2. Urinary System Disorders

ANSWER: B

-> albumin a protein in blood, and stays in blood

In a healthy glomerulus, where would you find albumin?

a. In the filtrate 

b. In the capillary lumen

ANSWER: D

• glucose is smaller 

• glucose is freely filtered @ the glomerulus, starts there and filtered thru lumen, cross Basement Membrane go thru tubule 

• hence D is the answer 

• Same with Na, any electrolyte, a.a’s, water

IN a healthy glomerulus, where would you find glucose?

a. Filtrate

b. Basement membrane 

c. Capillary lumen 

d. Everywhere 

Glomerular Disorders

• Generally referred to as glomerulopathies

  • Alterations to glomerular structure and function – endothelium, basement membrane, and/or podocytes

• Course of the disease

• Proportion and parts of glomeruli effected

• Histological

Glomerular disorders Can be classified according to:

• ________________:

  • Acute, rapidly progressive, chronic, insidious

• _______________________________:

  • Diffuse vs. focal; global vs. segmental

• __________ characteristics:

  • Minimal change, proliferative, membranous, sclerotic

• Etiologies

  • Primary vs. secondary vs. hereditary

These terms are sometimes combined to describe the glomerular abnormality

• Diffuse: All or nearly all glomeruli are involved

• Focal: Only some glomeruli are involved → concentrated in an area

Diffuse vs. focal glomerulopathies

global: The entire glomerular tuft is involved

segmental: Only a portion (segment) of the glomerular tuft is affected

global vs. segmental glomerulopathies

Glomerulopathies

Commonly result in:

• Proteinuria

• Hematuria

• RBC casts

• Decreased GFR

• Hypertension

Nephrotic syndrome

• Excessive (>3-3.5g/24 hr) loss of proteins in urine

  • Due to damage to podocyte slit pore proteins and increased glomerular permeability → proteins escape from capillaries into tubule

Nephritic syndrome

• Hematuria and RBC casts

  • will also have proteinuria but isnt a massive characteristic

• Due to glomerular inflammation and leakiness

Proteinuria

• Glomerular filtration membrane is made of three layers

• Endothelial cells, basement membrane, filtration slits (podocytes)

• Podocytes ultimately control what can pass through

  • Small proteins (e.g. cytokines, insulin) can cross slit diaphragm, but anything larger is prevented from crossing

• podocyte damage

• Proteinuria usually indicates _______________

  • Changes in slit diaphragm; increased permeability

  • Hallmark: presence of large proteins like albumin in urine

Hematuria

• Blood can come from anywhere in urinary tract

  • May indicate urological OR renal disorders

• ________________ usually indicates physical disruption to filtration membrane

• RBC fragments isolated from urinary casts often have abnormal shape

Glomerulonephritis

Variety of immune -mediated conditions that cause glomerular inflammation

• Primary

• Secondary

Etiology of Glomerulonephritis

• _______:

  • Autoantibodies against glomerular antigens

• _________:

  • Infectious or Autoimmune → from somewhere else in the body

    • Circulating antibody complexes get trapped in glomerular membrane

  • Metabolic (e.g. diabetes)

  • Hemodynamic (e.g. hypertension)

  • Toxic (e.g. drugs, chemicals, radiation)

• glomerular

Pathogenesis of Glomerulonephritis:

• Immune complex deposition or other causes of glomerular damage

• Recruitment of immune cells

• Damage to _________ BM → BM thickening → scarring → decreased GFR 

• Proteinuria and/or hematuria

• Hematuria

• Proteinuria and hypoproteinemia = edema

• Vulnerability to infections (loss of immunoglobulins)

• Vitamin D insufficiency (loss of vitamin D-binding protein)

• Edema → decrease plasma proteins

• Hyperlipidemia and lipiduria (fatty casts) → excessive compensation 

• Thrombotic complications (increased hepatic synthesis of clotting factors) → leans towards pro coag 

• Hypertension → decreased excretion = decreased GFR => positive feedback loop with damage to kidney further decline in GFR

• Renal impairment – uremia → mild toxicity, oliguria

Signs and symptoms of Glomerulonephritis

• Urinalysis (proteinuria, hematuria, WBCs, RBCs, casts)

• Serology (antibodies, creatinine, BUN, GFR measurements)

• Renal biopsy → find out type

Diagnosis of Glomerulonephritis

• Treat underlying disease

• Blood pressure control – ACE inhibitors

• Diet – salt restriction, protein and vitamin D supplements

• Diuretics

• Anti-hyperlipidemic drugs – e.g. niacin, statins

• Anti-coagulants

• Immunosuppressive agents – e.g. corticosteroids

• Dialysis

• Kidney transplant

treatment of Glomerulonephritis

• Some forms spontaneously recover

• Some forms are treatable

• Causes ~25% of end-stage renal failure

Prognosis of Glomerulonephritis

Nephrotic syndromes

Two Main Clinical Patterns - ______________:

• Characterized by proteinuria

  • Minimal change disease

  • Membranous nephropathy

  • Focal segmental glomerulosclerosis

Nephritic syndromes

Two Main Clinical Patterns -_______________:

• Characterized by hematuria

  • Acute proliferative glomerulonephritis

  • IgA nephropathy

  • Crescentic glomerulonephritis

ANSWER: C 

• if it said characterized then its nephrotic 

• in this case both have proteinuria, as if we have enough hole for RBC to go thru = also proteins go thru inapprop filtration membrane and enter kidney tubule

Proteinuria is associated with..

a. Nephritic syndromes

b. Nephrotic syndromes 

c. Both

d. Neither

ANSWER: A

Hematuria is associated w/…

a. Nephritic syndromes 

b. Nephrotic syndromes 

c. Both 

d. Neither

Answer: D

• Glucose starts in blood, goes into tubule, and gets reabsorbed, in the tubules 

• If its in urine (glycosuria) 

• If we have a problem with podocytes, does this effect flow of this, no

• If we have problem w/ inflam here in glomerulus and RBC here, does this effx glucose = no

• What would need to be defective to get glucose in urine = the tubular cells = tubulointerstitial disorders = glucose in urine 

• But nephrotic and nephritic = no impact on tubules - hence nothing to do w/ glycosuria or not

Glycosuria is associated with..

a. Nephritic syndromes 

b. Nephrotic syndromes 

c. Both 

d. Neither

The Normal Glomerulus

• Open capillary loops

• Sharp glomerular basement membrane

Nephrotic Glomerular Disease

• Damage to podocytes and loss of the negatively charged glycoprotein barrier lead to increased filtration of proteins into urine

• Changes to slit membrane; increase in podocyte/glomerular permeability

• Massive proteinuria (>3.5 g/24hr)

• Hypoalbuminemia (<30 g/L)

• Edema

• Hyperlipidemia

• Increased clotting factor synthesis

key features of Nephrotic Glomerular Disease

Minimal Change Disease

Compare the glomeruli in these light microscopy images:

• Open capillaries

• Sharp glomerular basement membrane

• Loss of digitating processes

Minimal Change Disease

Compare the podocytes in these scanning electron microscopy images:

• _______________ and podocytes become more permeable

Minimal Change Disease (previously Lipoid Nephrosis)

• Most common cause of childhood nephrotic syndrome

• Accounts for ~10% of nephrotic syndrome in adults

• Allergic or immune disorder → systemic T or B cell dysfunction → release of glomerular permeability factor → fusion of podocyte processes and loss of negatively charged proteoglycans

Pathogenesis of Minimal Change Disease

• Biopsy showing normal-appearing glomeruli on light microscopy

• Absence of complement or immunoglobulin deposits on immunofluorescence microscopy

Diagnosis of Minimal Change Disease

• Most patients are responsive to glucocorticoid treatment

• Remission of proteinuria in ~90% of cases

Prognosis of Minimal Change Disease

Membranous Nephropathy

Compare the glomeruli in these light microscopy images:

• Thickening of glomerular basement membrane

• Number of cells unchanged

Membranous Nephropathy

Compare the podocyte processes in these electron microscopy images:

• Dark patches (D) scattered within a thickened glomerular basement membrane (GBM)

primary glomer?

• Antibodies against antigens on podocyte foot processes → complement activation and MAC formation → loss of slit membrane integrity

• Injured podocytes secrete ECM proteins → GBM thickening

Pathogenesis of Membranous Nephropathy

• Complete or partial remission in some patients

• Others have persistent nephrotic syndrome that may proceed to end-stage renal disease

Prognosis of Membranous Nephropathy

ANSWER: B

• need to be able to dx based on images for tests & underlying etiology/patho

Membranous nenprhaty is caused by…

a. Prior step infection

b. Autoimmune attack of podocyte processes

c. Immune cell release of soluble factors

d. Accumulation of immune complexes

Focal Segmental Glomerulosclerosis

Compare the glomeruli in these light microscopy images:

• Deposition of excess matrix (pink material)

• Rest of glomerulus looks normal

Focal Segmental Glomerulosclerosis

Compare the podocyte processes in these electron microscopy images:

• Loss of normal podocyte architecture

Focal Segmental Glomerulosclerosis

• Found in ~35-50% of adult patients with idiopathic nephrotic syndrome

• Putative circulating permeability factors

  • Some patients develop recurrent FSGS after kidney transplant

  • Plasmapheresis reduces proteinuria in these patients

• Nephron injury or loss → decreased podocyte density in focal areas

• Nephron damage → cytokine release → accumulation of ECM components → scar formation

pathogensis of Focal Segmental Glomerulosclerosis

• Some patients are responsive to glucocorticoids

• Some patients develop rapidly progressive renal failure

prognosis of Focal Segmental Glomerulosclerosis

Nephritic Glomerular Diseases

• Destruction of glomerular filtration membrane (due to inflammation) leads to presence of red blood cells in urine

• Hematuria

• Proteinuria (may reach nephrotic range)

• Edema from sodium and fluid retention

• Hypertension

Key features of Nephritic Glomerular Diseases

Acute Proliferative Glomerulonephritis

Compare the glomeruli in these light microscopy images:

• Poorly defined capillary loops

• Increased number of cells

Acute Proliferative Glomerulonephritis

Compare these electron microscopy images:

• Dark patches (D) showing subepithelial immune deposits

• Neutrophil attached to GBM

Acute Proliferative Glomerulonephritis

• Most commonly caused by prior infection with group A β- hemolytic streptococcus (GAS)

• Most common cause of acute nephritis in children

• GAS infection → deposition of streptococcal antigens in the GBM → antibody binding and inflammatory response

pathogensis of Acute Proliferative Glomerulonephritis

• Clinical findings of acute nephritis + evidence of recent GAS infection (throat or skin culture, or serum antibodies)

• impetigo, cellulitis, necrotizing fasciitis

diagnosis of Acute Proliferative Glomerulonephritis

• Generally favourable (self-resolving), especially in children

• <1% of cases proceed to rapidly progressive GN

prognosis of Acute Proliferative Glomerulonephritis

IgA Nephropathy

Compare the glomeruli in these light microscopy images:

• Segmental areas of increased mesangial cell matrix

IgA Nephropathy

Compare these electron microscopy images:

• Immune deposits (D) limited to mesangial regions

• GBM appears normal

IgA Nephropathy

• Most common cause of GN worldwide

• Peak incidence during age 10 – 30, predominantly in Asian and Caucasian populations

• Often triggered by upper respiratory tract / GI infections → mucosa

• Mesangial deposition of circulating IgA immune complexes

• Impaired clearance of the complexes

• Injury, inflammation and scarring

pathogensis of IgA Nephropathy

• Biopsy and IgA immunofluorescence staining

diagnosis of IgA Nephropathy

• Supportive measures (e.g. BP control, ACE inhibitors)

• Glucocorticoids to treat underlying inflammation

treatment of IgA Nephropathy

• Some patients are asymptomatic

• Some patients have one episode of hematuria

• Some patients have recurrent, slowly progressive GN

• Some patients rapidly develop end-stage renal failure

prognosis of IgA Nephropathy

Crescentic Glomerulonephritis

Compare the glomeruli in these light microscopy images:

• Crescent made of proliferating epithelial cells

• Compression of glomerular capillaries

Crescentic Glomerulonephritis

Compare these electron microscopy images:

• Breaks in the GBM

• Fibrin leaks into glomerular capsule → crescent formation

Crescentic Glomerulonephritis

• Characterized by progressive loss of renal function over a short period of time (days to months)

• secondary autoimmune?

• Primary: Anti-GBM antibodies (e.g. Goodpasture’s disease)

• Secondary: Immune complexes (e.g. SLE)

Etiology of Crescentic Glomerulonephritis

• Severe injury to glomerulus → movement of fibrinogen and inflammatory cells into glomerular capsule

pathogenesis of Crescentic Glomerulonephritis

• Biopsy and immunofluorescence staining (e.g. anti-GBM antibodies, antinuclear antibodies)

• Decreased GFR

diagnosis of Crescentic Glomerulonephritis

• Supportive measures (e.g. BP control, ACE inhibitors)

• Glucocorticoids and other immunosuppressive therapies to treat underlying inflammation

• Plasmapheresis

treatment of Crescentic Glomerulonephritis

• Severity of disease depends on underlying cause

• Poor prognosis if patient has anuria

prognosis of Crescentic Glomerulonephritis

ANSWER: B

D) on light graph we would see crescent of prolif epithelial cells & fluids + compression of capillaries = not seen here

C) not minimal change = look very sim 

B and A) expect to see thickening of ECM = and we see that

What do we look to see to differentiate between the two = # of cells

→ not that many extra cells seen 

• Lets use the high tech microscope to see and confirm this 

• Podocytes are changed

• Deposition of material between podocytes but rest looks okay

• Consistent w/ dx of membranous nephropathy = caused by what?

What type of GN is this? How do you know?

a. Acute proliferative GN

b. Membranous nephropathy

c. Minimal change disease

d. Rapidly progressive GN

Tubulointerstitial Disorders

• Disorders that affect renal tubular structures and the surrounding tissues

• Altered tubular function → loss of sodium and water, retention of H+

• Pyelonephritis

• Tubulointerstitial nephritis

Two principle forms of Tubulointerstitial Disorders:

• _______________

  • Infectious causes (covered in UTIs)

• _________________________

  • Non-infectious causes

• Analgesics (e.g. aspirin, NSAIDs)

• Antibiotics (e.g. penicillin, tetracycline, streptomycin)

• Diuretics

• Heavy metals

• Toxins (e.g. mushroom poisons)

etiology of Tubulointerstitial Nephritis

• Damage to nephron tubules → inflammation of kidney interstitum → scarring → decline in renal function

• More common in older patients

pathogensis of Tubulointerstitial Nephritis

• Renal tubular acidosis

• Glycosuria and aminoaciduria

• Electrolyte wasting

• Oliguria → hypertension

• Azotemia (increased nitrogen substances in blood)

• Renal failure

manifestations of Tubulointerstitial Nephritis (depends on toxin, dose, and exposure)

• Elevated serum creatinine

• Urinalysis showing WBCs and WBC casts

• Biopsy

diagnosis of Tubulointerstitial Nephritis

• Remove underlying cause

• Glucocorticoids

• Supportive treatment for hypertension, electrolytes

treatment of Tubulointerstitial Nephritis

• Acute cases: (partial) recovery usually occurs if offending substance removed

• Chronic cases: inflammation and scarring cause irreversible loss of function

prognosis of Tubulointerstitial Nephritis

Renal Failure

Condition in which the kidneys:

• Fail to remove metabolic waste products from the blood

• Fail to regulate fluid → fluid overload = HTN, electrolyte → Increased K+ → lack secretion, and pH balance of the extracellular fluids

• ALL LEAD TO DECREASED GFR

• Acute

• Chronic

Two forms of Renal Failure:

• ______ – rapid onset, potentially reversible

• __________– develops slowly, irreparable damage

Acute Kidney Injury (AKI)

• Occurs in ~10% of hospitalized patients and 50% of patients in the ICU, with mortality rate ~40 – 75%

• Abrupt decrease in renal function characterized by decreased GFR

• Pre-renal

• Intra-renal

• Post-renal

etiology of Acute Kidney Injury (AKI)

Pre-Renal Kidney Injury

• AKI that results from diminished renal blood flow

• Hypovolemia

  • Dehydration

  • Hemorrhage

  • Diuretics

  • Vomiting or diarrhea

  • Burn injuries

• Decrease in circulating volume → still have fluid BUT NOT IN VESSELS

  • Shock – anaphylaxis, sepsis → mass vasodilation → decrease BP → decrease GFR

  • Third-spacing and edema → Alcholic liver disease → busy metaboliziing ethanol = decreased production of albumin

  • Decreased cardiac output (e.g. heart failure, myocardial infarct)

• Renal hemodynamic abnormalities

  • Renal artery occlusion

  • Drugs that interfere with renal autoregulation (e.g. NSAIDs, ACE inhibitors) → NSAIDS block COX-1 → produces prostaglandins → vasodilation of Afferent arteriole → remain too constricted

etiology of Pre-Renal Kidney Injury

• Oliguria

• Elevation of BUN:creatinine ratio

  • decreased GFR → travel through tubule slowly → increased BUN/Cr ratio

  • increased GFR → fast through tubule → decreased BUN/Cr ratio

• Activation of RAA system → renal vasoconstriction → increased vol by production of renin = fluid reab

• Renal hypoxia and tubular cell death if blood flow <25% of normal

manifestations of Pre-Renal Kidney Injury

• Restore adequate perfusion

• Can be reversed if cause is identified and corrected before damage occurs

treatment of Pre-Renal Kidney Injury

Post-Renal Kidney Injury

• Rare

• AKI that occurs due to bilateral obstruction of urine outflow from kidneys

  • Ureters – e.g. calculi and strictures → space occupying lesion

  • Bladder – e.g. tumours, neurogenic bladder

  • Urethra – e.g. prostate hyperplasia

• Increased capsular hydrostatic pressure = decreased GFR

• Remove obstruction as reestablish urine flow before permanent nephron damage occurs

treatment of Post-Renal Kidney Injury

Intra-Renal Kidney Injury

• AKI that results from damage to kidney structures

  • Glomerular, tubular, interstitial, vascular

  • Note: All cases AKI will eventually involve intra-renal kidney injury if not treated promptly

• Tubular cell injury → acute tubular necrosis

  • Most common cause of intra-renal kidney injury

• Glomerular: Acute GN

• Interstitial: Acute pyelonephritis, interstitial nephritis

• Vascular: Vasculitis, emboli, damage from hypertension

• Tubular: Ischemia, toxins, obstruction

  • Tubular cell injury → acute tubular necrosis

     Most common cause of intra-renal kidney injury

etiology of Intra-Renal Kidney Injury

Acute Tubular Necrosis

• Accounts for ~50% of AKI cases in hospitalized patients

• Tubular epithelial cells are very sensitive to ischemia and toxins

1. Ischemia → RAA activation → vasoconstriction of afferent arteriole

2. Damaged tubular epithelial cells are shed from BM and obstruct tubular flow

• Increasing tubular pressure forces filtrate through tubular BM into interstitial space → tubular back leak

3. Interstitial inflammation

Positive damaging feedback loop

mechanism of injury of Acute Tubular Necrosis

ANSWER: D

• (most common cause of intra-renal AKI) all of the following except for what?

• 2 most common causes = A & B 

• If have damage = need immune resp = WBC come in clean up and cause inflamm 

• If we get inflamm we often get casts in CD = casts get dislodged = in urine and see it = indicative fo renal inflam specific in tubule

• What we dont see is polyuria bc we get reduced GFR = leads to oliguria 

Acute tubular necrosis is NOT associated with:

a. Ischemia 

b. Nephrotoxins 

c. Interstitial inflammation

d. Polyuria

e. Urinary Casts 

1. Prodromal phase

Stages of Acute Tubular Necrosis:

• Decreased perfusion and/or increased toxicity → injury

2. Oliguric phase

Stages of Acute Tubular Necrosis:

• Decrease in GFR → oliguria

• Increased BUN and serum creatinine

• Retention of metabolites

• Fluid retention → hypertension

3. Post-oliguric phase

Stages of Acute Tubular Necrosis:

• Repair of renal tissue – normal function reestablished when damaged is stopped = sable to reverse effects

  • Removal of necrotic cells and casts, and regeneration of renal cells (depends on intact BM)

• however does not happen with everyone → can lead to acute kidney failure

ANSWER: D

• problem is blood flow to kidneys , cause v/c of afferent arteriole = even more lack of blood flow 

• A is incorrect b/c an example of INTRA renal 

• B is incorrect b/c post renal 

• C is incorrect b/c prob w/ intra (part of kidney)

Which of the following is a pre-renal cause of AKI?

a. Acute tubular necrosis

b. Bilateral kidney stones 

c. Glomerulonephritis

d. Severe hypotension 

ANSWER: C

• all forms of AKI, result in decr GFR, hence why they lead to kidney dysfunction 

Which of the following statements is TRUE?

a. Reduced GFR is only peasant in pre-renal AKI

b. Reduced GFR is only present in post-renal AKI

c. Both pre- and post- renal AKI are assoc with reduced GFR

d. Neither is associated with reduced GFR 

ANSWER: E

• Uremia = urine in blood ;stuff that should come out, stays in

• When we have uremia = do we have accum of nitrogenous wastes in the blood

• Anemia d/t EPO, and vit d = calcitriol

• General weakness = effx all body systems

Which of the following is NOT a symptom of uremia?

a. Accumulation of nitrogenous wastes in the blood 

b. Anemia and impaired vitamin D synthesis 

c. General weakness, fatigue, and nausea

d. HTN

e. All of the above are symptoms of uremia

• Oliguria (can last up to 8 weeks)

• Encephalopathy – disorientation, seizures, coma

• Motor and sensory deficits

• Bleeding and anemia → decreased EPO

• Increased risk of infection

• Nausea and vomiting

• Delayed wound healing

Signs and symptoms of Acute Kidney Injury

• Patient history and physical exam

• Urine output

• GFR measurement

• Urinalysis

  • Proteinuria

  • Hematuria

  • Casts or crystals

  • Urine osmolarity, pH, and electrolytes

• Blood tests

  • BUN

  • Creatinine

• Response to volume repletion

diagnosis of Acute Kidney Injury

Treatment – goal is to keep the patient alive until renal function has recovered:

• Acute dialysis

• Discontinuing nephrotoxic drugs

• Early treatment of obstruction

• Fluid and electrolyte management

• Monitoring and adjustment of blood parameters and pressure

• Antibiotics prn

• Diet to maintain nutrition

treatment of Acute Kidney Injury

• Incomplete recovery in 30% of patients

• 60% mortality rate

prognosis of Acute Kidney Injury