9: Sepsis Flashcards

1
Q

What are the characteristic features and causes of ATI?

A
  • Acute renal failure
    • Morphologic evidence of tubular injury - necrosis of tubular epithelial cells
    • Causes
      ○ Ischaemia due to reduced or interrupted blood flow
      § Diffuse involvement of intrarenal blood vessels
      □ Microscopic polyangiitis
      □ Microangiopathies
      § Decreased effective blood circulation
      □ Hypovolaemic shock
      ○ Direct toxic injury to tubules
      § Endogenous agents
      □ Myoglobin
      □ Haemoglobin
      □ Monoclonal light chains
      □ Bile/bilirubin
      § Exogenous agents
      □ Drugs
      □ Radiocontrast dyes
      □ Heavy metals
      □ Organic solvents
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Pathogenesis of ATI

A
  • Tubular cell injury
    ○ Tubular epithelial cells particularly sensitive to ischaemia and vulnerable to toxins
    ○ Several factors predispose tubules to toxic injury
    § Increased surface area for tubular reabsorption
    § Active transport systems for ions and organic acids
    § High rate of metabolism and oxygen consumptions required
    § Capability for resorption
    § Concentration of toxins
    ○ Ischaemia causes
    § Loss of cell polarity due to redistribution of membrane proteins from basolateral to luminal surface of tubular cells -> increased sodium delivery to distal tubules
    □ Incites vasoconstriction via tubuloglomerular feedback
    § Lowers GFR to maintain distal blood flow
    § Ischaemia tubular cells express cytokines and adhesion molecules
    □ Recruiting leukocytes
    § Injured cells detach from basement membranes and cause luminal obstruction, increased intratubular pressure and decrease GFR
    § Glomerular filtrate can leak back into interstitium -> interstitial oedema, increased interstitial pressure and further damage to the tubule
    • Disturbances in blood flow
      ○ Haemodynamic alterations cause reduced GFR
      ○ Intrarenal vasoconstriction
      § Reduced glomerular blood flow and reduced oxygen delivery
      ○ Several vasoconstrictive pathways implicated
      § Renin-angiotensin system - stimulated by decreased sodium in tubules as a result of decreased blood pressure
      § Sublethal endothelial injury
      □ Increased release of vasoconstrictor endothelin and decreased production of vasodilators nitric oxide and prostaglandin I2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Morphology of ATI

A
  • Tubular epithelial injury at multiple points along nephron

- Occlusion of lumens by casts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Stages of ATI

A
  • Initiation phase
    ○ Lasts 36 hours
    ○ Dominated by inciting medical, surgical or obstetric event
    ○ Slight decline in urine output with a rise in BUN
    • Maintenance phase
      ○ Sustained decrease in urine output between 40 and 400ml/day
      ○ Salt and water overload
      ○ Rising BUN concentrations
      ○ Hyperkalaemia
      ○ Metabolic acidosis
    • Recovery phase
      ○ Increase in urine volume to 3L/day
      ○ Tubules damaged so large amounts of water, sodium and potassium lost
      ○ Hypokalaemia
      ○ Increased vulnerability to infection
      ○ BUN and creatinine levels return to normal
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is tubulointerstitial nephritis?

A
  • Group of renal disease involves inflammatory injuries of the tubules and interstitium that are often insidious in onset
    • Principally manifest by azotaemia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Types of tubulointerstitial nephritis

A
- Acute 
		○ Rapid clinical onset
		○ Characterised histologically by
			§ Oedema
			§ Leukocytic infiltration or interstitium and tubules
	- Chronic
		○ Infiltration with mononuclear leukocytes
		○ Prominent interstitial fibrosis
		○ Widespread tubular atrophy
	- Secondary
		○ Present in a variety of vascular, cystic (PKD) and metabolic (diabetes) renal disorders
		○ Contribute to progressive damage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Common causes of tubulointerstitial nephritis

A
- Infections
		○ Acute bacterial pyelonephritis
		○ Chronic pyelonephritis
		○ Other infections
	- Toxins
		○ Drugs
		○ Acute-hypersensitivity interstitial nephritis
		○ Analgesics
		○ Heavy metals
		○ Lead, cadmium
	- Metabolic diseases
		○ Urate nephropathy
		○ Nephrocalcinosis
		○ Oxalate nephropathy
	- Physical factors
		○ Chronic urinary tract obstruction
		○ Neoplasms
		○ Multiple myeloma - light-chain cast nephropathy
	- Immunologic reactions
		○ Transplant rejection
		○ Sjogren syndrome
		○ Sarcoidosis
	- Vascular disease
	- Miscellaneous
		○ Nephronophthisis
		○ Idiopathic interstitial nephritis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Define pyelonephritis

A
  • Inflammation affecting the tubules, interstitium and renal pelvis
    • Serious complication of urinary tract infection
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Pathogenesis of pyelonephritis

A
- Haematogenous infection
		○ Commonly 
			§ Staphylococcus
			§ E.coli
		○ Bacteraemia spreads to kidneys
	- Ascending infection
		○ Common agents
			§ E.coli
			§ Proteus
			§ Enterobacter
		○ Bacterial colonisation - usually via instrumentation
		○ Bacteria enter bladder
		○ Deranged vesicoureteral junction
		○ Vesicoureteral reflux
		○ Intrarenal reflux
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What conditions predispose to pyelonephritis?

A
- Urinary Tract Obstruction
		○ Stasis of urine
		○ BPH, tumours, calculi
		○ Neurogenic bladder dysfunction
	- Vesicourethral Reflux
		○ Incompetence of vesicourethral valve
		○ Commonly congenital 
		○ Persistent bladder atony
	- Intrarenal Reflux
		○ Infected urine projected up to renal pelvis
		○ Most common in upper and lower poles
	- Immunosuppression
		○ Chemotherapy
		○ Corticosteroids
		○ AIDS
		○ Primary immune deficiency
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Clinical features of acute pyelonephritis

A
  • Flank pain
    • Myalgia
    • Flu-like symptoms
    • Raised temperature
    • Nausea and vomiting
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Morphology of acute pyelonephritis

A
  • Gross
    ○ Patchy inflammation and abscess formation
    ○ Patchy capsule surface
    ○ Cortical scarring
    ○ Papillary necrosis
    • Micro
      ○ Neutrophilic infiltration into tubules
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Clinical features of chronic pyelonephritis

A
  • Asymptomatic
    • Recurrent acute symptoms
    • Renal insufficiency and hypertension
    • Polyuria and nocturia
    • Proteinuria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Morphology of chronic pyelonephritis

A
- Gross
		○ Irregular cortico-medullary scarring
		○ Loss of papillae and blunting of calyces
	- Micro
		○ Inflammatory cell infiltrate 
		○ Presence of plasma cells
		○ Fibrosis and scar formation
		○ Thyroidisation - tubules show atrophy in some areas and hypertrophy/dilation in others
		○ Sclerosed glomeruli
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the main complications resulting from urinary tract obstruction?

A
  • Increase susceptibility to infection and stone formation

- Unrelieved obstruction almost always leads to permanent renal atrophy - hydronephrosis or obstructive uropathy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the common causes of obstructive lesions and how are they categorised?

A
- Intrinsic
		○ Urinary calci
		○ Sloughed papillae or blood clots
		○ Tumour of ureter or kidney
		○ Congenital abnormalities
			§ Posterior urethral valves
			§ Urethral strictures
			§ Bladder neck obstruction
			§ Ureteropelvic junction narrowing
			§ Severe vesicoureteral reflux
		○ Inflammation - ureterits, urethritis
	- Extrinsic
		○ Endometriosis
		○ Pregnancy
		○ BPH
		○ Ovarian cyst
		○ Tumours of prostate, bladder, cervix, uterus
		○ Inflammation - prostatitis, retroperitoneal fibrosis
		○ Uterine prolapse and cystocele
		○ Functional disorders
			§ Neurogenic - spinal cord damage or diabetic neuropathy
17
Q

Morphological features of obstruction

A
  • Sudden obstruction
    ○ Mild dilation of pelvis and calyces
    ○ Atrophy of renal parenchyma
    • Subtotal or intermittent obstruction
      ○ Dilation ensues
      ○ Hydronephrosis
    • Chronic cases
      ○ Cortical tubular atrophy with marked diffuse interstitial fibrosis
      ○ Progressive blunting of apices of pyramids occurs
      ○ In advanced cases kidney transformed into thin-walled cystic structure with striking parenchymal atrophy, total obliteration of pyramids and thinning of cortex
18
Q

What are the clinical features of urinary tract obstruction?

A
  • Acute obstruction
    ○ Pain
    ○ Symptoms associated with cause
    • Unilateral complete or partial hydronephrosis
      ○ Asymptomatic for long periods as kidneys maintain adequate function
      ○ Imaging studies
      ○ Relief of obstruction leads to reversion to normal function
    • Bilateral partial obstruction
      ○ Earliest manifestation inability to concentrate urine - polyuria and nocturia
      ○ Distal tubular acidosis, renal salt wasting, secondary renal calculi and chronic tubulinsteritial nephritis with scarring and atrophy of papilla and medulla
      ○ Hypertension common
    • Complete bilateral obstruction
      ○ Oliguria or anuria
      ○ Incompatible with survival unless obstruction relieved
      ○ Post-obstructive diuresis occurs
19
Q

Risk factors for renal calculi

A
  • Non-Modifiable:
    ○ Male
    ○ 40-60yrs old
    ○ Caucasian
    ○ Genetic conditions - Cystinuria, primary hyperoxaluria, renal tubular acidosis, and cystic fibrosis.
    ○ GI Conditions – Crohn’s
    ○ Anatomical abnormalities of the renal tract
    ○ 1st degree family history of renal calculi
    • Modifiable:
      ○ Diet - Excessive dietary intake of oxalate, urate, sodium, and animal protein
      ○ Chronic dehydration
      ○ Obesity
      ○ High ambient temperature environments
      ○ Drugs – 1% of all urinary calculi
20
Q

What are the four main types of calculi and what factors lead to their formation?

A
- Calcium oxalate stones
		○ Hypercalcaemia and hypercalciuria
			§ Hyperparathyroidism
			§ Diffuse bone disease
			§ Sarcoidosis
		○ Nucleation of calcium oxalate by uric acid crystals in collecting ducts
	- Magnesium ammonium phosphate stones
		○ Formed after infections by urea-splitting bacteria convert urea to ammonia
		○ Alkaline urine causes precipitation of magnesium ammonium phosphate salts
		○ Staghorn calculi
		○ Associated with infection
	- Uric acid stones
		○ Hyperuricaemia
			§ Gout
			§ Rapid cell turnover - leukaemia
		○ Cystine stones
			§ Genetic defects in renal reabsorption of amino acids leading to cystinuria
21
Q

Define acute lung injury

A

○ Abrupt onset hypoxaemia and bilateral pulmonary oedema in the absence of cardiac failure (non-cardiogenic pulmonary oedema)
○ ARDS is a manifestation of severe ALI
○ Well-recognised complication of various conditions

22
Q

What conditions are commonly associated with ARDS?

A
  • More than 50% associated with sepsis, diffuse pulmonary infections, gastric aspiration and trauma and head injuries
    • Infections
      ○ Sepsis*
      ○ Diffuse pulmonary infections*
      ○ Viral, mycoplasma & pneumocystis pneumonia
      ○ Miliary TB
      ○ Gastric aspiration*
    • Physical/injury
      ○ Trauma and head injuries*
      ○ Pulmonary contusions
      ○ Near-drowning
      ○ Fractures with fat embolism
      ○ Burns
      ○ Ionizing radiation
    • Inhaled irritants
      ○ Oxygen toxicity
      ○ Smoke
      ○ Irritant gases & chemicals
    • Chemical injury
      ○ Heroin or methadone overdose
      ○ Acetylsalicylic acid
      ○ Barbiturate overdose
      ○ Paraquat
    • Haematological conditions
    • Transfusion-associated lung injury
    • Disseminated intravascular coagulation
    • Other
      ○ Pancreatitis
      ○ Uraemia
      ○ Cardiopulmonary bypass
      ○ Hypersensitivity reactions (organic solvents, drugs)
    • Can appear in absence of know triggers and follows rapidly progressive clinical course - known as acute interstitial pneumonia
23
Q

Pathogenesis of ALI/ARDS

A
  • Initiated by pneumocyte and pulmonary endothelium injury
    • Causing increasing inflammation and pulmonary damage
    • Exudative phase
    • Proliferative phase
    • Fibrotic phase
    • Endothelial activation
      ○ Direct
      § Alveolar macrophages releasing inflammatory mediators after sensing damage to pneumocytes
      ○ Indirect
      § Circulating inflammatory mediators activate endothelium in tissue injury/sepsis
      ○ Some mediators injure endothelial cells while others induce endothelial cells to express increased adhesion molecules, pro-coagulant proteins and chemokines
    • Adhesion and extravasation of neutrophils
      ○ Neutrophils adhere to activated endothelium and migrate into the interstitium and the alveoli, where they degranulate and release inflammatory mediators including proteases, ROS and cytokines.
      ○ NETs are released and also contribute directly to lung damage
      ○ These injuries and associated inflammatory factors cause a vicious cycle of inflammation and endothelial damage which are at the heart of ALI/ARDS
    • Accumulation of intra-alveolar fluid and formation of hyaline membranes
      ○ Endothelial activation and injury make pulmonary capillaries leaky.
      ○ Allows interstitial and intra-alveolar fluid to form
      ○ Damage and necrosis of type 2 pneumocytes lead to surfactant abnormalities, further compromising alveolar gas exchange
      ○ Ultimately the protein-rich oedema fluid and debris from dead alveolar epithelial cells organise into hyaline membranes
    • Resolution of injury
      ○ Resolution of injury is impeded due to epithelial necrosis and inflammatory damage that impairs the ability of remaining cells to assist with oedema resorption
      ○ If the inflammatory stimulus lessens, macrophages remove intra-alveolar debris and release fibrogenic cytokines
      ○ This stimulates fibroblast growth and collagen deposition, leading to fibrosis of alveolar walls
      ○ Proliferation of residual type 2 pneumocytes proliferate to replace type 1 pneumocytes -> restored alveolar lining
      ○ Proliferation of uninjured capillary endothelium -> restored endothelium
24
Q

Morphology of ALI/ARDS

A

Exudate stage ~ 1-7 days
○ Macro
§ Diffuse consolidation
§ Lungs are firm, congested, red and boggy
○ Micro
§ Characteristic finding is diffuse alveolar damage:
§ Interstitial and intra-alveolar oedema, inflammation, fibrin deposition
§ Alveolar collapse
§ Alveolar walls become lined with waxy hyaline membranes
□ Consist of fibrin-rich oedema fluid mixed with remnants of necrotic epithelial cells
- Proliferative/organising stage
○ Type 2 pneumocytes proliferate, granulation tissue forms in alveolar walls and spaces
○ Proliferation of fibroblasts and myofibroblasts
○ In most cases, the granulation tissue resolves, leaving minimally functional impairment
- Fibrotic stage
○ Dense collagenous fibrosis with destruction of alveolar architecture

25
Clinical features of ARDS
- Dyspnoea and tachypnoea - Followed by increasing respiratory failure, hypoxaemia, cyanosis and appearance of diffuse bilateral infiltrates on radiographs - Hypoxaemia may be refractory to oxygen therapy due to ventilation-perfusion mismatch ○ Respiratory acidosis
26
Prognosis of ARDS
- No proven specific treatments - 2016 study found that in ICUs: ○ Incidence of ARDS was 10.4% ○ Mortality rate: § 35% for mild § 40% for moderate § 46% for severe - Majority of deaths due to sepsis, multiorgan failure, or severe lung injury - Most survivors recover lung function, usually after 6 months of initial injury - but in a minority, can lead to interstitial fibrosis and chronic lung disease - ALI/ARDS is more common and has worse prognosis in chronic alcoholics and smokers - Studies have identified a number of genetic variants that increase the risk of ARDS, some of which map to genes linked to inflammation and coagulation
27
What are the principle routes of CNS infection?
``` - Haematogenous spread ○ Anterograde arterial ○ Retrograde venous - Direct implantation ○ Trauma ○ Meningomyelocele - Local extension ○ Air sinuses ○ Teeth ○ Skull ○ Vertebrae - Peripheral nervous system ○ Rabies virus ○ Herpes Zoster virus ```
28
Explain acute meningitis and its subtypes.
``` - Duration ○ Acute < 1 day ○ Subacute 1 day to 1 week ○ Chronic > 1 week - Subtypes ○ Acute aseptic meningitis § No detectable bacterial growth on culture § Caused by viruses or partial antibiotic treatment ○ Acute pyogenic meningitis § Bacterial growth on culture § Bacterial cause ```
29
What are the common causative agents of acute pyogenic meningitis?
``` - Infants ○ Group B streptococcus ○ Escherichia coli ○ Listeria monocytogenes - Children ○ Neisseria meningitidis ○ Streptococcus pneumoniae ○ Haemophilus influenzae - Teenagers ○ Neisseria meningitidis ○ Streptococcus pneumoniae - Elderly ○ Neisseria meningitidis ○ Streptococcus pneumoniae ○ Listeria monocytogenes ```
30
Morphology of meningitis
``` - Macro ○ Engorged prominent vessels ○ Exudate found § Within subarachnoid space □ Inferior - haemophilus influenzae □ Within longitudinal fissure - streptococcus pneumoniae § Along blood vessels - Micro ○ Neutrophils fill subarachnoid space ○ Brain parenchyma relatively unaffected - Systemic ○ DIC § Non blanching rash ○ Waterhouse-Friedrichsen syndrome § Haemorrhage in adrenals ○ Ventriculitis § Exudate § Cortical infarcts ○ Obstructive hydrocephalus ○ Cerebral oedema +/- herniation ```
31
Causes of acute aseptic meningitis
``` - Viruses ○ Enteroviruses § ECHO § Coxsackie § Polio ○ Herpesviruses § Herpes simplex § Varicella zoster ○ HIV - Bacteria ○ Antibiotics given before LP - Drugs ○ Non-steroidal ○ Antibiotics ```
32
How is adrenocortical insufficiency categorised?
- Secondary adrenocortical insufficiency - Primary acute adrenocortical insufficiency - Primary chronic adrenal insufficiency (Addison's disease)
33
Precipitating factors of adrenocortical insufficiency
- Secondary adrenocortical insufficiency ○ Most common ○ Can be caused by any disorder of pituitary/hypothalamus § Withdrawal of exogenous steroids - low ACTH § Tumour § Metastatic cancer § Infection § Infarction § Irradiation ○ Clinical features similar to Addison disease - no hyperpigmentation ○ Adrenals appear small and flat with normal medulla - Primary acute adrenocortical insufficiency ○ Causes § Acute crisis in chronic AI § Withdrawal of steroids □ Failure to increase dose in response to physiological stress § Massive adrenal haemorrhage □ Traumatic birth □ Hypoxia □ Anticoagulation □ DIC □ Waterhouse-Friedrichsen syndrome ® Acute haemorrhagic necrosis of adrenal glands ◊ Usually Neisseria meningitidis ◊ Also Pseudomonas, pneumococci, Haemophilus, Staphylococci ® Children > adults ® Caused by overwhelming bacterial infection ® Rapidly progressive hypotension, shock, DIC, purpura ® Associated with massive bilateral adrenal haemorrhage ® 15% mortality rate, rises rapidly with delay in treatment - Primary chronic adrenal insufficiency (Addison's disease) ○ Progressive destruction of adrenal cortex ○ 80-90% caused by autoimmune adrenalitis ○ TB, AIDS, metastatic cancer ○ Autoimmune destruction of cells and auto-antibodies to hydrolase enzymes ○ 40% isolated, 60% part of autoimmune polyendocrinopathy syndrome
34
Clinical features of adrenocortocoinsufficiency
- Clinical features ○ Insidious presentation ○ Weakness and easy fatigability ○ Anorexia, nausea and vomiting, weight loss, diarrhoea ○ Hyperpigmentation § Sun-exposed sites and pressure points (elbows, knees, knuckles) § Increased levels of pro-opimelanocortin (POMC); common precursor to ACTH and MSH ○ Potassium retention, sodium loss § Hyperkalaemia, hyponatraemia (-> salt craving) § Volume depletion and hypotension § Hypoglycaemia - Features of adrenal crisis ○ Can be precipitated by infection, trauma, surgery etc ○ Vomiting, abdominal pain, hypotension, vascular collapse and coma ○ Can cause rapid death ○ Managed with IV hydrocortisone, fluids, glucose - Features of report ○ Missing without medication § Cushing syndrome ○ Recent illness without an increase in steroids ○ Head operations, brain tumours, radiation therapy ○ Metastatic cancer ○ Family history, PMH autoimmunity ○ Vomiting and abdominal pain
35
Post-mortem features of adrenal insufficiency
Primary adrenal insufficiency - Primary autoimmune adrenalitis ○ Irregular shrunken glands - difficult to identify within suprarenal adipose tissue ○ Histo § Cortex contains scattered residual cortical cells in collapsed network of connective tissue § Variable lymphoid infiltrate present in cortex and extends into medulla - Tuberculosis and fungal disease ○ Adrenal architecture effaced by granulomatous inflammatory reaction - Metastatic carcinoma ○ Adrenals enlarged ○ Normal architecture obscured by infiltrating neoplasm - Waterhouse-Friedrichsen syndrome ○ Deep purple widespread rash Secondary Adrenocortical Insufficiency - Gross ○ Adrenals moderately to markedly decreased in size ○ Small, flattened glands retains yellow colour as result of residual lipid - Micro ○ Cortex reduced to thin ribbon composed largely of zone glomerulosa ○ Medulla unaffected