract
what should be done with a patient with AKI
- Take a clinical history
- Perform a clinical examination
- Request appropriate investigations
- Clinical history in AKI
- Renal history – pre-existing renal disease, diabetes, family history
- Urine volume - ?acute oliguria
- Drug history – ? New drugs, nephrotoxic drugs (NSAIDs, ACEI, antibiotics)
- Systemic symptoms – diarrhoea, rashes etc
what does a clinical examination involve in AKI
Fluid status (JVP, postural BP) ?dehydrated
?evidence of infection
?rash, joint pathology
Arterial bruits ?underlying renovascular disease
Palpable bladder (obstruction)
Check drug chart!
what are investigations in AKI
Urine dipstick – simple BUT important (blood, protein) Urine culture Renal Ultrasound - if obstructed then decompress Renal biopsy (AKI and normal sized kidneys) Angiography ± intervention
what are the blood tests in AKI
FBC, blood film, clotting screen
Biochemistry including Ca2+, PO42- LFTs and albumin
Creatinine kinase (rhabdomyolysis) - black urine
Blood cultures
Virology and serology e.g Hep B, ASOT
what are the immunological tests in AKI
IgGs and serum electrophoresis (myeloma) Complement levels (SLE, post strep GN) Autoantibodies e.g. - Anti-nuclear factor (ANA) - SLE - Anti-neutrophil Ab (ANCA) - vasculitis - Anti-GBM Ab - Goodpasture’s syndrome,
what are some “other” tests in AKI
Urine: Bence Jones protein = light chains (myeloma)
Chest X ray (cardiac size, pulmonary oedema or haemorrhage)
ECG especially if hyperkalaemia
what is the general treatment for AKI
Optimise fluid balance and circulation
Stop exacerbating factors e.g. nephrotoxic drugs (check drug charts)
Appropriate prescribing (check BNF, discuss with pharmacist) e.g. opiates accumulate in AKI
Supportive treatment e.g. dialysis, nutrition
what are some specific treatments for AKI
Obstruction - drain renal tract Sepsis - effective antibiotics Rapidly progressing glomerular nephritis RPGN e.g. SLE (systemic lupus erythematosus) - immunosuppression Goodpasture’s syndrome - Plasma exchange Compartment syndrome - fasciotomy
when to give dialysis
Severe ‘uraemia’: - no prospect of immediate improvement - uraemic encephalopathy or seizures - uraemic pericarditis Hyperkalaemia unresponsive to medical treatment (>6.5)
Fluid overload, especially pulmonary oedema, resistant to treatment with diuretics/fluid restriction Severe acidosis (results in myocardial depression and hypotension)
complications with dialysis
Vascular access related complications -
Pneumothorax
Infection
Bleeding
Anticoagulation required which may be problematic in patients with bleeding.
Hypotension may be troublesome in some patients (sepsis, IHD, diabetes)
describe hypovolaemia-initial fluid resuscitation
- 500 mL 0.9% sodium chloride or plasmalyte over 15 minutes
- Reasonable to repeat if no response
- Do not give more than 2000 mL as resuscitation fluid without senior input
what are drugs which make AKI worse
- ACE inhibitors and angiotensin receptor blockers
- Blood pressure lowering drugs
- Diuretics
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Radiocontrast agents
how to treat hyperkalaemia
(for those >6.5 mmol/L)
• IV calcium salts if ECG abnormal
• Lasts around 30 minutes
- Insulin/glucose and nebulized salbutamol
- Push potassium into cells
- Lasts around 4-6 hours
- Treat underlying cause
- Need to get kidneys working to excrete potassium
how to diagnose systemic vasculitis
• Dipstick urinalysis
- Serum anti-neutrophil cytoplasmic antibodies
- Often present with coincident infection
- Tissue diagnosis
- Kidney most common
- Lung
- Nerve
how to treat systemic vasculitis
• Glucocorticoids • Oral prednisolone • Plasma Exchange • Significant renal disease and/or pulmonary haemorrhage
• Cyclophosphamide/Rituximab
what is important to remember in post-renal AKI
- Needs to block both kidneys to cause AKI
- Some people have a single kidney
- In women can be due to pelvis cancer-cervical, ovarian
- Bladder tumours can also occlude ureteric orifice
- Blood clot in bladder
what to do in the case of finding blood in protein in urine
• 2+ or more implies intrinsic renal disease and very unlikely to be explained by asymptomatic infection
o The correct response to a finding of proteinuria is NOT to send an MSU “to exclude infection”
• Quantify: albumin/creatinine ratio (timed collection rarely helpful)
• Test kidney renal function, consider systemic diseases
• NEVER ignore/dismiss it
describe the ranges of albuminuria
• Albumin/creatinine ratio (mg/mmol) can be performed on small urine sample taken at any time of day
• ACR x 10 approximates to mg/24 hours (eg in renal disease 100 reflects c 1g/24h)
• Normal ACR (eg) less than 3.5
o 3.5 – 30 microalbuminuria
o > 30 (macro)albuminuria
what are measurements of excretory renal function
- plasma/serum creatinine
- estimated GFR: MDRD formula (sex, age, race, creatinine)
- creatinine clearance
- isotope GFR (usually 51Cr EDTA)
what happens in congenital nephrotic syndrome
due to mutation in podocyte-specific gene eg nephrin
what is important in the case of blood and protein in urine
The presence of blood and protein in the urine implies glomerular disease and an urgent need to test excretory kidney function, consider systemic diseases such (eg vasculitis, lupus)
what can albuminuria suggest
- In diabetes mellitus, microalbuminuria is the earliest clinical feature of diabetic nephropathy; may initially be intermittent
- In hypertension, albuminuria suggests a primary renal cause
- In all patients, including in the absence of diabetes or hypertension, albuminuria carries prognostic significance
Albuminuria is a potent, independent cardiovascular risk factor in both diabetic and non-diabetic populations. Aggressive management of cardiovascular risk is indicated.
what is nephrotic syndrome
- Clinical syndrome comprising oedema, heavy proteinuria, hypoalbuminaemia
- Not included in the definition but often clinically important are thrombotic risk, propensity to infection and (often severe) hyperlipidaemia
- May or may not be associated with impairment of excretory kidney function
- Dominant symptoms often severe lethargy, reduced exercise tolerance, nausea, loss of appetite
- Causes include glomerulonephritis, diabetes, infections (hepatitis B/C, malaria, HIV), amyloid
what is important in blood in urine
Haematuria, whether visible (macroscopic) or non-visible (microscopic) can be a sign of a serious systemic disease for which diagnosis and treatment is very urgent, whether or not there is also albuminuria
don’t dismiss haematuria as “probably due to urine infection” without considering other possibilities: history, examination, investigations, possible specialist referral
diseases in which the glomerulus is damaged
(may present with proteinuria and/or haematuria)
• Rare genetic/developmental disorders
• Diabetes mellitus
• Vascular disease/ischaemia/age
• Inflammation of blood vessels “vasculitis isolated or as part of a systemic disease
• Inflammation of glomerulus itself (“glomerulonephritis”, various types)
• Deposition diseases eg amyloid,myeloma
Anything which damages blood vessels
