Renal Flashcards
cause of nephrotic syndrome
damage to the clusters of small blood vessels in your kidneys that filter waste and excess water from your blood
4 stages of diabetic nephropathy:
- hyperfiltration
- microalbuminuria
- macroalbuminuria
- end stage renal failure
nephrotic syndrome
Triad of:
- Proteinuria (> 3g/24hr) causing
- Hypoalbuminaemia (< 30g/L) and
- Oedema
complications of nephrotic syndrome
increased risk of thromboembolism related to loss of antithrombin III and plasminogen in the urine
hyperlipidaemia
chronic kidney disease
increased risk of infection due to urinary immunoglobulin loss
Upper urinary tract infection-
Lower urinary tract infection-
pyelonephritis
cystitis
Risk Factors for UTIs:
- Females
- Recurrent UTI
- Sexual activity
- Vaginal infection
- Diabetes
- Obesity
- Genetic susceptibility
- Older age
o Oestrogen deficiency
o Cognitive impairment
Risk Factors for Complicated UTIs:
Patients with factors that compromise the urinary tract or host defence
- Urinary obstruction, e.g. prolapse, prostatic enlargement
- Urinary retention caused by neurological disease
- Immunosuppression
- Renal failure
- Renal transplantation
- Pregnancy
- Presence of foreign bodies
o eg indwelling catheters (CAUTI) or other drainage devices
Organisms causing UTIs:
- Most common: E.coli UPEC
- Klebsiella pneumoniae
- Staphylococcus saprophyticus- common in sexually active young women
- Enterococcus spp.
Pathophysiology of UTIs
- Infection of urethra by pathogen
- Colonisation of urethra & organism swims up to bladder- colonisation and invasion of bladder wall, pili and adhesins allow them to hold onto wall despite system flushing urine through
Bacteria infiltrate neutrophils & multiply in cytoplasm of bladder wall- subvert immune system, form biofilms, epithelial damage,
Inflammation= pain in suprapubic region - Bacteria ascend to kidney and multiple there- they can infiltrate into the bloodstream > bacterial bloodstream infection
Biofilms are important in
allowing persistence infections causing relapses and acute prostatitis.
bacterial mechanisms in UTIs
Invades bladder cell wall using Type 1 pili.
Multiplication to form intracellular bacterial communities (IBC) and these exfoliate or form quiescent bacterial reservoirs (QIR).
To cause pyelonephritis bacteria must express pyelonephritis associated (P) pili.
MOST common cause of secondary bloodstream infections
CAUTI
what can UTIs cause?
- Bacteraemia common in pyelonephritis
- Perinephric abscesses
- Can rarely lead to remote deep seated infection
bacterial virulence factors
- Adherence: pili, adhesins
- Toxin production- haemolysins
- Immune evasion- capsule
- Iron acquisition
presentation of pyelonephritis
Pyelonephritis: Loin pain/flank tenderness, fever/rigors, sepsis
presentation of cystitis
Cystitis: Dysuria, frequency, urgency, suprapubic tenderness
presentation features of UTI in infants and elderly
In infants (<2yrs) –vomiting/fever In elderly - less localised symptoms – confusion/falls
most common causes of dysuria in elderly women
Atrophic vaginitis and oestrogen deficiency are the most common causes of dysuria in elderly women and often mistreated.
location of dysuria and differentials
o End of stream- external vagina
o Throughout- urethritis
Urine dipstick
The dipstick is only to be used in patients under 65
- useful only in presence of clinical UTI symptoms- presence of nitrites indicate a UTI as a possible diagnosis but it have 75% sensitivity
why can urine dipsticks only be used in people <65?
- can only be used <65 as elderly people often have asymptomatic bacteriuria which may be mistaken for UTI
when is urine culture bacteriuria significant?
• Generally significant if >105 CFU/mL
when is asymptomatic bacteriuria treated?
pregnant women- thought to decrease risk of development of pyelonephritis (pregnancy can dilate the ureters) which can lead to pre-term labour
when does bacteriuria signify a UTI?
Symptomatic bacteriuria: UTI
• Culture results SUPPORT clinical diagnosis only
Rapid Detection of UTI- point of care tests
• Flexicult – for primary care – culture at the bedside in 24 h.
• Rapid detection using molecular markers
- check for presence of bacteria (resistant) or inflammation
o >50% of elderly women have asymptomatic bacteriuria
o Urgent clinical need for indication of active inflammation specifically in urinary tract
• Nitrofurantoin should only be used for
cystitis
when should IV antibiotics be used over oral?
• If there are any signs of SIRS or sepsis, IV should be used over oral
o Some MDR organisms only have IV choices available
antimicrobial use increases
risk of recurrent UTI and antimicrobial resistance
Management of Upper UTI:
take blood cultures before giving IV antibiotics
gentamicin and consider adding amoxicillin
Diagnosis and Management of Catheter Associated UTI
review need for catheter
- Do not use urine dipstick for diagnosis
- Urine culture is often positive in catheterised patient, this does not differentiate between colonisation and infection
- Diagnosed clinically
Managment of Lower UTI
only for aamelioration and shortening of symptom duration in cystitis
Trimethoprim (if resistant then Nitrofurantoin)
All children with confirmed UTI need
investigation and consideration of vesico-ureteric reflux
recurrent UTI
Recurrent UTI occurs in ¼ women, antimicrobial exposure is a risk factor and it is often MDR organisms.
recurrent UTI management
advice- fluid intake, diet, lubrication, STI, supplements like cranberry extract
trial methenamine and high dose Vit C for 12 months
Most common causes of Chronic Kidney Disease
Diabetes Hypertension Chronic glomerulonephritis Polycystic kidney disease Renovascular Disease
how is estimated GFR found?
MDRD equation
GFR in each stage of CKD
Stage 1 CKD if eGFR is >90 ml/min/1.73m2 Stage 2 CKD- 60-89 Stage 3 CKD- 30-59 Stage 4 CKD- 15-30 Stage 5 CKD- <15
what else is required to diagnose stage 1&2 of CKD?
demonstrable kidney damage (e.g. haematuria or proteinuria)
biopsy or radiologically proven
strategies to prevent progression of CKD
Control blood pressure (RAS inhibition) Reduce proteinuria (RAS inhibition)
If diabetes, optimise glycaemic control
process of interstitial fibrosis in diabetes
normally protein in filtrate taken up into lysosomes and broken down into amino acids then taken up into peritubular capillaries
in diabetes, heavy proteinuria overloads the system and the tubular cell dies, it is cleared by fibroblasts -> scarring
marker of chronic progressive kidney disease
lots of interstitial fibrosis
toxic drugs in CKD
NSAIDs, contrast, gentamicin (aminoglycoside)
phosphate enemas- atopic bowel absorbs large amounts of phosphate
antibiotics in lower dosing
__% of elderly patients may have CKD
> 25%
consequences of hypertension in end stage renal disease
left ventricular hypertrophy, stroke, end organ damage- eyes, kidney
BP treatment goals in CKD
“normal” - 130/80
DM / Proteinuria 125/75
what potassium abnormality is present in CKD?
Hyperkalaemia common as GFR declines < 25
Causes of hyperkalemia in CKD:
–Diabetes and type 4 renal tubular acidosis - low renin and Aldo level
- ACE inhibitors
- High K Diet
reduced distal sodium delivery- increase potassium absorption
examples of potassium binders
patiromer, sodium zirconium
Acidosis in CKD- cause and management
Much acidosis in CRF is due to animal protein in food.
– Inability to acidify urine in CKD
• Aim to keep Serum HCO3 >22
• Replace with NaHCO3 / Sodium Bicarbonate
biochemical findings in CKD patients with anemia
Hb<12inmales/<11infemales
– Generally normochromic normocytic anaemia
why do CKD patients have anemia?
decreased response of EPO to a hypoxic stimulus (kidney) and decreased RBC survival, iron deficiency, blood loss
aluminum / hyper PTH / B12+Folate defic
EPO replacement criteria
All pts with Hb <105 and adequate iron stores should be on Epo
• Target Hb 100-120
EPO and relationship with aluminum / hyper PTH / B12+Folate defic
- PTH negative regulator of EPO
- aluminium stimulate eryptosis
- B12+Folate- required by erythroblasts for proliferation during their differentiation
features of renal osteodystrophy
Reduced bone density (Osteoporosis)
Reduced bone mineralisation (Osteomalcia)
Secondary/Tertiary Hyperparathyroidism
May get spinal osteosclerosis: Rugger Jersey spine
Pathophysiology of renal osteodystrophy
CKD: reduced calcitriol produced and reduced phosphate clearance –> low serum calcium
Secondary hyperparathyroidism to restore calcium levels–> bone resorption leading to osteoporosis
Calcitriol continues to reduce –> oesteomalacia
renal osteodystrophy management
Phosphate restrict (0.8-1.0g/kg/day) • binders- calcium or non-Ca binders – Vitamin D therapy (alfacalcidol) • increases Ca / decreases PO4 – Monitor PTH regularly – Parathyroidectomy may be required
consequences of hyperphosphatemia
Vessel calcification – Non-compliant vessels
– Systolic hypertension – L Vent Hypertrophy
– Diastolic hypotension - Myocardial ischaemia
• Calciphylaxis
medial calcification is a result of
hyperphosphatemia and hypercalcemia, doesn’t obstruct lumen
as CKD progresses, there is an increased risk of
CV death and death from all causes
malnutrition in CKD
common- dietary restrictions, decreased appetite
malnourished pts do worse on dialysis
Who should you refer to renal clinic?
Any patient with rapid increase in creatinine/ hypertension
• Stage 3 CKD with hypertension/proteinuria /haematuria/ rising creatinine
• Any stage 4/5 CKD who is suitable for treatment
choice of treatment in CKD
- haemodialysis
- peritoneal dialysis
- kidney transplant
- conservative care- no dialysis, symptomatic
body fluid compartments
intracellular- interstitial fluid, plasma and transcellular fluid.
extracellular
majority of body fluid is in which compartment?
intracellular
What happens when you add salt to the extracellular compartment?
raised osmolarity in extracellular compartment
Water will move out to balance osmolarity which depletes cellular water
external and internal osmotic pressures
pull water into compartments
sodium is principal extracellular osmotic pressure
internal hydrostatic pressure
pushing water out of compartment
external hydrostatic pressures
pull water into compartment
If you add water into the vascular space >
expand vascular space > flow into interstitial space > flow into cellular space because of dilution and raised hydrostatic pressure (increased volume) > water will move out to each compartment equally
dilution hyponatremia
define eu-, hypo- and hyper- volemia
Euvolaemic/normovolaemic: normal 55-60% total body water
Hypovolemic: volume deplete
Hypervolemic: volume overloaded
Clinical Signs of Hypovolemia
- Postural hypotension
- Tachycardia
- Absence of jugular venous pulse at 45
- Reduced skin turgor/ dry mucosa
- Supine hypotension
- Oliguria
- Organ failure
Clinical Signs of Hypervolemia:
- Hypertension
- Tachycardia
- Raised JVP
- Gallop rhythm
- Peripheral and pulmonary oedema (pitting oedema- different to adipose tissue)
- ‘third space gains’- excessive fluid in body cavities eg. pleural space
- Organ failure
Hypervolaemic hyponataemia
in which water gains exceed sodium gains
Causes of Hypervolaemic hyponataemia
Renal failure
Heart failure
Liver failure
Nephrotic syndrome
Hypovolaemic hyponatremia-
excessive sodium losses and water losses are insufficient to concentrate sodium back up, depends on volume of water loss
Causes of Hypovolaemic hyponatremia-
Burns Sweating Diarrhoea Vomiting Fistulae Addison's disease
Euvolemic hyponatremia
water evenly distributed across all compartments, hyponatremia is dilutional
Causes of Euvolemic hyponatremia
hypotonic IV fluids, hypothyroidism, SIADH
Why does SIADH cause euvolemic hyponatremia?
ADH secretion in excessive - Not suppressed by reduced tonicity - Water reabsorption is excessive (and inappropriate) - Sodium is diluted - Hyponatremia results Clinically euvolaemic
Treatment of Hypovolemia:
- Restoration of volume state o Blood if necessary o Crystalloid - Cessation of diuretics - Steroids for Addison’s
Treatment of Hypervolemia:
- Diuretics
o Usually loop diuretics eg. furosemide/ bumetanide
o Fluid restriction
o Treatment of underlying cause eg. Heart attack
Treatment of Euvolaemic Hyponatraemia:
- Treat underlying cause o Stop IV fluids o Thyroxine replacement - Fluid restriction down to 500ml/day - Rarely demeclocycline- reduces tubular sensitivity to ADH
Correcting sodium faster than 12mmol/L/day leads to a significant risk of
central pontine myelinosis because of fluid shifts.
Recommended rate of sodium correction:
o 4-10mmol/L/day if asymptomatic
o 8-12 mmol/l/day if symptomatic
o with careful monitoring / observation, needs to be brought up slowly
what is mostly commonly the underlying cause of hypernatremia?
- Hypovolaemia is almost always the case (concentration) > increased serum concentration due to loss of fluid
- The list of potential aetiologies is very similar to that for hypovolaemic hyponatraemia
renal clearance
volume of plasma cleared of a substance per unit time
GFR
volume of fluid filtered from the glomerular capillaries into the Bowman’s capsule per unit time
what is needed to estimate GFR?
substance completely lost from the plasma to urine
endogenous: creatinine, cystatin C
exogenous= inulin, radioisotope tracers
accuracy of creatinine clearance at low GFR
inaccurate- amount creatinine secreted becomes proportionally much larger
inconvenient for patient as requires urine collection
ACR
albumin: creatinine ratio, used in classification of CKD
severe= >30
NICE guideline for AKI
Rise in creatinine of ≥ 25 micromol/L in 48 hours
Rise in creatinine of ≥ 50% in 7 days
Urine output of <0.5ml/kg/hour for > 6 hours
what is AKI commonly characterised by?
oliguria & increases in plasma urea & creatinine often accompanied by a loss in ability to regulate water, electrolyte & acid-base balance.
acute on chronic kidney injury
acute insult on a background of chronic existing renal impairment
An increased risk of AKI is associated with:
Chronic kidney disease Diabetes with chronic kidney disease Heart failure Renal transplant Age 75 or over Hypovolaemia Contrast administration
renal tubular acidosis type 1
inability to generate acid urine (secrete H+) in distal tubule
causes hypokalaemia
complications include nephrocalcinosis and renal stones
causes of renal tubular acidosis
idiopathic, rheumatoid arthritis, SLE, Sjogren’s, amphotericin B toxicity, analgesic nephropathy
what can be used to confirm RTA T1?
ammonium chloride loading test
measures of electrolyte homeostasis
Spot urine- however urine conc varies throughout the day 24hr urine collection Measure creatinine (or osmolality) to correct for variability in urine conc.
plasma sodium is an indicator of
indicator of fluid balance, rather than total body sodium e.g. hypernatraemia tends to reflect water deficit, rather than sodium overload
Urine Na+ >30 mmol/L can signify
inappropriate loss – tubular dysfunction / damage / inadequate aldosterone action
e.g. intrinsic /established renal failure caused by un- treated pre-renal failure
urine concentrating ability is assessed by measuring
urine osmolality (and plasma osmolality for comparison)
loss of urine concentrating ability may be accompanied by
polyuria
dipstick urinalysis can include
Glucose (diabetes?)
• Ketones (ketoacidosis?)
• Protein (albumin) – not as sensitive as lab measurement
• Blood (detects Hb: calculi, glomerulonephritis)
pH
how can renal pathology be related to proteinuria?
• Increased glomerular permeability – increasing urinary albumin, detectable levels
of large MW proteins not normally found in urine
• Decreased tubular protein reabsorption – increased conc. of low MW proteins eg. Fancuni Syndrome
Proteinuria may be detected by
dipstick testing (not as sensitive as lab urine)
• lab-based albumin / protein measurement, sometimes 24hr collection but usually a spot urine using creatinine to adjust for urinary conc:
o protein:creatinine ratio (PCR)
o albumin:creatinine ratio (ACR) – used to classify CKD
microalbuminuria
Refers to abnormal level of albumin, usually too low for detection by urine dipstick
ACR > 3.5 mg/mmol in men, >2.5 mg/mmol in women
- confirmed with collection on 2/more sep occasions
transient causes of microalbuminuria
post-trauma, surgery, pyrexia, vigorous physical exercise
acid production- cellular and metabolic
cellular respiration produced CO2- react with water to make carbonic acid
metabolic processes- non volatile acids (can’t be removed by lungs) eg. ketones, lactate
countermeasures in acidosis
rapid buffers bind H+ and reduce acidity eg. proteins, bicarb
lungs- remove CO2, limited by bicarb reserves
slow kidneys- excrete H+, regen and recover bicarb
respiratory acidosis- sign, compensatory mechanism and consequence of decompensation
- raised CO2
- slow renal resorption of bicarbonate
- acidaemia consequence
respiratory alkalosis- sign, compensatory mechanism and consequence of decompensation
- low CO2
- renal excretion of bicarb (marginal)
- alkalemia consequence
metabolic acidosis- sign, compensatory mechanism and consequence of decompensation
- low bicarb
- increase RR to lower CO2, increased renal resorption of bicarb
- acidaemia consequence
metabolic alkalosis- sign, compensatory mechanism and consequence of decompensation
- raised bicarb
- lowered RR to increase CO2, renal excretion of excess bicarb (marginal)
- alkalemia consequence
What can be used to calculate pH/bicarb?
Henderson Hasselbalch equation
Which aspect of ABGs can tell you if a pt is adequately oxygenated?
pO2, FIO2, [Hb]
When only should BE be deranged?
BE should only be deranged where a metabolic disorder is present:
• metabolic acidosis -> neg BE
• metabolic alkalosis -> pos BE
When only should standard bicarb be deranged?
Std bicarb should only be deranged where a metabolic disorder is present:
• purely resp. disorder -> ref range std bicarb
• purely metabolic disorder -> approx equiv to actual bicarb
• mixed resp-met disorder -> significant difference with actual bicarb
Causes of metabolic acidosis with raised anion gap
Methanol uremia diabetic ketoacidosis (DKA) paraldehyde, phenformin iron, isoniazid lactic (ie, carbon monoxide [CO], cyanide) ethylene glycol salicylates.
anion gap
difference between most abundant [cations] and [anions]
= [Na+] – [Cl-] – [HCO3-]
What does the anion gap depend on?
no change: replaced with Cl- ions (hyperchloraemic acidosis)
• elevated: replaced with anions corresponding to lactate, keto-acids etc.
Causes of respiratory acidosis
COPD
Decompensation in other respiratory conditions e.g. Life-threatening asthma / pulmonary oedema
Neurological
Sedative drugs: benzodiazepines, opiate overdose
Causes of respiratory alkalosis
Usually acute
- asthma, COPD exacerbation, pulmonary embolism
- pain, panic attack
- iatrogenic (over-ventilation while under intubation)
- inappropriate stimulation of respiratory centre (brain stem): head injury, local tumour
- metabolic: hepatic encephalopathy, salicylate poisoning
Pregnancy- chronic
causes of metabolic alkalosis
Vomiting / aspiration (e.g. Peptic ulcer leading to pyloric stenosis, nasogastric suction) Diuretics Liquorice, carbenoxolone Hypokalaemia Primary hyperaldosteronism Cushing's syndrome
Stages of AKI
tage 1: creatinine rise of 1.5x compared to baseline or urine output <0.5 ml/kg/hour for 6 hours.
Stage 2: creatinine rise of 2x compared to baseline or urine output <0.5 ml/kg/hour for 12 hours.
Stage 3: creatinine rise of 3x compared to baseline or urine output <0.3 ml/kg/hour for 24 hours (or anuria for 12 hours) or serum creatinine >354umol/dl
pre renal causes of AKI
Inadequate blood supply to kidneys reducing filtration of blood, may be due to:
VOLUME DEPLETION → diarrhoea, bleeding, 3rd space fluid losses, diuresis, sepsis
HYPOTENSION → HF, sepsis, oedematous states, drugs (ACEi/ARBs)
RENAL ISCHAEMIA → hepatorenal syndrome, arterial occlusion
DRUGS → NSAIDs, calcineurin inhibitors, ACEi/ARBs
renal causes of AKI
intrinsic disease in the kidney leading to reduced filtration of blood, may be due to: Dysfunction in the glomeruli (acute glomerulonephritis) Tubules (acute tubular necrosis) Interstitial (acute interstitial nephritis) Renal vessels (haemolytic uraemia syndrome or vasculitis) Rhabdomyolysis
post renal causes of AKI
obstructive uropathy Obstruction may be caused by: Kidney stones Masses such as cancer in the abdomen or pelvis Ureter or uretral strictures Enlarged prostate or prostate cancer MUST BE IN ALL PRESENT KIDNEYS
obstructive uropathy
obstruction to the outflow of urine from the kidney, causing back-pressure into the kidney and reduced kidney function
myeloma kidney
obstruction of lumen of tubules, some patients can form casts that cause intratubular obstruction
investigation that all patients with significant AKI must have
ultrasound to exclude or demonstrate obstruction to renal tract
most common cause of AKI
acute tubular necrosis
can acute tubular necrosis be reversible?
in early stages, yes
two main causes of ATN
- ischaemia: shock, sepsis
2. nephrotoxins
nephrotoxic drugs
- aminoglycosides
- myoglobin secondary to rhabdomyolysis
- radiocontrast agents
- lead
- NSAIDs
- ACEi e.g. Ramipril
- ANGII receptor blocker e.g. Candesartan
- statins
Histopathological features of ATN
tubular epithelium necrosis: loss of nuclei and detachment of tubular cells from the basement membrane
dilatation of the tubules may occur
necrotic cells obstruct the tubule lumen
what can be seen in the urine in ATN?
muddy brown casts in urine
acute allergic interstitial nephritis
drug related eg. PPIs, antibiotics, diuretics, NSAIDs
may have an eosinophilia (no rash)
often responds well to steroids
rapidly progressive glomerulonephritis is characterised by
haematuria, proteinuria, autoimmune aetiology and glomerular crescents- mass of inflammatory cells outside glomerulus in Bowman’s space
Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by the triad of
thrombotic microangiopathy, thrombocytopenia, and AKI
How does E.coli cause intravascular thrombosis?
generates shiga toxin which is toxic to the vascular endothelial bed causing intravascular thrombosis (kidney is particularly susceptible)
creatinine kinase is a marker of
muscle damage
rhabdomyolysis
damage to muscle from statins/being unwell releasing muscle contents into blood, myoglobin is nephrotoxic
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
autoantibodies in SLE, vasculitis, Goodpasture’s syndrome
- Anti-nuclear factor (ANA) - SLE
- Anti-neutrophil Ab (ANCA) - vasculitis
- Anti-GBM Ab - Goodpasture’s syndrome,
Management of AKI
Fluid rehydration with IV fluids in pre-renal AKI
Stop nephrotoxic medications
Relieve obstruction in a post-renal AKI, for example insert a catheter for a patient in retention from an enlarged prostate
Drugs that may have to be stopped in AKI as increased risk of toxicity (but doesn’t usually worsen AKI itself)
- Metformin
- Lithium
- Digoxin
Renal replacement therapy (e.g. haemodialysis) is used when
patient is not responding to medical treatment of complications, for example hyperkalaemia, pulmonary oedema, acidosis or uraemia.
Complications of AKI
Hyperkalaemia
Fluid overload, heart failure and pulmonary oedema
Metabolic acidosis
Uraemia (high urea) can lead to encephalopathy or pericarditis
Class I molecules
- Expressed by most somatic cells of body
- If Class 1 HLA molecule is associated with virus-derived protein then the cell is recognised as infected and killed by cytotoxic T cells
Class II molecules
- 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)
transplant rejection is
directed at specific antigens and an be cell/antibody mediated
it is donor specific
how does transplant rejection exhibit memory?
a 2nd similar Tx is rejected MORE RAPIDLY and this results from the rapid generation of cytotoxic antibodies that recognise the Tx
HLA profiling
Used to allocate kidneys but less important for other organs such as liver (less immunogenic)
levels of kidney mismatch
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
drugs used in immunosuppression treatment in transplants
- corticosteroids
- calcineurin inhibitors- tacrolimus
- antiproliferative agents
What are monoclonal and polyclonal antibodies in immunosuppression treatment
directed against?
- IL-2 receptor blockers (IL-2 stimulates clonal expansion of T cells)
- T cells (cytotoxic complement fixing Abs)
- Co-stimulatory molecules
calcineurin inhibitors
Inhibit T cell activation by interfering with intracellular signaling pathways
types of transplantation
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
patient assessment for transplant
age, primary cause of renal failure eg. polycystic kidneys versus conditions which can recur in a Tx (e.g. aHUS, FSGS)
Comorbidities, History of infections & tumours, Urological disease
Which vessels and organs are the transplanted kidney attached to?
iliac vessels and bladder
renal vein anastomosis
criteria for a kidney Tx to go ahead
Blood group (ABO) compatible Immunological ‘X-match negative’- there are no antibodies in circulation against cells
What does a positive immunological X match mean?
there are antibodies in circulation against cells- the complement used during flow cytometry allows a lytic process to occur and green dye signifies dead cells
No Tx
sensitisation- production of 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
What can high sensitisation be derived from?
Highly sensitised patients exhibit high levels of cytotoxic Abs to many HLA antigens may be derived from: • Previous transfusions (WBC filtered) • Pregnancies- paternal antigens in baby • Previous Transplantation
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
Which HLA is most significant in transplantation?
DR > B > A
Based on mismatch effect
Types of transplant rejection
Hyperacute rejection (should not happen)
•Acute rejection- first few months
•Chronic rejection
What is hyperacute rejection?
total destruction due to pre-existing antibodies against ABO or HLA antigens
an example of a type II hypersensitivity reaction
treatment of hyperacute rejection?
no treatment is possible and the graft must be removed
Hyperacute Rejection- cellular mechanism
Cytotoxic antibodies bind endothelial cells and induces complement activation, platelet aggregation and intravascular thrombus formation → ischaemia and necrosis of the transplanted organ
Acute rejection (< 6 months) features
- Rise in creatinine (often only indication)
- Reduced urine output
- Tender transplant
- Fever
What must be excluded to diagnosis acute rejection?
Dehydration, renal obstruction, vascular catastrophe, drug toxicity (tacrolimus- nephrotoxic)
cellular features of acute rejection
tubulitis, vasculitis, large vessel involvement
treatment of 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)
features of chronic rejection
- Progressive renal dysfunction
* Interstitial fibrosis and vascular disease on renal biopsy
What must be excluded to diagnosis chronic rejection?
- Recurrent disease (membranous, MCGN)
- Obstruction (ultrasound)
- Renal artery stenosis (Doppler of renal artery +/- MRI angiography)
Causes of chronic graft failure (> 6 months)
both antibody and cell mediated mechanisms cause fibrosis to the transplanted kidney (chronic allograft nephropathy)
recurrence of original renal disease (MCGN > IgA > FSGS)
poor drug compliance (tacrolimus)
Cold ischaemia time impact on Tx
prolonged CIT of kidney prior to surgery increases risk of chronic rejection (CIT of living donor «_space;cadaveric donor)
Factors promoting graft failure
- Delayed graft function- doesn’t work for a few days bc of adverse impact of ischaemia on early graft function
- Cytomegalovirus (CMV) infection
- Age of donor and ‘donor disease’
- Poor BP control
- Proteinuria
Management of chronic Tx rejection
Most patients will eventually require dialysis and potentially a further Tx
• Optimise immunosuppression
• Proactive treatment of BP, lipids, proteinuria etc
Infective risk of immunosuppression- bacterial
UTI, chest infection
can be given prophylactic cotrimoxazole
Infective risk of immunosuppression- viral
CMV, herpes virus, parvo virus, BK virus (causes renal dysfunction)
can be given prophylactic valgancyclovir if recipent CMV –ve and donor CMV +ve
tumour risks of immunosuppression
increase incidence of all cancers and skin cancers common (skin surveillance, UV block)
Post Tx Lymphoproliferative Disorder (PTLD)
secondary to infection with Epstein Barr virus (reduce immunosuppression, may need chemotherapy)
side effects of immunosuppressive drugs in transplant
Plasma levels of tacrolimus (nephrotoxic) are measured regularly
Increased risk of diabetes (steroids and tacrolimus)
Hypertension (steroids and CNI)
Osteoporosis (steroids)
What mechanisms are affected in hypovolemia?
SNS- tachycardia, vascoconstriction
RAAS- vasoconstriction, Aldo stimulates salt and water retention
increased ADH, reduced urine output
initial treatment for hyperkalemia in AKI
IV calcium salts if ECG abnormal- protects myocardium
best investigation to confirm post renal AKI
USS renal tract- show bladder, estimate bladder volume
hydronephrosis
swelling of kidney due to build-up of urine when urine cannot drain out from the kidney to the bladder due to obstruction
more damage to cortex- CKD + loss of renal function
Benign prostatic hypertrophy
encroaches the bladder
- urine isn’t adequately excreted
- urine accumulation and increased pressure -> back pressure goes up to kidney
Complications of Benign prostatic hypertrophy
dilation of renal pelvis, hydronephrosis, hydroureter, renal impairment
treatment in benign prostatic hypertrophy
urinary catheter- decompression of renal tract, may become polyuric (can’t conc urine)
alpha blocker eg. tamsulosin- enable sphincter to be capable of relaxing
transurethral prostatic resection surgery (TURP)
compliance of the bladder
Bladder pressure remains constant despite increase in volume due to visco-elastic properties (elastin/collagen; detrusor relaxation without change in tension)
• Bladder filling- sensors detect increase in wall tension
volitional micturition controlled by?
Spino-bulbar reflex
• Modulation by Pontine Micturition Centre (Barrington’s nucleus)
• Onuf’s nucleus in intermediolateral S2,3,4
volume at which bladder is full
Fullness at 250ml; Uncomfortable at 500ml (detrusor contractions)
3 causes of black eyes
directly injured in eye
tracking of blood down to tissues around eye
raccoon eyes from base of skill fracture
micturition positive feedback loop
detrusor contraction -> wall tension rises -> afferent signals to PMC -> efferent signals increase detrusor contraction
central coordination of micturition
PMC- takes afferent and produces efferent signals
prefrontal, thalamic, hyperthalamic, cerebellar areas
excitatory neurones in micturition
cholinergic (Ach)
inhibitory neurones in micturition
GABA and glycine neurones
facilitation of voiding of bladder involves
contraction of detrusor and relaxation of sphincter when bladder less than full
inhibition of bladder allows
postponement of voiding
protein: 2+ or more implies
intrinsic renal disease and very unlikely to be explained by asymptomatic infection
congenital nephrotic syndrome is due to
mutation in podocyte specific gene eg. nephrin
symptoms: ascites, oedema, low levels of protein in body
The presence of blood and protein in the urine implies?
testing and differentials?
glomerular disease and an urgent need to test excretory kidney function, consider systemic diseases (eg vasculitis, lupus)
in hypertension, albuminuria suggests
primary renal cause
albuminuria is a risk factor for?
cardiovascular- aggressive management of cardiovascular risk is indicated
symptoms of nephrotic syndrome
severe lethargy, reduced exercise tolerance, nausea, loss of appetite
haematuria can be a sign of
serious systemic disease for which diagnosis and treatment is very urgent, whether or not there is also albuminuria
if you find proteinuria, what should you not do?
send MSU to exclude infection
diseases where the glomerulus is damaged (may have proteinuria/haematuria)
DM, vascular disease/ischameia, vasculitis, glomerulonephritis, deposition disease eg. amyloid, myeloma
storage lower urinary tract symptoms
- Urgency
- Frequency
- Nocturia
- UI: urinary incontinence
voiding LUTS
- Hesitancy
- Poor flow
- Intermittency
- Terminal dribbling
What is nocturia an effect of?
ageing, renal concentrating ability decreases with age increased renal blood flow at night (lying down) leading to increased urine production
Difference between nocturia and nocturnal polyuria
nocturia- <2x night
nocturnal polyuria- production of more that 1/3 of 24-hour urine at night
Causes of decreased bladder capacity and polyuria
DM/DI, polydipsia
reduced compliance, reduced functional capacity,
neurogenic bladder, irritation
What is post-void dribble?
Release of small amount of urine after micturition- Due to release of urine retained in bulbar/prostatic urethra
Straining in mictruition
Use of abdominal muscles to void (Valsalva only normally required at end of voiding)
decreased force of mictruition is usually secondary to
bladder outlet obstruction
urge incontinence
Involuntary loss of urine associated with strong desire to void (detrusor contraction)
stress incontinence
Involuntary loss of urine when intra-abdominal pressure rises without detrusor contraction eg with coughing, sneezing
IPSS
International Prostate Symptom Score assessing severity of LUTs
Uroflow Meter
subsequent bladder scan assesses residual volume
poor flow= bladder outflow obstruction
When is a urodynamic assessment indicated?
suspected neuro abnormality, complex voiding patterns, young patients with severe issues
What is a urodynamic assessment?
pressure transducers on bladder and rectum
Pressure from bladder and rectum measured during filling and voiding
• Patient asked to cough periodically to check transducers
• Subtracting rectal (abdominal) pressure from bladder = detrusor activity
bladder outlet obstruction presentation in urodynamic assessment
No unstable contractions during filling
• No leak whilst coughing during filling
• Very high pressure and low flow during voiding
urethra causes of LUTs
Strictures -the narrowing of the urethra
can be congenital or result from iatrogenic trauma- urethral instrumentation or anastomosis- or non-iatrogenic trauma
symptoms of outflow obstruction
storage symptoms may come before voiding symptoms
decompensation fo detrusor leading to:
- residual urine, chronic retention
- bladder failure
- renal failure from obstructive nephropathy
management of overactive bladder
Lifestyle (alcohol), anti-muscarinics (Solifenacin, Fesoterodine), selective β-3 adrenoreceptor agonist (Mirabegron), Intradetrusor Botox
management of stress incontinence
Pelvic floor exercises, weight loss, surgery (autologous rectus abdominis sling, artificial sphincter)
management of bladder outlet obstruction
Medical therapies: alpha- blockers (Tamsulosin), 5ARI (Finasteride), surgery (TURP, laser prostatectomy)
first line treatment for urge incontinence
bladder retraining
hyaline casts in the urine are seen in
normal urine after exercise, during fever or with use of loop diuretics
ECG signs of hyperkalaemia
small or absent P waves, tall-tented T waves, and broad bizarre QRS complexes- very broad QRS complexes form sinusoidal wave pattern
nephritic syndrome characterised by
haematuria with red cell casts, proteinuria (>3g/day), hypertension, oliguria, oedema
Indiacations for dialysis
A - Acidosis E - Electrolyte imbalance I - Intoxication (e.g. Aspirin, Barbiturates, Lithium, Alcohol, Salicylates and Theophylline) O - Overloaded with fluids U - Uraemia
IgA nephropathy is the most common
cause of glomerulonephritis in general
IgA nephropathy presents with
classically presents as macroscopic haematuria in young people following an upper respiratory tract infection.
cause of IgA nephropathy
caused by mesangial deposition of IgA immune complexes
Differentiating between IgA nephropathy and post-streptococcal glomerulonephritis
- post-streptococcal glomerulonephritis is associated with low complement levels
- main symptom in post-streptococcal glomerulonephritis is proteinuria (although haematuria can occur)
- typically an interval between URTI and the onset of renal problems in post-streptococcal glomerulonephritis
Minimal change disease presentation
common cause in children, presents as nephrotic syndrome
highly selective proteinuria- only intermediate-sized proteins such as albumin and transferrin leak through the glomerulus
Pathophysiology of Minimal change disease
T-cell and cytokine-mediated damage to the glomerular basement membrane → polyanion loss
the resultant reduction of electrostatic charge → increased glomerular permeability to serum albumin
Adult polycystic kidney disease increases the risk of
brain haemorrhage due to ruptured berry aneurysms
high UCR indicates
pre-renal cause of AKI
