9: Sepsis

Question 1

What are the characteristic features and causes of ATI?

Answer 1

• 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

Question 2

Pathogenesis of ATI

Answer 2

• 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

Question 3

Morphology of ATI

Answer 3

• Tubular epithelial injury at multiple points along nephron

- Occlusion of lumens by casts

Question 4

Stages of ATI

Answer 4

• 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

Question 5

What is tubulointerstitial nephritis?

Answer 5

• Group of renal disease involves inflammatory injuries of the tubules and interstitium that are often insidious in onset
  
  • Principally manifest by azotaemia

Question 6

Types of tubulointerstitial nephritis

Answer 6

- 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

Question 7

Common causes of tubulointerstitial nephritis

Answer 7

- 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

Question 8

Define pyelonephritis

Answer 8

• Inflammation affecting the tubules, interstitium and renal pelvis
  
  • Serious complication of urinary tract infection

Question 9

Pathogenesis of pyelonephritis

Answer 9

- 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

Question 10

What conditions predispose to pyelonephritis?

Answer 10

- 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

Question 11

Clinical features of acute pyelonephritis

Answer 11

• Flank pain
  
  • Myalgia
  • Flu-like symptoms
  • Raised temperature
  • Nausea and vomiting

Question 12

Morphology of acute pyelonephritis

Answer 12

• Gross
  ○ Patchy inflammation and abscess formation
  ○ Patchy capsule surface
  ○ Cortical scarring
  ○ Papillary necrosis
  
  • Micro
    ○ Neutrophilic infiltration into tubules

Question 13

Clinical features of chronic pyelonephritis

Answer 13

• Asymptomatic
  
  • Recurrent acute symptoms
  • Renal insufficiency and hypertension
  • Polyuria and nocturia
  • Proteinuria

Question 14

Morphology of chronic pyelonephritis

Answer 14

- 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

Question 15

What are the main complications resulting from urinary tract obstruction?

Answer 15

• Increase susceptibility to infection and stone formation

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

Question 16

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

Answer 16

- 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

Question 17

Morphological features of obstruction

Answer 17

• 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

Question 18

What are the clinical features of urinary tract obstruction?

Answer 18

• 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

Question 19

Risk factors for renal calculi

Answer 19

• 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

Question 20

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

Answer 20

- 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

Question 21

Define acute lung injury

Answer 21

○ 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

Question 22

What conditions are commonly associated with ARDS?

Answer 22

• 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

Question 23

Pathogenesis of ALI/ARDS

Answer 23

• 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

Question 24

Morphology of ALI/ARDS

Answer 24

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

Question 25

Clinical features of ARDS

Answer 25

- 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

Question 26

Prognosis of ARDS

Answer 26

- 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

Question 27

What are the principle routes of CNS infection?

Answer 27

``` - 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 ```

Question 28

Explain acute meningitis and its subtypes.

Answer 28

``` - 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 ```

Question 29

What are the common causative agents of acute pyogenic meningitis?

Answer 29

``` - 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 ```

Question 30

Morphology of meningitis

Answer 30

``` - 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 ```

Question 31

Causes of acute aseptic meningitis

Answer 31

``` - Viruses ○ Enteroviruses § ECHO § Coxsackie § Polio ○ Herpesviruses § Herpes simplex § Varicella zoster ○ HIV - Bacteria ○ Antibiotics given before LP - Drugs ○ Non-steroidal ○ Antibiotics ```

Question 32

How is adrenocortical insufficiency categorised?

Answer 32

- Secondary adrenocortical insufficiency - Primary acute adrenocortical insufficiency - Primary chronic adrenal insufficiency (Addison's disease)

Question 33

Precipitating factors of adrenocortical insufficiency

Answer 33

- 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

Question 34

Clinical features of adrenocortocoinsufficiency

Answer 34

- 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

Question 35

Post-mortem features of adrenal insufficiency

Answer 35

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