block 9 - week 1 summary slides
TRANSCRIPT
W1M1L1 – Intro to Kidney
Kidney Function
• ECF volume maintenance• Excretes metabolic
wastes• Adjusts urinary
water excretion• Endocrine• Renin, angiotensin,
prostaglandins, bradykinin
• Erythropoetin• 1, 25 dihydroxy
vitamin D
Clinical Presentation of Kidney Disease
• Pain• Midback pain
• Urinary Abnormalities• Protein in urine• Blood in urine
• Hypertension• Asymptomatic!
Control of GFREfferent Arteriole
• Prostaglandins cause vasodilation of efferent arteriole• Decrease GFR
Afferent Arteriole
• Angiotensin constricts the afferent arteriole• Decreases
GFR
Macula Densa
• Samples contents of arterioles, and produces vasoconstrictive / vasodilatory hormones• Low GFR -> High salt load to the distal nephron
Determinants of GFR
Oncotic pressure
• Pressure due to protein concentration difference in plasma vs filtrate (acts against filtration)
Hydrostatic Pressure
• Outward force pushing blood into glomerulus (filtration)• Can be considered “what is left of blood pressure”
GFR Calculation
• Total GFR = snGFR x nephron mass• snGFR = filtration rate of a single nephron
= unit permeability capillary wall x net pressure gradient (Starling Force) = LpS x [ (P(gc – bs) – OP (gc – bs) ]
- Lp = permeability capillary wall, S = surface area of capillary
Renal Failure
• GFR is a measure of renal function. Decreased GFR indicates renal failure• Causes of renal failure (reduced GFR)• Reduced number of glomeruli
• Surgical removal of kidney tissue• Drop out of individual glomeruli, as in aging
• Reduction in snGFR• Reduced renal plasma flow (shock)• Increased oncotic pressure
OP bs is usually negligible
GFR Estimation
• GFR estimation = The amount of filtration of the ideal filtration marker• Ideal filtration marker characteristics• Freely filtered• Not protein bound in plasma• Not secreted or reabsorbed• Endogenously produced• Easily measured
Filtration Markers
• Inulin• Freely filtered, not protein-bound in plasma, not secreted or reabsorbed. • BUT not endogenously produced. So not measured clinically
• Creatine• Freely filtered, not protein-bound, in plasma, not reabsorbed, slightly secreted• Produced endogenously from muscle• Tends to overestimate GFR
•Blood Urea Nitrogen (BUN• Not produced at a constant rate. • Reabsorbed – clearance decreases with volume depletion (BUN:creatinine ratio
increases)
• Glomerulus Permselectivity• The glomerular basement membrane has charge
selectivity and size selectivity• Water and small molecules pass freely • Macromolecules ( > 5nm ) do not pass• Albumin (3.6 nm) passes in small amounts
Glomerular Selectivity
Slit Diaphragm
• Podocytes form slit pores, through which small molecules can pass• The slit diaphragm contains nephrin
Slit diaphragm, made of nephrin
• Indication of damage to the glomerular filtration barrier• Degree• < 200 mg / day = Normal• 30 – 300 mg/ day = Microalbuminurea• > 300 mg / day = Proteinurea• > 3 g / day = Heavy proteinurea
Proteinurea
• Definition• Syndrome of four conditions
• Heavy proteinurea• Hyperlipidemia
• The body makes more lipids to compensate for the lost albumin
• Hypoalbuminemia• Edema
Nephrotic Syndrome
• Common Causes of Nephrotic Syndrome• Minimal Change Nephrotic Syndrome
• Commonest cause of nephrotic syndrome in children (unusual in adults)
• LM = normal glomeruli (kidney looks normal!)• EM = foot process effacement• Responds to corticosteroids
• Focal and Segmental Nephrosclerosis• LM = segmental sclerosis and hyalinosis• May be primary or secondary
• HIV patients – most common cause of glomerular disease
W1T1L2 – Regulation of Salt and Water
Fluid compartments
60% of body mass is water
2/3 of body’s water is inside cells!
1/3 of body’s water is outside cells!
Plasma and Body Osmolality
Plasma osmolality = Body osmolality = 2 x Na + glucose / 18 + BUN / 2.8 ~ 2 x Na
• Na, glucose, and urea nitrogen are the most abundant electrolytes. In the body • Na and its counter ions are the single most abundant, so osmolality can be estimated with 2 x Na alone• Normal – 280-290
Effective Solute = solutes that can’t move across cell membrane (Na, glucose)
Ineffective Solute = solutes that can move in and out of cell membranes (urea)
Effective and Ineffective Solutes
Osmoregulation vs Volume Regulation
Osmoregulation Volume Regulation
What is sensed? Plasma osmolality Effective circulating volume
What are the sensors?
Hypothalamic osmoreceptors
Carotid sinusAfferent arterioleAtria and ventricles
What are the effectors?
ADH -> H2O excretionThirst -> H2O intake
Sympathetic NSADHRAAS -> Na+ retentionANP -> Na excretion
What is affected? Urine osmolalityWater intake / excretion
Urinary Na and water excretionThirst
Osmoregulation vs Volume Regulation
Osmoregulation Volume Regulation
What is sensed? Plasma osmolality Effective circulating volume
What are the sensors?
Hypothalamic osmoreceptors
Carotid sinusAfferent arterioleAtria and ventricles
What are the effectors?
ADH -> H2O excretionThirst -> H2O intake
Sympathetic NSADHRAAS -> Na+ retentionANP -> Na excretion
What is affected? Urine osmolalityWater intake / excretion
Urinary Na and water excretionThirst
Note ADH is used to control osmoregulation and volume regulation. When volume is depleted (drastically), it will sacrifice osmolality balance and cause water retention
Common Na / Volume Balance Clinical Scenarios
Infusion of Normal Saline
Effective circulating volume (ECV) increase
Carotid sinus, afferent arteriole, and atria and ventricles sense ↑ECV
Infusion of Normal Saline
↓SNS, ↓ADH, ↓RAAS, ↑ANP (Na excretion)
Urinary Na and water excretionDecreased thirst
Common Na / Volume Balance Clinical Scenarios
Drinking water
↓Plasma osmolality
↓Hypothalamic osmoreceptor firing
Free water Ingestion
↓ADH
↓water permeability at late distal tubule and collecting duct
↓water urine osmolality↑ urinary volume
Increases plasma osmolality toward normal
Common Na / Volume Balance Clinical Scenarios
Eat potato chips
Intracellular water shifts to extracellular space (↑ECV)
↓Hypothalamic osmoreceptor firing
Eating potato chips!
↓ADH
↓water permeability at late distal tubule and collecting duct
↓water urine osmolality↑ urinary volume
Increases plasma osmolality toward normal
W1T2L3 – Sodium Disorders
Hepatorenal Syndrome
Pathophysiology
W1W1L4 – Disorders of K+ Balance
Hyperkalemia
Pathophysiology
Hyperkalemia
Pseudohyperkalemia True Hyperkalemia
Hyperkalemia Pathophysiology
Hyperkalemia
Pseudohyperkalemia True Hyperkalemia
Leukocytosis• WBC > 100,000
Thrombocytosis• Plt > 1,000,000
Release of K+ during blood clotting
Hyperkalemia
Pseudohyperkalemia True Hyperkalemia
Hyperkalemia Pathophysiology
Redistribution
Tissue Necrosis
Hypoaldosteronism
Decreased urinary K secretion
Voltage-dependent secretory defect
True Hyperkalemia
Hyperkalemia Pathophysiology
Redistribution
B-adrenergic activity / insulin
Metabolic Acidosis
Hyperosmolarity
True Hyperkalemia
Hyperkalemia Pathophysiology
Tissue Necrosis
Tumor lysis
Rhabdomyolsis
In vivo hemolysis
True Hyperkalemia
Hyperkalemia Pathophysiology
Hypoaldosteronism
• Aldosterone• Aldosterone causes Na+
reabsorption and K+ excretion
• Lack of Aldosterone causes decreased K excretion, causing hyperkalemia
• Causes of hypoaldosteronism• Type IV RTA• Adrenal insufficiency• NSAIDs, ACEI, ARB, heparin
• (review)
True Hyperkalemia
Hyperkalemia Pathophysiology
Voltage-dependent secretory defect
Tumor lysis
Rhabdomyolsis
In vivo hemolysis
True Hyperkalemia
Hyperkalemia Pathophysiology
Decreased urinary K secretion
Tumor lysis
Rhabdomyolsis
In vivo hemolysis
Hyperkalemia
Hyperkalemia Treatment
Antagonism of K
Drive K into cells
Remove K from the body
Hyperkalemia
Hyperkalemia Treatment
Antagonism of K
Drive K into cells
Remove K from the body
Calcium• Check how this works
Hyperkalemia
Hyperkalemia Treatment
Antagonism of K
Drive K into cells
Remove K from the body
Insulin and glucose
Sodium bicarbonate
B2 – adrenergic agonist
Hyperkalemia
Hyperkalemia Treatment
Antagonism of K
Drive K into cells
Remove K from the body
Diuretics
Cation exchange resin• Kayexelate
Dialysis
True Hypokalemia
Extra-renal causes Intra-renal causes
Hypokalemia Pathophysiology
↓K intake
↑ Sweat loss Redistribution
↑ GI Loss
W1W2L5 – Acute Kidney Injury
Acute Kidney Injury
Definition / Significance
• Acute Kidney Injury (AKI)• Sudden impairment in kidney function
• Increase in serum creatinine, BUN• Decrease in urine output
• Time course• Hours or days• Contrast with rapidly progressive renal failure (weeks to months)
and chronic kidney disease ( > 3 months)• Significance
AKI Pathophysiology
Pre-renal
Intrinsic renal
Post-renal
• Glomerular filtration falls due to inadequate renal perfusion• Causes• Hypovolemia• Cardiac Causes• Liver disease
• Hepatorenal syndrome
• Nephrotic syndrome
• Renovascular
AKI Pathophysiology
Pre-renal
Intrinsic renal
Post-renal
• Glomerular• Acute glomerulonephritis
• Tubulointerstitial • Acute tubular necrosis
• MOST IMPORTANT CAUSE• Acute tubulointerstitial nephritis• Intra-tubular crystal deposition
• Vascular• Vasogenic• Microangiopathic hemolyic
anemia • Cholesterol Emboli
AKI Pathophysiology
Pre-renal
Intrinsic renal
Post-renal
• Acute tubular necrosis• Classification
• Ischemic ATN• Toxic ATN
• Pathophysiology
AKI Pathophysiology
Pre-renal
Intrinsic renal
Post-renal
• Acute tubulointerstitial nephritis• Pathophysiology
• Usually reaction to medications• Beta lactams• PPI’s
• May be associated with fever, skin rash
AKI Treatment
•
W1Th1,2L6,7 – Glomerular Diseases
Normal Renal Anatomy and Histology
• Glomerular Histology• Glomerulus – a network of
anastomosing capillaries lined by endothelial cells and covered by epithelial cells
Glomerular Anatomy
Endothelium of BV
Foot processes
Mesangium
Basement membrane• Covers both endothelium and mesangium
Electron Microscopy of Glomerulus
Podocytes• The presence of podocytes indicates we’re in Bowmna’s space
Mesangial matrix
Mesangial cell
Normal Glomerulus
Bowman’s space
Arteriole lumen
Mesangial matrix
Electron Microscopy of Glomerular Capillary
Endothelial layer
Mesangium
Capillary lumen
RBC
Podocytes
Bowman’s space
Parietal epithelial cell
Electron Microscopy of slit diaphragms
Slit diaphragms
Glomerular Disease Terminology
• Number of glomeruli• Focal – involving few glomeruli ( < 50%)• Diffuse – involving most glomeruli ( > 50% )
• How much of one glomeruli• Segmental – involving only a portion of one
glomerulus• A “segment” of one glomeruli
• Global – involving most of one glomerulus
Segmental sclerosis – only a portion of one glomerulus
Glomerular Histopathology
Glomerular hypercellularity• Increased number of
inflammatory cells in the capillary loops
• The lumens are closed from too many cells
Glomerular Injury (and Histopathology )
Types of Injury• Nephrotic Syndrome• Membranous nephropathy• Minimal change nephropathy• Focal and segmental
glomerulonsclerosis• Amyloidosis• Diabetes• Alport’s syndrome
•Nephritic Syndrome• Post streptococcal
glomerulonephritis• IGA nephropathy (Berger’s Disease)• Crescentic Glomerulonephritis• Alport’s syndrome
• Pauci-immune glomerulonephritis• Anti-GBM disease• Henoch Schonlein purpura
Nephrotic Syndrome
Overview
Membranous Nephropathy
• Most common cause of nephrotic syndrome in adults• Pathophys • Subepithelial immune complex deposits• Granular IgG and complement by IF• Thickened basement membranes
• Classification• Primary
• Autoimmune disease• Secondary
• Infections• Malignancy• Rheumatologic
Nephrotic Syndrome
Microscopy
Membranous Nephropathy
• LM – Glomeruli enlarged and hypercellular, neutrophils, “lumpy bumpy appearance”
• EM – subepithelial immune complex (IC) humps• “spikes” of basement membrane between deposits
•IF – granular apperance due to IgM, IgG, and C3 deposition
Nephrotic Syndrome
Overview
Minimal Change Nephropathy
• Most common cause of nephrotic syndrome in children• Pathophys• LM - Normal glomeruli• IF - negative • Increased lipoproteins in proximal tubular epithelial
cells• Associated with T cell disorders
• Frequently follows viral disorders• Can be presenting symptom of Hodgkin’s
lymphoma• Treatment• Treated with steroids• Children usually don’t need biopsy
Nephrotic Syndrome
Microscopy
Minimal Change Nephropathy
• LM – Normal glomeruli • EM – podocyte effacement
•IF – Negative
Nephrotic Syndrome
Overview
Focal Segmental Glomerulosclerosis
• Nomenclature• Focal – some but not all glomeruli• Segmental – only a portion of one glomerulus (one
segment)• Progression• Sclerosis progresses to diffuse and global
• Classification• Primary• Secondary
• Part of glomerular ablation nephropathy • Due to hyperfilation of remaining
glomeruli• Congenital
• Mutation in nephrin, podocin
W1F1L8 – Acid / Base
Bicarbonate – Carbon Dioxide System
• Acute Kidney Injur
W1F1L9 – Case Presentation, Acute Kidney Disease
Acute Kidney Injury
• Overview• Markers
• Electrolytes• Creatinine
• Men – usually less than 1.5• Women – less than 1.3• Reflective of amount of muscle
• BUN• Normally 5-25• A waste product
• Extracellular volume• Urinalysis
• Dipstick• FeNa• Renal Ultrasound
Acute Kidney Injury
Pre-renal
Intrinsic renal
Post-renal
• Glomerular• Acute glomerulonephritis
• Tubulointerstitial • Acute tubular necrosis
• MOST IMPORTANT CAUSE• Acute tubulointerstitial nephritis• Intra-tubular crystal deposition
• Vascular• Vasogenic• Microangiopathic hemolyic
anemia • Cholesterol Emboli
Mechanism of Acute Kidney Injury
Volume ↓ Prerenal
Renal Vascular: Stenosis, vasculitis
Acute Glomerulo-
nephritis
Acute tubular damage
Interstitial damage
Post-renal Obstruction
Mechanism of Acute Kidney Injury
Volume ↓ Prerenal
Renal Vascular: Stenosis, vasculitis
Acute Glomerulo-
nephritis Acute tubular damage
Interstitial damage
Post-renal Obstruction
• Urinalysis with urine sediment: Red cell casts are pathognomonic
• Urinalysis with urine sediment: Renal tubular cell casts are suggestive
• Urinalysis with urine sediment: RBCs with NO RBC casts
• Orthostatic hypotension, low BP
Acute Kidney Injury
Overview
• Case 1 – Volume Depletion• 50 yo man with low blood pressure, especially upon
standing. Creatinine elevated. Negative urinalysis• Diagnosed with acute renal failure due to volume
depletion• Next diagnostic step: Get FeNa – it should be less
than 1%, because body is trying to hold on to Na+• Treatment: Give patient PO intake and aggressive
hydration (restore volume quickly• Case 2 – Post renal obstruction• 60 yo man with increased urgency, frequency, and
hesitancy of urination. Has not urinated for more than 24 hours. BUN 140, Cr 6.
• Diagnosed with post renal obstruction• Treatment: Placement of bladder catheter. Send
him to ICU and be sure to decompress bladder slowly
Acute Kidney Injury
• Case 3 – Volume Depletion• 22 yo with right flank pain, red colored urine,
swelling of lower extremities, and sore throat. BP 160/11, some edema. BUN 60, Creatinine 5.2.
• Diagnosed with acute glomerulonephritis. • Next diagnostic step: Urinalysis with urine
sediment. The presence of red blood cell casts would be diagnostic for glomerulonephritis
• Confirm diagnosis: Serum complement levels. They should be low due to consumption. If C3 is low, there are 3 possibilities: post infectious GN, lupus, or MPGN (membranoproliferative GN
•Case 4– Post renal obstruction• 82 yo female with obstructive gall bladder disease.
Temp 102. Small woman with no recent weight changes. On Gentamicin, amikacin, for six days. On sixth day, BUN 50, Cr 4.5
• Diagnosed with acute tubular necrosis due to drug toxicity.• Next diagnositc step: urine sediment. Look for
renal tubular cell casts
Acute Kidney Injury
• Case 4 (continued)• Be careful when interpreting elevated Cr. ↑ Cr and
↓GFR are normal with advanced age• Treatment: Withdraw nephrotoxic agents
• Case 5 – Acute Interstitial Nephritis• 35 yo female with dysuria. Given ampicillin for UTI.
Has a skin rash and fever. BUN 75, Cr 5. Lots of RBCs in urine but no casts.
• Diagnosed with acute interstitial nephritis. • Presence of RBCs but NO RBC casts indicates
the cells did not pass through the glomerulus. They must have entered directly through the glomerulus
• Next diagnostic step: Eosinophiluria• Treatment: Withdrawal of ampicillin and prescribe
oral or IV steroids • Case 6 – Acute tubular necrosis due to rhabdomyolysis• Long shoreman with crush injury. BP 90 / 70. Redfish