block 9 - week 1 summary slides

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


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


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


Leukocytosis• WBC > 100,000

Thrombocytosis• Plt > 1,000,000

Release of K+ during blood clotting

Hyperkalemia



Redistribution

Tissue Necrosis

Hypoaldosteronism

Decreased urinary K secretion

Voltage-dependent secretory defect

True Hyperkalemia


Redistribution

B-adrenergic activity / insulin

Metabolic Acidosis

Hyperosmolarity

True Hyperkalemia


Tissue Necrosis

Tumor lysis

Rhabdomyolsis

In vivo hemolysis

True Hyperkalemia


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


Voltage-dependent secretory defect

Tumor lysis

Rhabdomyolsis

In vivo hemolysis

True Hyperkalemia


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


Antagonism of K

Drive K into cells


Calcium• Check how this works

Hyperkalemia


Antagonism of K

Drive K into cells


Insulin and glucose

Sodium bicarbonate

B2 – adrenergic agonist

Hyperkalemia


Antagonism of K

Drive K into cells


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

block 9 - week 1 summary slides

Documents

late distal

dependent

hypothalamic

hyperkalemia

h2o excretion

water excretion

hyperkalemia

acute kidney