Case 2: Matthew Clarke

Kidney Anatomy: Cortex

Outer layer

• Surround renal medulla

Contain nephrons (corpuscle) and renal tubules (proximal and distal convoluted tubules)

Kidney Anatomy: Medulla

Kidney inner

Contain renal tubules (loop of Henle) and collecting ducts

Connect to minor calyces

Kidney Anatomy: Columns

Renal cortex extensions into medulla

Contain interlobular arteries and veins

Kidney Anatomy: Pyramids

Medullary sections

Formed from renal columns (cortex) projecting into medulla

Kidney Anatomy: Papillae

Renal pyramid apex

Connect to minor calyx

Kidney Anatomy: Nephron

Filtration unit in kidney

Renal corpuscle → Tubules → Collecting ducts → Ureter

Contains renal corpuscle and filtration barrier

Nephron: Renal Corpuscle

Hollow double-layered epithelial cell sphere (Bowman’s capsule)

Layers:

• Parietal: Structural integrity

• Visceral: Podocytes

Contain capillaries and arterioles

• Capillaries: Glomerulus

• Arterioles: Blood transport to and from glomerulus

  • Afferent: Blood to

  • Efferent: Blood away

Renal Corpuscle: Bowman’s Space

Empty space between layers in capsule

Renal Corpuscle: Juxtaglomerular (JG) Apparatus

Between distal tubule and arterioles

Cells:

• Macula Densa: Tubular epithelial cells

• JG: Afferent arterial wall cells

Nephron: Filtration Barrier

Separate plasma (glomerular capillaries) from fluid (Bowman’s space)

3 layers:

• Endothelial Cells: Inner layer

• Basement Membrane: Middle layer

• Podocytes (Epithelial cells): Outer layer

Filtration Barrier: Endothelial Cells

From capillaries

Fenestrae (holes)

• Permeable to blood content

• Impermeable to cells and platelets

Filtration Barrier: Basement Membrane

From capillaries

Glycoprotein and proteoglycan mesh

Filtration Barrier: Podocytes

Pedicels (foot processes) embed in basement membrane

Slit Diaphragms: Covered in ECM = Bridge slits between pedicels

Kidney Physiology: Cortex

Corpuscle: Filtration

Tubules: Solute and water reabsorption

Kidney Physiology: Medulla

Urine concentration

Tubules + Ducts: Maintain concentration gradients for water/ion reabsorption

Kidney Physiology: Columns

Structural support and blood supply to cortex and medulla

Kidney Physiology: Pyramids

Same as medulla

Kidney Physiology: Papillae

Urine concentration

Conduct urine to calyces

Modify urine osmolality

Kidney Physiology: Nephron

Renal Corpuscle

Filtration Barrier

Nephron: Renal Corpuscle

Filtration through glomerular filtration barrier

Arterioles: Vessel tone maintains glomerular filtration rate (GFR)

• Afferent: Vasodilation = Increase filtration

  • Myogenic response

• Efferent: Vasoconstriction = Increase filtration

  • Tubuloglomerular feedback from macula densa

JG Apparatus: Regulate BP, ECF, and electrolyte balance

• Macula Densa Cells: Sense NaCl concentration

• JG Cells: Produce renin

Nephron: Filtration Barrier

Selective filtration

• By size

  • Small Particles: Freely cross (ions, glucose, urea, amino acids)

  • Large Particles: Blocked (albumin, macromolecules)

• By charge

  • Negative: Less filtration

    • Negative coating on filtration barrier repels negative molecules

  • Positive: More filtration

Depend on Starling forces

Filtration Barrier: Starling Forces

Regulate fluid movement between intravascular and interstitial (Bowman’s capsule) spaces

Hydrostatic Pressure: Pressure pushing fluid out

• High intravascular fluid volume (pressure) = Fluid from vessels → Bowman’s capsule

• High Bowman’s capsule volume (pressure) = Fluid from Bowman’s capsule → Vessels

Oncotic Pressure: Pressure drawing fluid in

• High intravascular solutes (low fluid volume/pressure) = Fluid from Bowman’s capsule → Vessels

• High Bowman’s capsule solutes (low fluid volume/pressure) = Fluid from vessels → Bowman’s capsule

Nephrotic Syndrome

Signs and symptoms indicating damage to the glomerular filtration barrier

Usually…

• Proteinuria > 3.5 g/day

• Hypoalbunimeia

• Edema

Nephritic Syndrome

Signs and symptoms indicating glomerular inflammation

• Glomerular hematuria

• Proteinuria < 3.5 g/day

• Hypertension

Nephrotic Syndrome: Epidemiology

Glomerular disorders

Systemic diseases

Toxic exposure

Nephrotic Syndrome: Etiology

Primary/Idiopathic: Common

• Minimal change disease: Flat podocytes

  • After viral infection

  • In children

• Focal segmental glomerulosclerosis: Lost foot processes on podocytes

  • Glomerular lesions

• Membranous nephropathy: Retracted podocytes

  • Thick glomerular capillaries

Secondary:

• Diabetes

• Amyloidosis

• Lupus

• Infection (Hep B and C, malaria)

• Medications (NSAIDs)

• Malignancies

Nephrotic Syndrome: Pathogenesis

Damaged glomerular filtration barrier causing proteinuria/hypoalbuminemia and edema

Nephrotic Syndrome: Proteinuria/Hypoalbuminemia

≥1 filtration barrier layers damaged = Albumin/proteins pass into from blood vessels into urine (filtrate)

Barrier Damage:

• Podocytes: Loss of - charge = Increased albumin filtration (- charge)

• Basement Membrane: Macromolecule filtration = Increased protein filtration (non-selective)

Results:

• High protein in urine

• Low protein in blood

  • Albumin, antithrombin III, vit D binding protein

Nephrotic Syndrome: Edema

Net fluid filtration from plasma into interstitium

Underfill Hypothesis: Intravascular volume depletion

• Decreased plasma albumin concentration = Low oncotic pressure

• Fluid from intravascular space → Interstitial space = Hypervolemia

*Overfill Hypothesis: Intravascular volume expansion

• Renal Na+ retention from epithelial Na+ channel activation = Increase intravascular water reabsorption = High hydrostatic pressure

• Fluid from intravascular space → Interstitial space = Hypervolemia

Nephrotic Syndrome: Clinical Presentation

Edema + weight gain → Position/Gravity-dependent

• Peripheral (lower limbs, presacral area)

• Periorbital

• Pleural effusion

• Pericardial effusion

• Acites

Fatigue

SOB

Hypoalbuminemia

Proteinuria

• Frothy urine

Hyperlipidemia

Nephrotic Syndrome: Investigations

Urine dipstick

Urinalysis

Urine sediment microscopy

Blood test

BP

Biopsy

Nephrotic Syndrome: Urine Dipstick

≥ 3+ proteins

Hematuria

• Not always in nephrotic

• Usually in nephritic (inflammation)

Nephrotic Syndrome: Urinalysis

Protein excretion > 3.5 g/day

Urine protein:creatinine ratio > 3.5 g/g

Nephrotic Syndrome: Urine Sediment Microscopy

Nephrotic sediments

• Lipiduria: Fatty casts + Maltese cross under polarized light

Hematuria

Nephrotic Syndrome: Blood Test

Low serum protein

Low coagulation factors

Hyperlipidemia

Nephrotic Syndrome: BP

If high

• Usually nephritic

• Prescribe diuretics

Nephrotic Syndrome: Biopsy

Determine cause for adults

NOT usually for children

Nephrotic Syndrome: Treatment/Management

Steroids

Diet changes**

Diuretics

RAAS inhibitors

Statins

Nephrotic Syndrome Treatment: Steroids

Idiopathic: Inhibit autoimmune reaction attacking podocytes

Nephrotic Syndrome Treatment: Diet Changes

Decrease Na+, fluids, and protein

Benefits:

• Control edema, BP, and proteinuria

• Prevent metabolic complications (hyperlipidemia)

Risks:

• Malnutrition (low protein, hyponatremia)

Nephrotic Syndrome Treatment: Diuretics

First-Line: Oral loop diuretic

Second-Line: + oral thiazide diuretic, IV loop diuretic

Consider: + IV albumin

Loop Diuretics MOA

Inhibit Na+/K+/2Cl- cotransporter in thick ascending loop of Henle = Decrease Na+ and Cl- reabsorption = Increase water excretion

Ex: Furosemide

Thiazide Diuretics MOA

Inhibit Na+/Cl- cotransporters in distal convoluted tubule = Increase Na+ and Cl- excretion = Increase water excretion

Diuretics: Benefits and Risks

Benefits: Decrease edema (pulmonary, skin breakdown from peripheral)

Risks: Hypovolemia, AKI, electrolyte disturbances (hypokalemia, hypernatremia)

Nephrotic Syndrome Treatment: RAAS Inhibitors

Ex: ACE inhibitor (ramipril), ARB (losartan)

Decrease proteinuria and hypertension

Slow renal disease

NOT for patients with AKI, hyperkalemia, or sudden nephrotic syndrome

Nephrotic Syndrome Treatment: Statins

Decrease lipids

Nephrotic Syndrome: Complications

Thrombotic events (antithrombin loss)

• Thromboembolism

• Renal vein thrombosis

Chronic kidney disease

Atherosclerotic complications

Vit D deficiency

• From vit D binding protein loss in urine

Anemia

• Urinary loss of iron, erythropoietin, and transferrin

Nephrotic Syndrome: Prognosis

90-95% remission

• Children and adults

Fluid Retention: Physical Findings

Weight gain

Ascites

Pulmonary edema (SOB, orthopnea)

Congestive HF

Fluid Retention with Contracted Circulation

Increased intravascular fluid → Interstitial space (misdistribution) = Decreased effective arterial blood volume = Low tissue perfusion

From:

• Low CO (CHF)

• Arterial vasodilation

• Low oncotic pressure

  • Protein loss (kidney disease)

  • Low protein synthesis (liver disease)

Compensatory neurohormonal activation = Increase Na+ and water retention = Worsen edema

• RAAS

• SNS (epinephrine/norepinephrine)

• ADH release (vasopressin)

Prerenal Conditions

Conditions leading to decreased renal perfusion (hypoperfusion) without intrinsic damage

• Hypovolemia

• Hypotension

• Decreased effective arterial volume

• Renal artery stenosis

• Drugs affecting glomerular perfusion

Prerenal Conditions: Kidney Response

Reabsorb Na+ and water = Increase intravascular fluid = Increase perfusion

Prerenal Conditions: Blood Abnormalities

Increased blood urea nitrogen (BUN)/creatinine ratio

• Hypoperfusion → Increased proximal tubular urea reabsorption

Increased serum creatinine

• From impaired filtration → Low GFR

• Normal: 62-106 umol/L

Hemoconcentration: High RBC concentration

• Blood volume loss = Increase solute (RBC) concentration

Prerenal Conditions: Urine Abnormalities

Low Na+

• Hypoperfusion → Increased tubular Na+ reabsorption

High osmolality and specific gravity

• Density of solutes in fluid (compared to water)

  • Osmolality: more precise

  • Specific Gravity:

    • < 1.010: Dilute

    • > 1.020: Concentrated

  • Increased water reabsorption = High urine concentration