9: Sepsis Flashcards
What are the characteristic features and causes of ATI?
- 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
Pathogenesis of ATI
- 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
- Disturbances in blood flow
Morphology of ATI
- Tubular epithelial injury at multiple points along nephron
- Occlusion of lumens by casts
Stages of ATI
- 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
- Maintenance phase
What is tubulointerstitial nephritis?
- Group of renal disease involves inflammatory injuries of the tubules and interstitium that are often insidious in onset
- Principally manifest by azotaemia
Types of tubulointerstitial nephritis
- 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
Common causes of tubulointerstitial nephritis
- 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
Define pyelonephritis
- Inflammation affecting the tubules, interstitium and renal pelvis
- Serious complication of urinary tract infection
Pathogenesis of pyelonephritis
- 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
What conditions predispose to pyelonephritis?
- 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
Clinical features of acute pyelonephritis
- Flank pain
- Myalgia
- Flu-like symptoms
- Raised temperature
- Nausea and vomiting
Morphology of acute pyelonephritis
- Gross
○ Patchy inflammation and abscess formation
○ Patchy capsule surface
○ Cortical scarring
○ Papillary necrosis- Micro
○ Neutrophilic infiltration into tubules
- Micro
Clinical features of chronic pyelonephritis
- Asymptomatic
- Recurrent acute symptoms
- Renal insufficiency and hypertension
- Polyuria and nocturia
- Proteinuria
Morphology of chronic pyelonephritis
- 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
What are the main complications resulting from urinary tract obstruction?
- Increase susceptibility to infection and stone formation
- Unrelieved obstruction almost always leads to permanent renal atrophy - hydronephrosis or obstructive uropathy
What are the common causes of obstructive lesions and how are they categorised?
- 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
Morphological features of obstruction
- 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
- Subtotal or intermittent obstruction
What are the clinical features of urinary tract obstruction?
- 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
- Unilateral complete or partial hydronephrosis
Risk factors for renal calculi
- 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
- Modifiable:
What are the four main types of calculi and what factors lead to their formation?
- 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
Define acute lung injury
○ 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
What conditions are commonly associated with ARDS?
- 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
- Infections
Pathogenesis of ALI/ARDS
- 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
Morphology of ALI/ARDS
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