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Nichols: Glomerular Disease Flashcards

1
Q

The glomerular compartment made black in this special stain is?

A

The basement membrane

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2
Q

What do each of these colors represent? What are 1 and 2?

A
  • Green: podocytes and foot processes
  • Yellow: basement membrane
  • Purple: endothelium
  • Stippled black and blue: mesangium
  • 1 = endothelial cell (urinary space to the left)
  • 2 = mesangial compartment
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3
Q

Identify the labeled items.

A
  • CL = capillary lumen
  • US = urinary space
  • GBM = glomerular basement membrane
  • Arrows: 3 pedicels from same podocyte
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4
Q

How does the GBM vary by sex?

A
  • GBM of men significantly thicker than that of women
  • Anti-GBM disease is significantly more common in men, especially young white men
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5
Q

What do you see beneath the red arrow? What is surrounding the capillary?

A
  • Fenestrations (seen from the capillary lumen side)
  • Surrounded by interdigitating podocyte pedicels
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6
Q

What do you see here? Why are these important?

A
  • Fenestrations: as much as 50% of capillary surface may be made up of these
  • Lack of a continuous cytoplasmic barrier facilitates filtration and accessibility of macromolecules (incl. antibodies in disease) to the GBM
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7
Q

Are the cells lining the proximal tubule continuous with the podocytes?

A
  • Technically, yes
  • Visceral epithelial cells (podocytes) are in a layer continuous with parietal cells (Bowman capsule), which are continuous with the cells lining the proximal tubule
  • This is so b/c glomeruli form from blood vessels pushing into the blind end of a tube (like the heart pushes into the pericardial sac)
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8
Q

What is pathologic here?

A
  • In conditions causing severe loss of protein through the glomeruli (nephrotic syndrome), electron microscopy frequently shows what looks like fusion of the foot processes (shown here around the two glomerular capillaries) -> EFFACEMENT
  • This is a retraction of foot processes, and loss of the split-pore diaphragm, so it is as though long segments of the capillary are invested by the cytoplasm of a single podocyte (this is a simplification)
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9
Q

What does this illustrate?

A
  • Detachment of foot processes from the basement membrane, and degradation of the GBM, allowing plasma to leak into the urinary space
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10
Q

What is this called?

A

Interdigitation

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11
Q

What is unique about the GBM? Note the various identified structures here.

A
  • Most BM’s are bilaminar, but the GBM is trilaminar
    1. Lamina lucida (or rara) interna (closer to endo)
    2. Lamina densa of double the usual thickness (and double the thickness of the lamina rara)
    3. Lamina rara externa (closer to epithelial cells)
  • Structure represents the embryologic fusion, at the level of the lamina densa, of two BM’s: endo and epi
  • Minimal space b/t 2 pedicels the filtration slit; thin structure bridging that space is the slit pore diaphragm
  • Pore = endothelial cell fenestration
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12
Q

What proteins compose the slit pore diaphragm?

A
  • Multiple types of proteins, all secreted by podocytes
  • Some, such as cadherin and FAT, serve to bind adjacent pedicels
  • Others, like nephrin and podocin play a role in filtration
    1. Mutations in nephrin and podocin genes result in congenital nephrotic syndromes due to loss of lg amounts of protein in urine from defective slit pore diaphragm filtration
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13
Q

What is THE major component of the glomerular GBM?

A
  • Type IV collagen
  • 6 numbered alpha chains, but only 3 alpha chains needed to form a collagen molecule -> significant variability in the composition of individual molecules (and basement membranes)
  • Most alpha chains are in the characteristic helical conformation of collagens, but there is a non-helical globular domain called a “non-collagenous” (NC) domain
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14
Q

What are the 4 major components of the GBM?

A
  • Perlecan: highly charged proteoglycan containing heparan sulfate that imparts most of the charge properties of basement membranes
  • Entactin: glycoprotein with Ca-binding properties
  • Laminin: family of complex glycoproteins formed by three different chains
  • Type IV collage__n
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15
Q

What’s wrong with this guy? How do you know?

History: 17 y/o WM w/recent onset of lower extremity swelling

Physical Exam: BP 135/80 mm Hg (normal), lower extremity pitting edema

Bloodwork: BUN 15 mg/dL (10-20 mg/dl), creatinine 0.9 mg/dL (0.5-1.27 mg/dl), albumin 1.7 g/dl (3.5-5 g/dL)

Urine Analysis: 4+ proteinuria, spot urine protein creatinine ratio = 10.8

Microscopic exam: oval fat bodies, hyaline casts, rare RBCs

A
  • Nephrotic syndrome
  • Key things: normal BP and creatinine, NO RBC casts
  • Additional things: lower extremity swelling, pitting edema, albumin 1.7 (low), 4+ proteinuria, spot urine protein creatinine ration 10.8 (high)
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16
Q

What’s wrong with this guy? How do you know?

History: 16 y/o WF w/ sudden onset periorbital swelling, dark maroon urine, sore throat & upper respiratory tract sx 2 weeks prior, fever x 3 days

Physical Exam: BP 150/105 mm Hg, facial edema, minimal pharyngeal redness

Bloodwork: BUN 32 mg/dL (10-20 mg/dl), creatinine 2.1 mg/dL (0.5-1 mg/dL), albumin 3.7 g/dL (3.5-5 g/dL)

Urine Analysis: 1+ protein, lg amt of blood

Microscopic exam: dysmorphic (abnormal) RBCs, occasional RBC & granular casts, spot urine protein creatinine ratio = 1

A
  • Nephritic syndrome
  • Key things: BP 150/105 (high), BUN 32 (high), creatinine 2.1 (high), dysmorphic abnormal RBC’s, occasional RBC and granular casts, spot urine protein creatinine ratio 1 (normal <0.15)
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17
Q

What are the key features of nephrotic syndrome?

A
  • Prominent edema and roteinuria – nephrotic range (more severe than in nephritic syndrome)
  • Inactive urinary sediment (no RBC or RBC casts)
  • Hypoalbuminemia
  • Hyperlipidemia
  • Non-Inflammatory
  • Normal blood pressure
  • Normal or mild elevation in serum creatinine
  • Key cell involved: visceral epi cell (aka podocyte)
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18
Q

What are the key features of nephritic syndrome?

A
  • Edema (mild) and proteinuria (less severe than in nephrotic syndrome)
  • Active Urinary Sediment: dysmorphic RBCs, and RBC casts
  • Inflammation
  • Hypertension
  • Elevated serum creatinine
  • Crescents on kidney biopsy in very severe forms
  • Key cell involved: endothelial cell
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19
Q

What is this?

A

Urinary dipstick showing proteinuria and hematuria

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20
Q

What’s up with these RBC’s?

A
  • Normal biconcave shaped RBCs
  • Would only see these if you had a kidney stone, or some kind of damage to the ureter, etc.
  • NEED TO KNOW if these are dysmorphic or normal (e.g., if you get a test back that says RBC’s in urine, you want it to indicate whether they are normal or abnormal)
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21
Q

What’s up with these RBC’s?

A
  • Most of the RBCs are abnormal, one normal shaped RBC (in lower, right-hand corner)
  • Dysmorphic RBCs are indicative of damage to glomerular capillary
  • Slide showing urine microscopy
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22
Q

What is this? When might you see it?

A
  • Hyaline cast
  • Fairly non-specific: usually seen in concentrated urine with any renal pathology, such as dehydration, vigorous exercise, use of diuretics, low urine flow, acidic envo
  • Can also be associated different types of proteinuria
  • Solidified Tamm-Horsfall mucoprotein secreted from the tubular epithelial cells of individual nephrons
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23
Q

What do you see? When might you see this?

A
  • White cell casts
  • Can be seen in nephritic syndrome or UTI’s
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24
Q

What do you see? When might you see this?

A
  • RBC cast
  • Can be seen in nephritic syndrome.
  • Only found in glomerular disease
  • Not all nephritic syndromes will have RBC casts, but if you see RBC casts, you can be pretty certain that it is nephritic syndrome
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25
Q

What do you see? When might you see this?

A
  • Granular cast
  • Seen when there is tubular damage from any cause, such as acute tubular necrosis (ATN)
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26
Q

What are the 3 groups of nephrotic syndrome mechanisms?

A
  • Podocyte injury (effacement, fusion): minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS)
  • Subepithelial space immune complex formation & complement activation: membranous nephropathy
  • Glomerular capillary wall deposition diseases: light chain deposition disease, amyloidosis, diabetic nephropathy
  • Nephrotic syndrome is one without inflammation
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27
Q

What are the 3 groups of nephritic syndrome mechanisms?

A
  • Subendo space (b/t endo and BM) or mesangial immune complex formation & complement activation: post-infectious glomerulonephritis (supepi later in the disease, when kidney is usually biopsied), IgA nephropathy, lupus nephritis
  • Abs directed at glomerular BM: anti-Glomerular basement disease (rare)
  • Necrotizing injury and inflammation of the vascular and glomerular capillary wall: antibodies against neutrophil cytoplasmic antigens (ANCA) associated disease (Churg-Strauss, micropolyangiitis, Wegeners)
  • Nephritic syndrome is one with inflammation
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28
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Asymptomatic: only abnormality will be found in lab tests, such as mild proteinuria or hematuria
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29
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Macroscopic hematuria -> IgA nephropathy
  • Hematuria can be present intermittently; have flares, often with upper respiratory infections, but recover spontaneously
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30
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Nephrotic syndrome: membranous nephropathy, FSGS, MCD
  • Large proteinuria
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31
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Nephritic syndrome: dysmorphic RBC’s and RBC casts
  • Hematuria, proteinuria, hypertension, and renal dysfunction
  • Severe form of this nephritic syndrome is rapid progressive glomerulonephritis (RPGN), which will present similar to nephritic syndrome but its progression is rapid -> typical example would be ANCA associated vasculitis, lupus nephritis
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32
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Rapidly progressive glomerulonephritis: lupus nephritis, ANCA vasculitis
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33
Q

What diagnosis does this clinical presentation of glomerular disease suggest?

A
  • Chronic glomerulonephritis: diabetic nephropathy, hypertensive nephropathy
  • Slowly progressing renal dysfunction, along with proteinuia
  • NOTE: in some types of glomerular disease, there is overlap b/t nephrotic and nephritic syndrome. For example, common presentation of lupus nephritis is nephritic syndrome or RPGN, however, it can also present as plain nephrotic syndrome, just as macroscopic hematuria. Similarly common clinical presentation of IgA nephropathy is macroscopic hematuria, however, it can also present as nephritis syndrome and RPGN
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34
Q

What 3 properties of glomerular filtration predispose it to immune complex entrapment or formation?

A
  1. High plasma flow rate (~20% of cardiac output to the kidney)
  2. High intraglomerular pressure
  3. High glomerular hydraulic conductivity (permeability)
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35
Q

What 2 factors determine the spectrum of immune complex kidney disease?

A
  • Nature of the antigen involved
  • Site of immune complex deposition
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36
Q

What is going on at 1-5?

A
  1. Subepi deposits: post-infectious GN (not intrinsic to the podocytes)
  2. Membranous nephropathy (intrinsic to podocytes, so continuous)
  3. Subendothelial (post-infectious GN starts here)
  4. Mesangial deposits: can be formed locally, but more commonly from passive entrapment of circulating ICs (assoc with subendo deposits) -> IgA nephropathy
  5. Anti-GBM Ab Disease: Abs bind in a linear fashion (Goodpasture’s syndrome)
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37
Q

What are the major causes of immune complex mediated glomerular diseases?

A
  • Subepithelial deposits: nephrotic picture
    1. Membranous nephropathy – idiopathic or systemic disorders like SLE, diabetes mellitus, Hepatitis B, drugs (e.g, gold, penicillamine)
    2. Post-infectious glomerulonephritis – seen later in course of disease
  • Subendothelial and mesangial deposits: nephritic syndrome
    1. Focal or diffuse proliferative lupus (SLE)
    2. Post-infect glomerulonephritis – early phase
    3. IgA nephropathy: w/prominent IgA deposits in the mesangium
  • Anti-glomerular BM disease: usually nphritic with crescentic GN -> crescents in the biopsy
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38
Q

What are the 4 common clinical features of nephrotic syndrome?

A
  • Edema: usually generalized, but can be limited to lower extremities only
  • Proteinuria (large): urine protein excretion >50 mg/kg/d, >3.5 g/d in adults, >40 mg/hr/m2 in children
  • Hypoalbuminemia: less than 3.5 mg/dL
  • Hypercholesterolemia/lipiduria: hypoproteinemia stimulates protein syn in liver, so overproduction of lipoproteins, cholesterol, and triglycerides
    1. Normally lipoprotein lipase (LPL) breaks down VLDL (to LDL), but in NS, LPL level decreases (lost in urine), leading to increased level of VLDL
    2. Lipid catabolism DEC due to lower levels of LPL, main enzyme in lipoprotein breakdown
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39
Q

What should you do if there is generalized edema?

A
  • Evaluate for proteinuria
  • Large amount of proteinuria in nephrotic syndrome one of the common cause of generalized edema; other causes include congestive heart failure and cirrhosis of the liver
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40
Q

What are these? When might you see them?

A
  • Oval fat bodies
  • Commonly seen in nephrotic syndrome
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41
Q

What are these? When might you see them?

A
  • Maltese cross
  • Oval fat bodies under polarized light
  • Commonly seen in nephrotic syndrome
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42
Q

What is going on here?

A
  • Xanthelasma -> nephrotic syndrome
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43
Q

What are some things that can occur in both nephrotic and nephritic syndrome?

A
  • Hematuria
  • Proteinuria
  • Edema
  • HTN
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44
Q

What is the primary difference between nephrotic and nephritic syndromes?

A
  • Nephrotic: abnormal filter WITHOUT inflammation
  • Nephritic: abnormal filter WITH inflammation
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45
Q

When might you order a kidney biopsy? What kind of special preparations are in order?

A
  • Purposes: diagnosis, prognosis, guide therapy
  • Slide preparations (unique to renal medical biopsy): a) light microscopy, b) immunofluorescence, c) e- microscopy
    1. Each requires different tissue processing, and all require rapid placement in appropriate preservative -> planning and coordination to have right reagents on hand and right transport
  • NOTE: sometimes dx of glomerular disease can be made on clinical grounds alone, but in many cases a biopsy is required to ascertain the exact diagnosis. In other cases, biopsy allows more precise prognosis (e.g. patients with SLE glomerular disease). Guiding therapy or elucidating a failure to respond to therapy is an indication for biopsy
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46
Q

What are the contraindications for and potential complications with renal biopsy?

A
  • Absolute contraindications: bleeding diathesis, uncontrolled hypertension
  • Relative contraindications: single kidney, high pressure hydronephrosis (swelling of kidney due to buildup of urine), adult polycystic kidney disease
  • Complications: vary from clinically insignificant (microhematuria in 90-100% of cases) to the need for nephrectomy (1/10,000)
    1. Nichols also mentioned potential fatality
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47
Q

Foot process effacement (fusion)

A

Minimal change disease (also seen with FSGS) on EM

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48
Q

Spike and dome

A

Membranous nephropathy on EM

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49
Q

Sub-epithelial humps

A

Post-infectious (commonly strep) glomerulonephritis on EM

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50
Q

Tram tracks

A

Membranoproliferative glomerulonephritis

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51
Q

Basketweave

A

Alport syndrome

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52
Q

Wire loops

A

Lupus nephritis

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53
Q

Onion-skin

A

Hypertensive nephropathy (arterioles)

or

Scleroderma (larger vessels)

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54
Q

What three characteristics limit movement through glomerular filtration barrier?

A
  • Prevents filtration of formed blood elements and proteins into urinary space of Bowman’s capsule due to:
    1. Charge
    2. Size
    3. Shape
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55
Q

What does this graph show?

A
  • Size + charges of the molecule affect the clearance
  • Size barrier: main site of hindrance for larger molecules is lamina densa of GBM and the slit diaphragm -> estimated glomerular pore radius for spherical molecules is 42 angstroms
  • Charge barrier: main site of hindrance is the anionic charge on the lamina rara interna, and on fenestrated capillary endothelium
  • Small size and cationic substances easily filtered
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56
Q

This is the glomerular filtration barrier -> what is important here?

A
  • Two podocyte foot processes bridged by slit mem, GBM, and porous capillary endothelium -> surfaces of podocytes and the endo are covered w/(-) charged glycocalix containing sialoprotein podocalyxin (PC)
  • GBM composed mainly of collagen IV (α3, α4 and α5), laminin 11 (α5, β2 and γ1 chains) and the heparan sulphate proteoglycan agrin
  • Slit membrane: porous proteinaceous mem with nephrin, Neph 1, 2 and 3, P-cadherin and FAT1. β1α3 integrin dimers connect TVP complex (talin, paxillin and vinculin) to laminin 11; the α and β dystroglycans connect utrophin (U) to agrin
    1. Slit mem proteins joined to cytoskeleton by various adaptor proteins, incl podocin, zonula occludens protein 1 (ZO-1; Z), CD2-associated protein (CD) and catenins (Cat). TRPC6 associates with podocin and nephrin at slit mem
  • Among the many surface receptors, only the angiotensin II (ANG II) type 1 receptor (AT1) is shown
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57
Q

How does the size and charge barrier prevent albuminuria?

A
  • BOTH charge AND size affect clearance
  • Uncharged macromolecules < 1.8 nm filter freely
  • Molecules > 4 nm completely restricted
  • Albumin has effective radius of 3.6 nm, so if not for the charge barrier, a significant albuminuria would occur
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58
Q

Why are these proteins important?

A
  • Magnifying view of the slit diaphragm showing the various proteins
  • Dysfunction of each of these protein can lead to one specific type of disease -> all of them will cause nephrotic syndrome
    1. FSGS: alpha-actinin, podocin, TRPC6
    2. MCD-like disease: NEPH-1, p-cadherin, FAT
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59
Q

What are the parameters of the glomerular filtration size barrier? What happens to the proteins that do make it through?

A
  • Molecular weight of proteins:
    1. High: IgG (mol radius 55A) -> completely restricted
    2. Intermediate: albumin (mol radius 36A) -> 1 mg/dL makes it to Bowman’s space
    3. Low: molecular radius <30A (e.g., B2 microglobulin)
  • Almost all proteins that arrive in tubule’s lumen are reabsorbed in prox tubule so only a tiny amt actually excreted in urine -> epithelial cells that line the prox tubule take up protein via endocytosis (multiligand receptor-mediated: megalin, cubulin)
    1. Endocytic vesicles fuse w/lysosomes, proteins are hydrolyzed into AA’s that cross basolateral mem of tubular epi cell and re-enter circulation
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60
Q

What does this image show? How is IG pressure involved?

A
  • Glomerular capillary wall under normal & proteinuric (i.e., nephrotic, nephritic syndrome) states
  • GCW damage to visceral epithelial cells (nephritic) or podocytes (nephrotic)
  • Filtration of substance like albumin is affected by intraglomerular pressure, so if we DEC IG pressure, that will help lower albumin loss, in spite of podocyte injury -> amount of protein that reaches Bowman’s space is a direct fxn of intraglomerular pressure, a target for anti-HTN meds
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61
Q

What does this graph tell you about glomerular permeability in nephrotic syndrome?

A
  • Nephrotic pts have:
    1. Lower excretion of small mol weight dextrans (<48) secondary to loss of filtration surface area (easier to leak through, but amount less due to decreased SA)
    2. Increased clearance of large mol weight dextrans (>52), compared with normal subjects bc of INC in large pores; also INC excretion of IgG (neutral charge) due to loss of size barrier
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62
Q

What are the three different types of proteinuria?

A
  • Glomerular: seen w/any glomerulonephritis; albumin is the dominant protein in the urine
  • Tubular: secondary to tubulointerstitial disease; low molecular weight proteins
  • Overflow: production and hence filtration exceeds reabsorption capacity, e.g. multiple myeloma
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63
Q

What protein does urine dipstick measure?

A

Albumin

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64
Q

How much proteinuria is too much?

A
  • Healthy kidney: may excrete 40-80 mg/day of protein (150 mg/day upper range of normal)
    1. Excrete up to 30 mg/day albumin
  • Tamm-Horsfall mucoprotein excreted at rate of 30-50 mg/day (from uromodulin: most abundant protein excreted in normal urine; DEC if kidney stones)
  • Urine dipstick only picks up when albumin excretion > 300-500 mg/day (+)
  • To detect proteinuria <300 mg, need to use rate of albumin and Cr, or the microalbuminuria:
    1. Spot urine albumin/creatinine ratio (normal <30 mg/g) -> corresponds fairly accurately w/proteins in 24-hour urine collection
    2. Spot sample: microalbuminuria defined as 30-300 mg/day (persistent)
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65
Q

What are the three methods of urine protein measurements? What is nephrotic range proteinuria?

A
  • Urine dip sticks: absent normally (1+, 2+, 3+ = proteinuria)
  • 24-hour urine collections: <150 mg normal
  • Spot urine protein creatinine ratio (corresponds accurately to 24-hr urine collection): <0.15 normal
  • Nephrotic range proteinuria:
    1. 24-hr urine collection: >3.5 gm
    2. Spot protein CR ratio: >3.5
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66
Q

How are primary and secondary nephrotic syndrome generally managed?

A
  • Goal: preserve kidney function
  • Most important predictor: proteinuria
  • Supportive measures: control HTN -> low salt diet, ACEI, ARB
  • Disease modifiers: meds that can treat underlying mechanism causing the disease
    1. Steroids
    2. Immunosuppressive drugs: cyclosporin, cyclosphosphamide, mycophenalate mofetil, tacrolimus
    3. Treat the cause (if secondary)
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67
Q

Nephrotic summary

A
  • Edema
  • Heavy proteinuria
  • Hypoalbuminemia
  • Hyperlipidemia
  • Inactive urinary sediment
  • Mechanism: non-inflammatory injury to glomerular capillary wall
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68
Q

Nephritic summary

A
  • Active urinary sediment
  • Dysmorphic RBCs
  • RBC casts
  • Mechanism: inflammatory injury to the glomerular capillary wall
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69
Q

Glomerular capillary wall summary

A
  • Selective permeability barrier: restricts molecules based on size, charge, and conformation
  • Made up of three layers: endo, GBM, podocyte visceral epi cell layer
  • Albumin too big and too negatively charged to filter through a normal / intact glomerular capillary wall
    1. Finding of heavy albumin (protein) in urine can be sign of defective glomerular capillary wall (e.g., kidney disease)
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70
Q

A 5-year-old white male has peri-orbital edema and 3+ proteinuria, with no urinary casts, and normal blood pressure and creatinine. The site of his glomerular injury is most likely…?

A.Endothelial cells
B.Basement membrane
C.Bowman space
D.Podocytes

A

Podocytes

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71
Q

A 45-year-old black male has ankle edema and 3+ proteinuria, with no urinary casts, and normal blood pressure. The blood test most likely to be abnormal is…?

A.Albumin
B.Blood urea nitrogen
C.Creatinine
D.Potassium
E.WBC count

A

Albumin

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72
Q

What are the 2 podocytopathies?

A

Minimal change disease

Focal segmental glomerulosclerosis

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73
Q

What’s up with this patient?

History: 15 y/o WF w/recent onset of facial and lower extremity edema

Physical Exam: BP 110/75 mm Hg, 3+ lower extremity pitting edema

Bloodwork: BUN 15 mg/dL, creatinine 0.9 mg/dL, albumin 1.7 g/dL, secondary causes tests all (-)

Urine: 4+ proteinuria, urine protein/creat ratio = 18

Micro Exam: oval fat bodies & Hyaline casts

A

Minimal change disease (no RBC casts: helps you know that this is not nephritic syndrome)

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74
Q

MCD basics

A
  • Bimodal age distribution (very young and very old
  • Most common cause of nephrotic syndrome in children (many children who present w/NS started on steroid even w/o renal biopsy)
  • Insidious onset of edema (localized, or anasarca)
  • Blood pressure - usually normal
  • Renal function - usually normal. Occasional Acute kidney injury (mostly adult >40)
  • Highly selective proteinuria - albumin
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75
Q

What are the cause and pathogenesis of MCD?

A
  • Pathogenesis not clear: T-cells produce circulating permeability factor -> podocyte damage
  • Primary: idiopathic (usually)
  • Secondary:
    1. Malignancy: Hodgkin’s lymphoma
    2. Drugs: NSAIDs, interferon alpha
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76
Q

What do you see here?

A

Minimal change disease -> minimal pathology

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77
Q

What do you see here?

A

Minimal change disease -> minimal pathology

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78
Q

What’s going on here? Blue? Red?

A
  • Blue: effacement/fusion (obliterating slit diaphragm openings)
  • Red: detachment of foot processes
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79
Q

What’s going on here?

A

Effacement/fusion of the foot processes (MCD)

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80
Q

What is the treatment for MCD?

A
  • Supportive Measures:
    1. Control blood pressure: ACEI/ARB
    2. Treat hyperlipidemia
  • Disease Modifier:
    1. Oral glucocorticoids -> cornerstone of therapy
    2. Excellent response to steroid in kids -> quick, not usually > 6 wks of therapy (>90%); response to steroid in adults is slow (2-3 months)
    4. Recurrence common, esp. in kids, some on steroids for long time; can lead to side effects
    5. If poor response to steroid, look for o/cause (esp. in kids) -> FSGS might look like MCD if biopsy misses areas with FSGS scarring
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81
Q

What’s up with this case?

History: 51 y/o AAM w/recent onset lower extremity edema

Physical Exam: BP 156/94 mm Hg, 2+ lower extremity pitting edema

Bloodwork: BUN 32 mg/dL, creatinine 1.78 mg/dL, albumin 2.9 g/dL, secondary cause tests all (-)

Urine Analysis: 4+ proteinuria, urine protein creatinine ratio = 7.8

Micro exam: oval fat bodies & hyaline casts

A

FSGS (BP elevated, renal function impaired compared to MCD)

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82
Q

FSGS basics

A
  • Recent biopsy series suggest may be increasing in incidence
  • Proteinuria is nonselective
  • Hypertension may be present
  • 50% of patients with FSGS devo ESRD w/in 10 years of diagnosis -> usually associated with impairment of kidney function (other types can progress rapidly and pt can develop ESRD within a few months)
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83
Q

What is supar?

A
  • Soluble urokinase-type plasminogen activator receptor -> novel discovery in FSGS
  • Circulating permeability factor produced by neutro, monocytes, and other cells, i.e., T-cells
  • In glomerulus, suPAR binds B3 integrin protein that binds podocyte to GBM and activates it, leading to dysfunction of podocytes, and effacement -> proteinuria
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84
Q

What are the causes of FSGS?

A
  • Primary: idiopathic (usually)
  • Secondary:
    1. Familial: muts in genes for several GBM proteins, incl alpha- actinin- 4, podocin, TRPC6, or apolipoprotein L1 gene (APOL1) -> see image
    2. Infection: HIV (common assoc; faster disease progression in these pts), parvo virus
    3. Drugs: pamidronate, heroin, lithium
    4. Adaptive structural-functional response: loss of nephron mass (partial kidney tissue removal); usually pts with partial nephrectomy (not those born without one, for example)
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85
Q

How is the ApoL1 mutation implicated in FSGS?

A
  • Sequence variant in apolipoprotein L1 gene (APOL1) on chrom 22 appears to be strongly associated with increased risk of FSGS and renal failure in people of African descent
  • Recent discovery
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86
Q

How is the ApoL1 gene important evolutionarily?

A
  • ApoL1 protects against sleeping sickness caused by the protozoa tryponosoma
  • Wild-type can kill T brucie protozoa via lysosomal swelling of the parasites -> but, o/gp of tryponosoma, T brucie rhodesience devo’d resistance to ApoL1 via SRA protein that prevents effect of APOL1
  • However, some ppl have mut in ApoL1 gene, and the mutated protein is resistant to the effect of SRA, meaning it can kill the protozoa, making those ppl resistant to sleeping sickness
  • Contains a pore-forming domain (red) and a membrane-addressing domain (blue)
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87
Q

What is the epi of the ApoL1 mutation?

A
  • Not all ppl have APOL1 gene mutation; very common in Africa, esp. sub-saharan & west Africa -> about 46%
  • Same muts in 36% of AA in N. America, but almost 0% of Europeans (or Asians) -> mut happened within last 20,000 years
  • Ppl w/this mut more susceptible to some kidney diseases, namely FSGS and HIV nephropathy, which might explain higher prevalence of FSGS, HIV nephropathy, and hypertensive kidney disease in AA population in N America
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88
Q

What do you see here?

A
  • FSGS: 1 involved, 2 un-involved glomeruli, showing that this disease is FOCAL
  • Involved glomerulus has large area of disease, illustrating that it is SEGMENTAL
  • NOTE: membranous most common in white Americans, but FSGS most common in AA
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89
Q

What is going on here? Green arrow? Black arrows?

A
  • FSGS: hyalinosis -> accumulation of leaked plasma proteins and lipids
  • Green: large accumulation
  • Black: small accumulations
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90
Q

What is the pathology here (2 things) and associated disease?

A
  • FSGS: adhesion of involved segment to Bowman’s capsule
  • Hyalonisis at the bottom right
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91
Q

What’s going on here? Left vs right?

A
  • FSGS: foot process effacement
  • Looks very similar to MCD on EM
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92
Q

What are the subtypes of FSGS?

A
  • Collapsing: 11%; heavier proteinuria and worst renal survival (ESRD for almost everyone in this category; rapid progression -> w/in months)
  • Tip: 17%; heavier proteinuria; more likely to obtain remission (best prognosis -> focalized, on opposite pole)
  • Cellular: 3%
  • Perihilar: 26%
  • Not otherwise specified: 42%
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93
Q

What is going on here?

A
  • Collapsing type FSGS: highlight of collapsed BM and 2 adhesions
  • Silver stain
  • May have collapsed sequentially -> still segments
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94
Q

What is going on here?

A
  • Collapsing type FSGS: highlight of collapsed BM
  • Electron microscopy
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95
Q

How do MCD and FSGS appear on immunoflourescence microscopy?

A
  • Non-inflammatory -> BOTH NEGATIVE
  • MCD: negative -> no fluorescent Abs detected
  • FSGS: negative -> no specific fluorescent Abs detected (although may have non-specific IgM in scarred glomerular segments)
96
Q

What is the treatment for FSGS?

A
  • Supportive Measures:
    1. Control blood pressure: ACEI/ARB
    2. Treat hyperlipidemia
  • Disease Modifier: don’t have very good tx options
    1. Corticosteroids most commonly used, but response to corticosteroids poor (usually steroid Rx should continue 3-6 mos to see response)
    2. Other tx options: calcineurin inhibitors (cyclosporine: typical 2nd-line tx after steroid, but response usually not great; or tacrolimus) -> nephrotoxins, so can further damage kidney
97
Q

Why is steroid sensitivity important in nephrotic syndrome? Which of these images is more likely to be steroid sensitive?

A
  • Steroid sensitive NS: proteinuria remits w/ tx, and minimal change on biopsy more likely
    1. Good prognosis
  • Steroid resistant NS: proteinuria persists despite tx, and FSGS on biopsy more likely
    1. Bad prognosis
  • Note the scarring on the right with FSGS (this one is more likely to be steroid resistant)
98
Q

Why have some researchers suggested MCD and FSGS are one and the same?

A
  • May be part of the same disease spectrum
  • Sampling error possible bc FSGS focal & localized more to deep juxtamedullary glomeruli
  • Repeated relapses of MCD in children with steroid responsive nephrotic syndrome may devo into FSGS 2o to repeated renal injury -> evolutionary process
  • Non-scarred glomeruli of pts with FSGS resemble those of MCD
  • Loss of glomerular capillary charge barrier in both leads to heavy proteinuria, though proteinuria may be less selective in FSGS secondary to large pores
99
Q

What are 1 and 2?

A
  • 1 = post-infectious glomerulonephritis
  • 2 = membranous nephropathy
100
Q

What are the 2 models for subepi deposits?

A
  • Filtered cationic Ag: deposits from circulation cross endo and GBM, are filtered, and localize in subepi spaces, restricted by size of slit diaphragm -> Abs localize, activate complement, leading to nephritis (e.g. endostreptosin, nephritis strain-associated protein (NSAP), and SpeB virulence factor in acute post-streptococcal glomerulonephritis, APSGN)
  • Autoimmunity Model: locally generated endogenous Ag (protein/glycoprotein on podocyte cell mem) & filtered autoantibody
    1. M-type phospholipase A2 receptor, PLA2R in primary MN
    2. Neutral Endopeptidase, NEP: target Ag in congenital MN
  • Lg circulating immune complexes cannot deposit in subepi regions bc too big to pass through glomerular basement membrane (GBM)
101
Q

What is this image showing?

A
  • In situ immune complex formation
  • Locally generated Ag theory: Ab Ig move from circulation and bind w/Ag in GBM, then AgAb complex activates complement
    1. AgAb complex forms deposits in subepi space, and complement complexes move inside the podocytes
    2. There they release several enzymes that damage GBM, leading to leakage of protein -> proteinuria
102
Q

What is the M-type phospholipase A2 receptor?

A
  • Recent study: 70% of pts w/idiopathic, but not 2o MN had auto-Abs to M-type PLA2R (Ag in GBM) -> helps differentiate b/t primary and secondary MN
  • PLA2R (185-kD glycoprotein) expressed by podocytes in normal human glomeruli, and co-localized with IgG4, the predominant Ig subclass in immune deposits in glomeruli of pts w/idiopathic MN
  • Conclusion: majority of pts w/idiopathic MN have Abs against a conformation-dependent epitope in PLA2R. PLA2R present in normal podocytes and in immune deposits in pts w/idiopathic MN, indicating that PLA2R is a major antigen in this disease
103
Q

What are the causes of MN?

A
  • Primary: idiopathic
  • Secondary:
    1. Infection: hep B, syphilis, malaria
    2. Autoimmune: SLE (common cause)
    3. Drugs: Gold, penicillamine, Captopril (ACEI; rarely), NSAID
    4. Malignancy: lung, colon cancer, melanoma -> if someone over age 50 presents with idiopathic MN, check that pt for cancer (prostate check, skin check, CT scan, colonoscopy)
    5. Other secondary causes: complement deficiencies (esp. C2), sickle cell
104
Q

MN basics

A
  • Most common cause of nephrotic syndrome in caucasian adults
  • Peak incidence in the 4th to 6th decades
  • Male preponderance (M:F 2-3:1)
  • Spontaneous resolution in about 30% (gets better w/o tx)
  • Progressive renal failure in about 40% (usually a pretty slow progression, unlike FSGS)
  • Persistent proteinuria w/variable renal dysfunction in about 30%
  • Majority of cases of MN do not cause ESRD, so Rx for MN selective; usually Rx for pts who are at high risk for progression to ESRD -> these things are important when considering treatment
105
Q

What are the risk factors for loss of renal function in MN?

A
  • Risk factors for loss of renal function:
    1. Male gender
    2. >10 g/24 hours proteinuria
    3. Hypertension
    4. Azotemia
    5. Tubulointerstitial fibrosis
    6. Glomerulosclerosis
106
Q

What is going on here?

A
  • MN: light microscopy showing thickened BM w/o increased cellularity
  • PAS stain: particularly helpful for membranous and membranoproliferative
107
Q

What do you see here?

A
  • MN: immunofluorescence -> granular deposits of Ig (in this case IgG) and complement (not shown here but would look the same)
  • Granularity is sort of subtle
  • Post-infectious has the least subtle granularity
108
Q

What do you see here?

A
  • MN: low power electron microscopy -> diffusely thickened BM with sub-epi deposits separated by spikes of new GBM (SPIKE AND DOME PATTERN)
109
Q

What do you see here?

A
  • MN: low power electron microscopy -> diffusely thickened BM with sub-epi deposits separated by spikes of new GBM
  • Spike and dome pattern: blue arrow spikes, green arrows domes
110
Q

What is going on here?

A
  • MN: high power EM -> thickened BM with subepi deposits (colored blue here) separated by spikes of new GBM
  • Spike and dome pattern
111
Q

What is the treatment for MN?

A
  • Usually depends on degree of proteinuria
    1. < 4gm: BP < 125/75 via ACEI or ARB
    2. > 4gm: BP < 125/75 via ACEI or ARB + other supportive measures, then cytotoxic agents, i.e., steroids or calcineurin inhibitors
112
Q

What is going on in this case?

History: 37 y/o WF w/recent onset of dark colored urine, weight gain, DEC urine output, and hx of URI

Physical Exam: BP 160/96 mm Hg, 1+ lower extremity pitting edema

Bloodwork: BUN 42 mg/dL, creatinine 2.5 mg/dL, albumin 2.7 g/dL, tests for 2o causes all (-), low C3, normal C4

Urine analysis: 3+ proteinuria, urine protein creatinine ratio = 3.6

Micro exam: many RBCs

A
  • Post-infectious glomerulonephritis
  • URI at same time as renal presentation = IgA; if post-URI, then post-infectious
113
Q

Post-infectious glomerulonephritis basics

A
  • Most freq in school-age kids with M:F ratio 2:1
  • Usually assoc w/recent infection: upper respiratory tract, skin, sepsis -> infection often inapparent when glomerulonephritic symptoms present
  • Gross hematuria: “tea or cola-colored” urine
  • Hypertension is common
  • Signs of fluid retention: peripheral edema, ascites
  • Proteinuria, impaired renal function
114
Q

What are the typical lab results with post-infectious glomerulonephritis?

A
  • Hypocomplementemia: low C3, normal C4 levels (alternative pathway) in almost all pts; resolves 2 mos
  • Elevated anti-streptolysin O (ASO) titers if preceded by throat infection (1-3 wks b4 renal sx)
  • Elevated Anti-DNAse B, antihyaluronidase titers if preceded by skin infection (3-6 wks b4 renal sx)
  • Positive blood culture in sepsis
  • Low level cryoglobulinemia is frequent
115
Q

What are the common symptoms at presentation of post-infectious glomerulonephritis?

A
  • Nephrotic/non-nephrotic proteinuria: 96%
  • Edema: 85%
  • Azotemia: 74%
  • Hypertension (60%)
  • Gross hematuria: 50%
  • Oligoanuria (35%) -> low output of urine in which there may even be a temporary cessation of flow
  • Gastrointestinal complaints (29%)
  • Ascites (particularly in children) (26%)
  • Pulmonary symptoms (23%)
  • Lethargy, confusion, seizures (20%)
116
Q

What do you see here?

A
  • Post-streptococcal glomerulonephritis: light microscopy -> diffuse endocapillary proliferation and infiltration by numerous neutrophils (polys)
117
Q

What do you see here?

A
  • Post-streptococcal glomerulonephritis
  • Immunofluorescence: diffuse granular deposits in capillary walls and mesangium (esp. IgG and C3)
  • Diffuse is kind of the equivalent of global -> the whole of the glomerulus, as opposed to FSGS, where it will only be part of it
118
Q

What do you see here?

A
  • Post-streptococcal glomerulonephritis: EM of dome-shaped subepithelial humps (colored blue here)
119
Q

What are the tx/prognosis for PIGN?

A
  • Supportive measures:
    1. Control HTN: anti-HTNsives (tx aggressively, esp. in kids, who can have HTN seizures), diuretics (for comfort)
    2. Renal replacement therapy if severe kidney dysfunction (renal prognosis favorable in kids, except with severe acute disease)
    3. Supportive dialysis, as necessary
  • Treatment of infection: tx of underlying infection -> give AB (generally good prognosis)
    1. Resolution of HTN over a few weeks
    2. Normalization of C3 levels by about 6 weeks
    3. Resolution of hematuria within 12 months
    4. Up to 40% of adults devo chronic azotemia
120
Q

MCD summary: tx and imaging

A
  • More likely to remit with steroid therapy (steroid responsive)
  • BIOPSY
    1. Light microscopy: normal
    2. Immunofluorescence: normal (negative)
    3. EM: podocyte foot process effacement, fusion
121
Q

FSGS summary

A
  • Solubility factor: suPAR may be involved in etiology of 1o FSGS
  • Reduced nephron mass assoc with 2o FSGS
  • Less likely to remit with steroid therapy
  • High risk of developing end-stage renal disease
  • BIOPSY:
    1. Light microscopy: scarring, obliterated cap lumen, adhesion to Bowman’s capsule
    2. Immunofluorescence: normal (negative)
    3. EM: podocyte foot process effacement, fusion
122
Q

MC summary

A
  • M-type phospholipase A2 receptor target Ag
  • Progressive renal failure in about 30%
  • BIOPSY:
    1. Light microscopy: diffuse thickening of the glomerular BM w/normal cellularity (how you distinguish from membranoproliferative)
    2. Immunofluorescence: fine granular staining w/IgG and complement
    3. EM: subepithelial deposits
123
Q

Acute post-strep glomerulonephritis summary

A
  • Presents 1 to 3 weeks after pharyngitis or strep skin infection
  • Good prognosis w/resolution of HTN over few wks, normal C3 levels by about 6 weeks, and resolution of hematuria within 12 months
  • BIOPSY:
    1. Light: proliferation, inflammation
    2. IF: granular deposition of C3 or IgG
    3. EM: subepithelial humps
124
Q

Which 2 glomerular diseases involve visceral epi injury?

A
  • Podocyte disorders
    1. Minimal change disease
    2. Focal segmental glomerulosclerosis
125
Q

Which 4 glomerular diseases involve immune complex formation?

A
  1. Membranous nephropathy (subepithelial)
  2. Post-infectious glomerulonephritis (subepithelial)
  3. Membranoproliferative glomerulonephritis (subendothelial)
  4. IgA nephropathy (mesangial)
126
Q

Which 3 glomerular diseases involve the BM?

A
  • Glomerular basement membrane disease:
    1. Anti-glomerular basement membrane disease (Goodpasture’s: when lungs involved)
    2. Alport’s syndrome
    3. Thin basement membrane
127
Q

Which glomerular diseases involve vascular injury?

A
  • Vascular injury syndromes:
    1. ANCA-associated glomerulonephritis/pauci-immune glomerulonephritis
    2. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
128
Q

What clinical features are characteristic of acute nephritic syndrome?

A
  • Acute onset of:
    1. Hematuria: microscopic or macroscopic -> red blood cell (RBC) casts
    2. Hypertension
    3. Oliguria: low output of urine
    4. Edema –usually moderate
    5. Mild to moderate proteinuria
    6. Azotemia (renal dysfunction)
129
Q

What diseases are associated with subendothelial and mesangial immune deposits?

A
  • Membranoproliferative GN (subendothelial)
  • IgA nephropathy (mesangial)
  • Lupus nephritis
  • Post-infectious GN (sub-epithelial humps)
  • These diseases are assoc w/circulating immune complexes that are planted at specific sites due to size, charge, and/or other affinity characteristics
130
Q

What disease is represented by the green? Blue?

A
  • Green: membranoproliferative glomerulonephritis (subendothelial deposits)
  • Blue: IgA nephropathy (mesangial deposits)
131
Q

What are the causes of endo cell injury in glomerular disease? What are the results of this damage?

A
  • Depo of immune complexes in subendo space
  • Thrombotic microangiopathies (HUS/TTP)
  • Entrapment of paraproteins: M protein, spike protein, myeloma protein (Ig fragment or light chain)
    1. B-cell lymphoproliferative disorders
    2. Plasma cell dyscrasias
    3. Multiple myeloma
  • Results of endo damage:
    1. Cytokines, autacoids (Ang, NO, endothelin -> act like hormones w/brief duration near site of syn) + activated complement up-regulate adhesion molecules on endo and circulating immune cells -> enhancement of local inflammatory response
    2. HEMATURIA is seen clinically
132
Q

What is going on with this case?

History: 14-y/o WM with nephrotic syndrome and microhematuria; no hx of fever, rash, arthralgias, or gross hematuria. PMH unremarkable

Physical Exam: BP 138/80 mmHg (high for teen), 2+ lower extremity edema

Labs: serum creatinine level of 1.3 mg/dl (should be <1, unless super athletic), BUN of 43 mg/dl, 24-hour urine protein of 5.12 g, serum albumin of 2.7 g/dl, hemoglobin 10 g/dl, white blood cell count of 7200, platelets of 340,000, and normal serum electrolytes

UA: 3+ protein and microhematuria w/o RBC casts

Serologies: negative (incl. negative ANA, ANCA, hepatitis B surface antigen, hep C virus Ab, and HIV). C3 was low

Kidney size: ultrasound -> 10.4 and 10.3 cm (normal)

-> A renal biopsy was performed

A

Membranoproliferative glomerulonephritis

133
Q

What are the 3 types of MPGN?

A
  • Type I: most common form; immune complexes
    1. Mesangial hypercellularity w/subendo and mesangial immune complex deposits, capillary wall mesangial interposition, and monocyte infiltration -> IF shows granular mesangial and capillary wall IgG, C3, IgM
    2. May be seen in pts (esp. adults) w/underlying neoplasm, infections, collagen-vascular disease
  • Type II (dense deposit disease): less common; may be deficiency or absence of complement Factor H
    1. Partial lipodystrophy (less commonly o/types)
  • Type III: rare; immune-complex mediated
    1. Subepi and subendo deposits associated with GBM disruption and lamina densa layering
  • All 3 types have double-contoured GBM
134
Q

How does MPGN Type 1 present?

A
  • Multiple presentations possible:
    1. Asymptomatic w/microscopic hematuria
    2. Non-nephrotic range proteinuria
    3. Nephrotic syndrome
    4. Acute nephritic syndrome
    5. Crescentic rapidly progressive glomerulonephritis (RPGN)
  • May be idiopathic, but often associated with hep C infection in adults -> 80% (occasionally hep B)
  • Usually associated with low C3 levels; 70-90% of pts (acute post-strep GN also assoc with low C3)
135
Q

What are some of the clinical features of MPGN?

A
  • HTN, diminished GFR may be present at diagnosis
  • Cryoglobulinemic vasculitis may complicate hep C-associated MPGN -> present with low C3 and/or C4, rheumatoid factor, positive ANA (approximately 20%), arthritis, and skin leukocytoclastic vasculitis
  • Some families: factor H deficiency induces cont’d C3 activation
  • Usually sporadic; some hereditary, esp. Type 2, 3
  • Slow progression to ESRD Type 1, 2 more than 3
    1. Spontaneous remission occurs rarely
  • All may recur in renal allografts, particularly with a live-related donor
  • 2o causes: infections (bac, viral: hep B, C, HIV, fungal, protozoal), autoimm (SLE), paraproteinemias, neoplasia (leukemia, lymphoma, neuroblastoma)
136
Q

What is the histological presentation of MPGN type 1?

A
  • Hypercellular glomerular tuft -> INC mononuclear cells in expanded mesangium & capillary lumens
    1. Numerous leukocytes contribute to glomerular hypercellularity
    2. Advanced disease: glomeruli may appaear lobular
  • Capillary wall changes result in a double contour appearance to GBM -> “tram track appearance”
    1. Duplication of BM from endo displaced by sub-endo immune deposits and infiltrating mesangial cells at mesangial - endo interface
    2. Mesangial proliferation, response to circulating imm complexes -> enlarged glomeruli
  • Aka, mesangiocapillary glomerulonephritis
  • IF: depo of C3, C4, IgG at periphery of glomerular tuft (C4 depo distinguishes type I from type III)
137
Q

What is the treatment/prognosis for MPGN type 1?

A
  • No consensus regarding tx of idiopathic disease
  • Spontaneous remission may occur rarely
  • Usually slow progression to ESRD
  • NOTE -> all of the following have been used (notes section on slide):
    1. Singly or combo: glucocorticoids, warfarin, dipyridamole, +/- aspirin (+/- cyclophosphamide)
    2. Steroids/immunosuppressives may enhance viral replication in hep-associated; may need with complicating cryoglobulinemic vasculitis
    3. Cyclosporine, mycophenolate mofetil, IV Igs used anecdotally
    4. ACEI/ARB for their antiproteinuric effects
    5. Pegylated INF, ribavirin have not been studied systematically for effects on nephritis
    6. Ribavirin contraindicated with decreased GFR
138
Q

What is dense deposit disease?

A
  • Clinical presentation similar to MPGN type 1
  • Also usually have low C3 levels
  • ~80% have C3 nephritic factor (results in continued consumption of complement)
  • May be assoc with macular deposits in eyes and/or acquired partial lipodystrophy (loss of subcutaneous fat in upper half of the body)
  • C3 depo on IF, but Ig depo usually absent
  • EM: characteristic electron-dense deposits in GBM
139
Q

What do you see here?

A
  • MPGN
  • Light microscopy: glomeruli enlarged with increased mesangial matrix and cellularity, and thickened, split, double contour “tram track” basement membranes
  • Glomeruli are too big
  • There are too many cells, but not as hypercellular as post-infectious (nor as many ants)
140
Q

What do you see on the left? Right?

A
  • Membranoproliferative glomerulonephritis
  • Highlighting abundant increased cellularity on the left
  • Normal on the right for comparison
141
Q

What do you see on the left? Right?

A
  • Membranoproliferative glomerulonephritis
  • Highlighting abundant increased mesangial matrix on the left
  • Normal on the right for comparison
142
Q

What do you see here?

A
  • Membranoproliferative glomerulonephritis
  • Silver stain highlighting thickened split double contour BM’s due to new membrane formation & debris deposited within BM -> tram tracks
143
Q

What do you see here?

A
  • MPGN
  • EM showing deposits (within the BM, so not sub-epi or sub-endo)
144
Q

What’s going on here? In which glomerular disease might you see this?

A
  • Membranoproliferative glomerulonephritis can be associated with a monoclonal gammopathy (i.e., multiple myeloma) and then the immunoglobulin will be exclusively kappa or lambda as shown in this pair of immunofluorescence stains
145
Q

What is the pathophysiology of immune-complex mediated MPGN (type 1)?

A
  • Complement activation via classical pathway
  • Leukocyte recruitment
  • Damage to endothelial cells, BM, and epithelial cells by proteases (P), etc. from leukocytes
  • Repair with formation of new BM incorporating debris
  • Epithelial cells are becoming effaced (fused)
146
Q

What is the pathophysiology of complement-mediated MPGN?

A
  • Dysregulation of controls on complement activation
  • Complement activation via alternative pathway
  • Leukocyte recruitment
  • Damage to endo cells, BM, and epi by proteases (P), etc. from leukocytes
  • Repair with formation of new BM, incorporating debris
  • Low C3, but normal C4
    1. Difference b/t this and imm-complex mediated MPGN is the complement pathway -> alternative here, but classical in other, i.e., Ig’s in classical)
147
Q

What do you see here?

A
  • Dense deposit disease
  • EM: ribbons of dense dark material in GBMs
    1. Not lumpy, not granules, not humps
    2. Thick, continuous ribbon
148
Q

What do you see here?

A
  • Dense deposit disease
  • EM: ribbons of dense dark material in GBMs
    1. Not lumpy, not granules, not humps
    2. Thick, continuous ribbon
149
Q

What do you see here?

A
  • Dense deposit disease
  • EM: ribbons of dense dark material in GBMs
    1. Not lumpy, not granules, not humps
    2. Thick, continuous ribbon
150
Q

What is this?

A
  • Dense deposit disease
  • EM: ribbons of dense dark material in GBMs
    1. Not lumpy, not granules, not humps
    2. Thick, continuous ribbon
151
Q

What is going on with this case?

History: 14-y/o WM with nephrotic syndrome and microhematuria; no hx of fever, rash, arthralgias, or gross hematuria. PMH unremarkable

Physical Exam: BP 138/80 mmHg (high for teen), 2+ lower extremity edema

Labs: serum creatinine level of 1.3 mg/dl (should be <1, unless super athletic), BUN of 43 mg/dl, 24-hour urine protein of 5.12 g, serum albumin of 2.7 g/dl, hemoglobin 10 g/dl, white blood cell count of 7200, platelets of 340,000, and normal serum electrolytes

UA: 3+ protein and microhematuria w/o RBC casts

Serologies: negative (incl. negative ANA, ANCA, hepatitis B surface antigen, hep C virus Ab, and HIV). C3 and C4 levels are normal

Kidney size: ultrasound -> 10.4 and 10.3 cm (normal)

-> A renal biopsy was performed

A
  • Same as MPGN case, but C3 and C4 levels are normal -> IgA nephropathy
  • Differences in these diseases can be really subtle, which is why the renal biopsies are so important
152
Q

What is IgA nephropathy? What are some of its 2o causes?

A
  • Aka, “Berger’s Disease;” primary or secondary
  • Most common 1o glomerulonephritis worldwide
  • Characterized by deposition of IgA-containing immune complexes predominantly in the mesangium
    1. Mesangioproliferative pattern of injury
  • Secondary IgA:
    1. Henoch-Schoenlein purpura (childhood vascular disease)
    2. Ankylosing spondylitis
    3. Dermatitis herpetiformis
    4. Celiac disease
    5. Inflammatory bowel disease
    6. Cirrhosis
    7. Psoriasis
  • Screened for in Asia, Japan
  • Clinically, most often seen in the setting of cirrhosis
153
Q

What is the pathogenesis of IgA nephropathy?

A
  • May be triggered by URI or GI tract infection
    1. “Synpharyngitic” –> nephritic sediment within 1 to 2 days of infection
  • Galactose deficient IgA1 is produced and forms immune complexes in the circulation
    1. High levels of under-galactosylated IgA1 (O-linked glycans in the hinge region) -> IgG, IgA1 auto-Abs recognize O-link glycans terminating w/N-acetylgalactosamine instead of galactose
    2. Circulating immune complexes (CICs) deposit in mesangium and may result in a proliferative and occasionally necrotizing glomerulitis
    3. IgA1 may derive from bone marrow, mucosa
    4. Binding of IgA to mesangial Fc receptors, and immune complex dep -> mesangial growth factor, cytokine, chemokine release, inducing mesangial proliferation, infiltrating monocytes, and matrix expansion
  • Episodes of gross hematuria at times of infection (possible to not have hematuria too)
154
Q

What is the presentation of IgA nephropathy?

A
  • Variable presentation:
    1. Asymptomatic
    2. Microscopic hematuria
    3. Intermittent gross hematuria
    4. Synpharyngitic hematuria
    5. Nephrotic (15%) or non-nephrotic proteinuria
    6. Acute glomerulonephritis
    7. Rapidly progressive glomerulonephritis
  • Often associated with hypertension
  • Only 50% of pts have increased serum IgA levels (this is not going to help you out much)
155
Q

What is the prognosis for IgA nephropathy? What are the risk factors for loss of renal function?

A
  • Risk factors for loss of renal function:
    1. Heavy proteinuria
    2. Decreased GFR at onset
    3. Older age at onset
    4. Uncontrolled hypertension
    5. Crescents, tubulointerstitial fibrosis/atrophy
  • 20-year renal survival approximately 50% to 70%
  • Prognostic value of gross hematuria is controversial
  • Recurrent IgA deposits in renal allografts rarely induce clinical disease
156
Q

What is the treatment for IgA nephropathy?

A
  • Controversial: varies substantially by local practices
    1. ACEI/ARB for antiproteinuric effects
    2. Eicosapentaenoic acid/docasahexaenoic acid slowed progression in some but not all studies
    3. Steroids +/- short-term cyclophosphamide, followed by azathioprine; combos of steroids, cytotoxics, coumadin, dipyridamole beneficial in some but not all studies
    4. Mycophenolate mofetil under study in randomized trials
  • NOTE: she did not explicitly address this, but it was in the notes
157
Q

What are these arrows pointing to?

A
  • Top: O-linked glycans
  • Bottom: N-linked glycans
158
Q

What is going on in each of these images? What glomerular disease might this be?

A
  • IgA nephropathy
  • Bottom line: highly variable
    1. Top left: almost normal
    2. Top right: increased mesangium (H&E)
    3. Bottom left: increased mesangium (silver)
    4. Bottom right: small crescent
  • Random Nichols fact: concentrated in patients that do not drink milk or have a lactose deficiency
159
Q

What do you see here?

A
  • IgA nephropathy
  • IF on left, EM on right
  • RBC going through the capillary on the EM
160
Q

What do you see here?

A
  • IgA mesangial deposits
  • Deposits labeled D
  • MC = mesangial cell
161
Q

What is this characteristic of?

A

Anti-GBM disease

162
Q

What is anti-GBM disease?

A
  • Formation of auto-Abs against noncollagenous portion of the α-3 subunit of type IV collagen
  • Anti-GBM antibodies (usually IgG) bind in a relatively uniform manner leading to a linear (not granular) appearance on immunofluorescence
    1. No correlation b/t anti-GBM titers & disease activity
  • Rapid development of kidney failure due to focal glomerular necrosis and crescent formation
  • Rapidly progressive glomerulonephritis (classic)
    1. Most of these pts end up on dialysis -> horrible prognosis
  • More common in whites
163
Q

What is Goodpasture’s?

A
  • Cough, dyspnea, crackles, hemoptysis may precede or coincide w/renal dysfunction (renal-pulmonary)
  • Pulmonary hemorrhage exacerbated by exposures to tobacco smoke, influenza, volatile hydrocarbons (classically a smoker)
  • Rapidly progressive renal failure with azotemia at presentation in 50 to 70% of cases
  • Anemia out of proportion to renal insufficiency (due to pulmonary blood loss probably)
  • Arthritis/arthralgias common
  • HTN only in about 20% (not esp. hypertensive)
  • Tx: IV corticosteroids, plasmapheresis (therapeutic plasma exchange), cytotoxic agents (cyclophosph)
164
Q

What do you see here?

A
  • Anti-GBM/Goodpasture’s
  • LM: necrotizing, crescentic glomerulonephritis (not specific for anti-GBM)
    1. Bowman’s space expanded and filled in with cells: inflammatory (more commonly macros than polys) and proliferating parietal epi cells
165
Q

What do you see?

A
  • Anti-GBM/Goodpasture’s
  • IF: linear IgG deposits (deposits in most other diseases are granular)
166
Q

What are crescents?

A
  • Accumulation and proliferation of cells outside the glomerular tuft -> can result in compression of the tuft with rapid progression to renal failure
  • Diffuse crescentic glomerulonephritis if >50% glomeruli involved on LM
  • Initially segmental proliferative and necrotizing lesions -> cellular crescents -> fibrocellular crescents -> fibrous crescents
  • Can see breaks in the BM on light microscopy
  • Capillary wall damage thought to contribute to the crescent development -> things getting into Bowman’s space that shouldn’t be there
167
Q

What is the pathogenesis of crescents?

A
  • Not well characterized
  • May be due to severe damage to capillary walls, which tear and necrose the GBM
  • Red blood cells, white blood cells, fibrinogen, and plasma constituents enter Bowman’s space and cause proliferation of mononuclear cells and parietal epithelial cells
  • Both antibody and cell-mediated processes may be involved
168
Q

What do these images show?

A
  • Rapidly progressive (crescentic) glomerulonephritis (can be seen in anti-GBM/Goodpasture’s)
  • Proliferating parietal epi cells on the right
169
Q

What do you see here?

A

Rapidly progressive cresentic glomerulonephritis (pauci-immune)

170
Q

What is the difference between these two images?

A
  • Top: linear
  • Bottom: granular
171
Q

What do you see here?

A
  • Type II crescentic glomerulonephritis
  • Characteristic, but not specific granular deposits on IF (remember: T1 linear, T3 pauci-immune) -> immune complexes
  • PAS stain: mesangium and BM stain purple
172
Q

What do you see here?

A
  • Type III crescentic glomerulonephritis
  • Pauci-immune: few or no immune deposits; ANCA–associated is related to small vessel vasculitis (SVV) and may be renal-limited or part of a systemic disease, like granulomatosis with polyangiitis (GPA), previously known as Wegener granulomatosis or microscopic polyangiitis (MPA)
  • Remember: T1 linear and T2 granular (immune complex mediated)
173
Q

Is RPGN a medical emergency?

A
  • IMPORTANT CONCEPT
  • NOT a medical emergency, but it certainly does require prompt diagnosis and treatment to prevent severe permanent renal damage and failure
174
Q

What is Alport syndrome?

A
  • Aka, hereditary nephritis
  • X-linked (defects in α-5 collagen type IV; COL4A5) in 80% of cases; may be autosomal recessive
    1. Hetero F may have hematuria and thin BMs
    2. Affected males have persistent hematuria, progressive proteinuria, and ultimately ESRD (defective GBM assembly, then degeneration)
  • Associated with sensorineural hearing loss, lens abnormalities, platelet defects; rarely esophageal leiomyomas (complain of dysphagia)
  • Biopsy shows abnormally thin BMs w/splintering of lamina densa causing a “basket weave appearance”
  • Generally, a teenage boy with hematuria with mom with hematuria and uncle who has been on dialysis -> males present in adolescence, F may never present
  • NOTE: additional notes at bottom of slide not included in cards
175
Q

How do you diagnose and treat Alport’s? What is the histopathology (all 3 media)?

A
  • Diagnosis: depends on clinical features, family hx, screening family members for hematuria, or classical renal biopsy findings; genetic testing is presently in limited use due to the variability in genetic mutations
  • Course: ESRD usually occurs in M with AS in their late teens to mid-30s but may be later
  • Treatment: no proven benefit of any therapy in AS, but tx with an ACEI or ARB prudent
  • Histopathology:
    1. LM: Focal, segmental, or global g-sclerosis w/interstitial fibrosis & foam cells in adv cases
    2. IF: NO deposits present; absence of GBM staining w/Ab to 5 type IV collagen -> X-linked
    3. EM: Irregular thinning and thickening of GBM with a lamellated basket-weave appearance; podocyte foot processes are focally effaced
176
Q

What does this schematic show you about the GBM?

A
  • It results from embryologic fusion of epithelial basement membrane (green) & endothelial basement membrane (blue)
177
Q

What is this?

A
  • Hereditary nephritis -> Alport Syndrome (basket-weave appearance of GBM)
178
Q

What does this image show?

A
  • Hereditary Nephritis/Alport Syndrome
  • Basket weave pattern basement membrane
179
Q

What is thin BM disease?

A
  • Usually benign as long as heterozygous (NOT homozygous or compound)
  • Assoc with defects in α-3 or α-4 collagen type IV
  • GBM thickness is uniformly reduced and about ½ normal
  • About 20 different measurements of BM thickness when biopsy completed
180
Q

Membranoproliferative Glomerulonephritis Summary

A
  • May present with micro hematuria, non-nephrotic range proteinuria, nephrotic syndrome, acute nephritic syndrome, RPGN
  • May be idiopathic, but often assoc with hepatitis C infection in adults (occasionally hepatitis B)
  • Usually associated with low C3 levels (always think MPGN or PIGN)
  • BIOPSY:
    1. LM: hypercellularity, duplication of GBM with double contour appearance (tram track)
    2. IF: complement deposition in a rim pattern outlining the glomerular capillary wall
    3. EM: thickening of glomerular capillary wall in type 1; dense, ribbon-like appearance of sub-endo and intramembranous material in dense deposit disease
181
Q

IgA Nephropathy Summary

A
  • Most common 1o glomerulonephritis worldwide
  • Characterized by deposition of IgA-containing immune complexes predominantly in the mesangium
  • Pathogenesis related to aberrant glycosylation of IgA w/formation of auto-Abs to this aberrant IgA
  • BIOPSY:
    1. LM: variable; may see mesangial expansion
    2. IF: dominant or co-dominant deposition of IgA
    3. EM: mesangial deposits
  • Normal LM glomerulus may also be seen with MCD
  • NOTE: pure Abs have a neutral charge, so IgA Abs may flow from wherever they are deposited to the mesangium, where mesangial cells can phagocytose them
182
Q

Anti-GBM Disease Summary

A
  • Aka, Goodpasture’s (when lungs involved)
  • Rapid development of renal failure due to auto-antibodies binding to a noncollagenous portion of the α-3 subunit of type IV collagen
  • Linear pattern on immunofluorescence
183
Q

Hereditary Nephritis Summary

A
  • Aka, Alport’s syndrome
  • Related to defects in α-5 collagen type IV
  • Abnormally thin BM’s with splintering of the lamina densa causing a “basket weave appearance”
184
Q

Why do post-strep exotoxins more readily pass through BM than some other molecules?

A
  • Pyogenic exotoxin cationic, so these more readily pass through BM to other side (so this protein in particular likely to cross BM and be on the outside, or sub-epi hump)
  • Immune complexes that form in situ to planted Ag (gets all the way through due to cationic nature)
  • All goes back to basic science
185
Q

What vascular injury syndromes are associated with kidney disease?

A
  • ANCA-associated disease (pauci-immune glomerulonephritis)
  • Thrombotic microangiopathy
  • Lupus nephritis
  • Scleroderma
186
Q

What are some systemic diseases associated with kidney disease?

A
  • Diabetic nephropathy
  • Sickle cell nephropathy
  • Amyloidosis
  • Light chain disease
187
Q

What viral-associated diseases are associated with kidney disease?

A
  • HIV-associated nephropathy
  • Cryoglobulinemia
188
Q

In brief, what are the 2 pathologies of vascular disorders?

A
  1. Inflammation of blood vessels as in vasculitides

or

  1. Loss of thromboresistance as in the thrombotic microangiopathies
189
Q

What is the difference between the pathogenesis of medium and small vessel diseases in the kidney? Provide some examples.

A
  • Medium vessel disease -> renal infarcts
    1. Ex: classical polyarteritis nodosa
    2. Distal glomerular ischemia may -> DEC GFR
    3. Not associated with glomerular inflammation with RBC casts (usually ANCA negative)
  • Small vessel disease -> focal necrotizing lesions with crescent formation
    1. Ex: microscopic polyangiitis, granulomatosis w/polyangiitis (AKA Wegener’s), Churg-Strauss
    2. Active urinary sediment (hematuria) and rapid progression of kidney failure (usually ANCA +)
190
Q

What is polyarteritis nodosa?

A
  • Systemic necrotizing vasculitis that typically affects medium-sized muscular arteries (NOT veins)
  • Not associated w/ANCA’s
  • Most commonly seen in middle-aged or older adults with a peak incidence in the sixth decade of life
  • Usually idiopathic, although may be assoc w/hep B (MN), hep C (MPGN), and hairy cell leukemia
  • Pathogenesis is poorly understood
  • Systemic symptoms: fatigue, weight loss, weakness, fever, arthralgias -> if you see these, think vasculitis
  • May also see skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain
191
Q

What do you see here? What are the top arrows pointing to? The bottom one?

A
  • Polyarteritis nodosa: segmental, transmural, necrotizing (remember these 3 adjectives) vasculitis
  • Top arrows: neutrophils early in the disease
  • Bottom arrow: fibrinoid necrosis of the vessel wall
192
Q

What do you see here? What might have caused this?

A
  • Aneurysm
  • Renal arteriogram of patient with polyarteritis nodosa in the kidney (segmental, transmural, necrotizing)
193
Q

What do you see here? What are the different arrows pointing at?

A
  • White arrows: renal (cortical) infarcts
  • Black arrows: arterial aneurysms
  • Red arrow: rupture -> aneurysm burst (present with hypotension, syncope, and retroperitoneal bleed -> don’t feel pain here; do a CT)
  • All due to polyarteritis nodosa (segmental, transmural, necrotizing)
  • Can also get severely inflamed aneurysms on skin
194
Q

What is pauci-immune glomerulonephritis?

A
  • Negative IF studies (absence of immune deposits), usually in setting of crescentic glomerulonephritis (lympho, mono infiltration in Bowman’s space)
    1. Abnormal immunoregulatory mechs (perhaps genetically defined) permit dysregulation of autoreactive T- and/or B-cell clones -> initiators unkown
  • Often associated with ANCAs w/extrarenal findings (arthritis, athralgias, myalgias, fatigue)
    1. ANCA titers may not always parallel disease activity (similar to anti-GBM disease, where these things don’t correlate either)
    2. Clinical examples: Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss, and idiopathic crescentic glomerulonephritis
  • May be ANCA (-) and without extrarenal findings
195
Q

What are anti-cytoplasmic antibodies?

A
  • C-ANCA (aka PR3-ANCA):
    1. Diffuse (fine granular) cytoplasmic reactivity (in ETOH-fixed neutros) -> Abs to 29kD cytoplasmic neutral serine protease, proteinase 3
    2. Positivity strongly suggests granulomatosis with polyangiitis -> 95% specificity
  • P-ANCA (aka MPO-ANCA):
    1. Perinuclear reactivity only -> Abs directed at a lysosomal myeloperoxidase
    2. May be (+) in up to 30% of pts with anti-GBM disease; low titers may be seen in SLE -> not a very specific test
    a. Found in many pts w/microscopic poly-angiitis and some pts w/focal necrotizing and crescentic GN
    3. Nonmyeloperoxidase P-ANCA has been detected in sclerosing cholangitis, ulcerative colitis, and Crohn’s disease
196
Q

What does this IF stain show? Right vs. left?

A
  • Left: C-ANCA
  • Right: P-ANCA
197
Q

Are ANCA’s pathogenic?

A
  • YES
  • Binding of ANCAs to neutros => poly activation
    1. INC contact and adhesion (B-2 integrin, Mac-1, Fc-g) w/endo cells and vascular structures
    2. Endo cells are 1o target in sm vessel vasculitis
  • ANCAs play a significant role in disease genesis
  • Important for making the diagnosis AND causing the disease
198
Q

What is granulomatosis with polyangiitis?

A
  • Sinopulmonary renal syndrome (lung involvement in 80% of pts; 80-90% 1-yr mortality if untreated)
  • Rhinorrhea, sinusitis, nasopharyngeal mucosal ulcerations
  • Cough, dyspnea, hemoptysis, transient pulmonary infiltrates on chest x-ray
  • Only about 10% have azotemia at presentation
  • Fever, weight loss, arthralgias/arthritis, mononeuritis multiplex, skin lesions (papules, vesicles, purpura) may be seen
  • C-ANCA (PR3-ANCA) is sensitive and specific
  • Some may have P-ANCA positivity or be ANCA negative particularly if partially treated
  • Aka, Wegener’s granulomatosis
199
Q

What does granulomatosis with polyangiitis look like with the 3 different staining techniques?

A
  • LM: granulomatous vasculitis of medium sized to small arterioles and venules
  • IF: pauci-immune glomerulonephritis; fibrin may be present in crescents; tubulointerstitial granulomas
  • EM: no immune deposits are seen
  • NOTE: renal biopsy may be normal, show mesangial proliferative glomerulonephritis (GN), segmental necrotizing GN, or crescents
200
Q

What do you see here? What are 1-4 and the blue haze?

A
  • Granulomatosis with polyangiitis: necrotizing granulomatous inflammation
  • 1-4: multinucleated giant cells
  • Necrosis (blue haze): nuclear dust -> mostly from breakdown of neutrophils (and other inflammatory cells, rather than parenchymal cells)
  • Geographic necrosis
201
Q

What do you see here?

A
  • Vascular necrosis & thrombosis of granulomatosis with polyangiitis
  • Former blood vessel
202
Q

What do you see here?

A
  • Crescentic glomerulonephritis of granulomatosis with polyangiitis
203
Q

What is going on here?

A
  • Glomerular damage of granulomatosis with polyangiitis
  • Don’t be too literal about the word crescent -> may also be all the way around the glomerulus
204
Q

How do you treat granulomatosis with polyangiitis?

A
  • Cyclophosphamide-based regimens, steroids, and/or plasmapheresis
    1. High incidence of bladder cancer the decade aftter prolonged daily oral cyclophosphamide tx (IV advised to diminish side effects)
    2. Steroids useful adjunctive therapy, esp. in pts w/severe renal or pulmonary disease, skin or cerebral vasculitis, eye involvement, pericarditis
    3. In pts with severe pulmonary hemorrhage and fulminant renal disease, plasmapheresis may confer additional benefit
  • Most pts will respond initially, but relapse occurs in 25-50% of patients with 3 to 5 years of follow-up -> monitor them to catch these early
205
Q

What are the 2 thrombotic microangiopathies (and their key characteristics)?

A
  • Hemolytic uremic syndrome (HUS)
    1. Hemolytic anemia (schistocyte blood smear)
    2. Renal dysfunction
    3. Thrombocytopenia (platelet consumption)
  • Thrombotic thrombocytopenic purpura (TTP)
    1. Fever
    2. Hemolytic anemia
    3. Thrombocytopenia
    4. Renal dysfunction
    5. Neurologic dysfunction (eg. seizures)
  • You can see pts that don’t check all of the boxes, especially with TTP (i.e., they may not have fever)
206
Q

What is the pathogenesis of thrombotic microangiopathy?

A
  • Loss of thromboresistance by the endothelial cell
  • Platelet activation
  • Deposition of platelet and fibrin thrombi in lumen of affected vessels
  • Fibrin deposition may also occur in the sub-intima and media of the vessels
  • “Onion-skin” appearance to the vessels (arterioles) on biopsy (not specific for TTP -> can also see onion skinning with scleroderma, HTN, etc. but would probs be larger vessels, esp. in scleroderma)
207
Q

What do you see here (arrow)?

A
  • Thrombotic microangiopathy in a glomerulus (thrombosed capillary)
  • Decreased resistance to thrombosis
208
Q

What is this?

A
  • Thrombotic microangiopathy (thrombosed arteriole)
  • Decreased resistance to thrombosis
209
Q

What are some toxins and drugs that can cause endothelial cell injury?

A
  • Verotoxin producing E. coli H7:O157 may cause cytotoxic antiendothelial antibodies
  • Chemotherapeutic agents: cyclosporine, gemcitabine, bleomycin/cisplatin
  • Radiation: bone marrow transplant patients
210
Q

What are some common causes of thrombotic microangiopathy (table)?

A
  • Multiple pathways
  • Low levels or Abs to ADAMST13 -> auto-Ab pts can benefit from plasmapharesis
  • SLE
211
Q

What are some causes of platelet activation in TTP?

A
  • INC levels of von Willebrand factor multimers may directly enhance platelet aggregation
  • Familial TTP: genetic deficiency of vWf-cleaving protease (Low ADAMTS 13 activity; <10%)
  • Autoimmune TTP: auto-Ab to vWf–cleaving protease (ADAMTS 13 auto-antibodies)
  • Also occurs in the setting of autoimmune diseases (antiphospholipid syndrome) associated with autoantibodies to inhibitors of platelet aggregation
212
Q

How might you distinguish between thrombotic microangiopathy (TMA) and DIC?

A
  • Prothrombin time and partial thromboplastin (PT and PTT) times normal in TMA but prolonged in DIC
  • TMAs are associated with a thrombotic diathesis as opposed to a bleeding diathesis seen in DIC
  • TTP is an indication for plasma exchange
213
Q

What would you do next?

History: 27-y/o WF w/10-yr hix of SLE w/new onset hematuria, proteinuria. Prev SLE manifestations incl pericarditis, alopecia, a malar rash, and arthralgias.

Meds: prednisone 5mg, hydroxychloroquine 200mg

Physical exam: BP 122/76, erythematous facial rash, no edema

Laboratory results: serum creatinine 0.9 mg/dl, spot urine protein to creatinine ratio 2.9 (normal <0.2), serum albumin 2.8 g/dl, WBC 2400/L, hemoglobin 10.5 g/dl, platelet count 127,000/L (low), ANA titer 1:1280, anti-dsDNA Ab 500 IU/ml, low C3 and C4

Urine sediment: dysmorphic RBCs, no significant white blood cells, and no cellular casts, kidneys measure 12.1 and 11.5 cm by ultrasound (normal)

A

Systemic lupus erythematosus (SLE)

Renal biopsy

214
Q

What is lupus? How does survival vary according to ethnic group?

A
  • “Lupus erythematosus” initially coined in the 1800s to describe skin lesions
  • Systemic disease sparing no organ system and caused by an aberrant immune response
  • Prevalence ranges from 20 to 150 cases per 100,000 population; highest prevalence in Brazil
  • Ten-year survival rate is about 70%
  • You will see this in Memphis
215
Q

What are some of the common criteria for lupus?

A
  • Discoid rash not as common as malar rash\
  • Strange skin lesions after sun exposure: photosensitivity
  • Positive RPR’s don’t always mean syphilis -> can also mean lupus (common test question; screening test for syphilis -> not confirmatory)
  • Oral ulcers, arthritis, serositis, renal (proteinuria, casts) and/or neuro disorders, heme (hemolytic anemia, leukopenia, thrombocytopenia), immuno disorders (anti-DNA, anti-smith)
216
Q

What are the 6 classes of lupus nephritis and their prevalence?

A
  • Class I: minimal mesangial (rare; no image)
  • Class II: mesangial proliferative 15%* (mild)
  • Class III: focal proliferative 25% (moderate)
  • Class IV: diffuse proliferative 50% (severe: wire loops, lots of excess cells)
  • Class V: membranous 10% (nephrotic)
  • Class VI: advanced sclerosing (no image)
  • NOTE: %’s are vague round numbers to give a rough idea
217
Q

What do you see?

A
  • Lupus nephritis class II: mesangial proliferative
  • Mild
  • Increased # of mesangial cells
218
Q

What do you see?

A
  • Lupus nephritis class III: focal proliferative
  • Moderate
  • FSGS would be in the differential here
219
Q

What do you see?

A
  • Lupus nephritis class IV: diffuse proliferative
  • Lots of excess cell: inflammatory, mesangial, and capillary endothelial cells
  • Most common, by far
  • SEVERE
  • More than 50% of nephrons have disease (commonly, all of them)
220
Q

What do you see?

A
  • Lupus nephritis class IV: diffuse proliferative
  • Wireloop lesions, hyaline thrombus in capillary
  • SEVERE
  • Hyaline thrombus: not actually a thrombus, but the wall projecting into the lumen (just called that)
221
Q

What do you see?

A
  • Lupus nephritis class IV: diffuse proliferative
  • Damaged glomerulus, crescent formation, and lots of excess cells of various types
  • SEVERE
  • Can have crescents
222
Q

What do you see?

A
  • Lupus nephritis class V: membranous
  • Nephrotic
223
Q

What do you see here?

A
  • Lupus nephritis EM: subendothelial and mesangial deposits
224
Q

What do you see?

A
  • Lupus nephritis EM: subendothelial and mesangial deposits
225
Q

What do you see?

A
  • Lupus nephritis EM: subendothelial and mesangial deposits
226
Q

What is this?

A
  • Lupus nephritis: immunofluorescence
  • In lupus, staining of deposits with antisera to all 3 Igs (IgG, IgM and IgA), C3, & C4 is typical and is often called: FULL HOUSE IMMUNOFLUORESCENCE
227
Q

What is the typical prognosis for SLE renal survival?

A

Class IV is the one that has really poor renal survival (global or segmental -> often end up on dialysis)

228
Q

What is the treatment for SLE?

A
  • Aspirin
  • Glucocorticoids: pretty big doses
  • Immunosuppressive agents:
    1. Cyclophosphamide (Cytoxan): most common
    2. Methotrexate
    3. Azathioprine
    4. Mycophenolate mofetil: oral med as good or better than cyclo (can cause GI sxs; 2-3q/day)
  • Inhibition of toll-like receptor: hydroxychloroquine
  • Hormone manipulation: dehydroepiandrosterone
  • Modulation of cell signaling: tacrolimus, sirolimus
  • Only ASA, glucocorticoids, hydroxychloroquine are approved by the FDA for the treatment of lupus
229
Q

What is scleroderma?

A
  • Aka, systemic sclerosis
  • Involves connective tissue and the microvasculature with fibrosis and vascular occlusion
  • Affects 1 in 4,000 adults in the United States, shows a female preponderance, and is more frequent in African-Americans
  • Patients are grouped into limited cutaneous (lc) or diffuse cutaneous (dc) SSc subsets based on the pattern of skin involvement
230
Q

What are the clinical features of diffuse and limited scleroderma?

A
  • Diffuse: musculoskeletal (arthralgia, stiffness, myalgia), GI (heartburn), cardiopulmonary disease (myocarditis, pericardial effusion), Raynaud’s not as sommon, more concern for renal involvement
  • Limited: Raynaud’s, occasional joint stiffness, heartburn, usually NO cardiopulmonary or renal involvement
231
Q

How is the kidney involved in scleroderma?

A
  • Mild renal involvement frequent, manifesting as mild renal dysfunction, proteinuria, and HTN (diffuse scleroderma)
  • Scleroderma renal crisis: new onset of accelerated arterial hypertension and/or rapidly progressive oliguric renal failure
    1. Treated with ACEI’s, though no controlled trial data (unique use of ACEI in these pts)
232
Q

What is scleroderma renal crisis? What are the risk factors?

A
  • Intimal & medial proliferation with luminal narrowing typically occurs in arcuate arteries
  • Fibrinoid necrosis and thrombosis common
  • Vascular changes (mucoid intimal thickening and thrombosis) associated with poorer outcome
  • Risk factors:
    1. Early diffuse systemic sclerosis
    2. Rapidly progressive skin disease
    3. Anti-RNA polymerase antibodies
    4. Corticosteroid therapy
233
Q

What is this?

A
  • Pathology of systemic sclerosis: scleroderma
  • Kidney: concentric sclerosing intimal thickening of interlobar arteries 150-500 microns in diameter resembling onion skin
    1. Bigger arteries than in the other diseases we have been talking about
234
Q

Granulomatosis with polyangiitis summary

A
  • Aka, Wegener’s granulomatosis
  • Sinopulmonary renal disease (classic)
  • Pauci-immune glomerulonephritis: negative IF staining
  • Associated with C-ANCA (PR3-ANCA) positivity
235
Q

Thrombotic microangiopathy summary

A
  • Hemolytic uremic syndrome
    1. Hemolytic anemia: schistocytes blood smear
    2. Renal dysfunction
    3. Thrombocytopenia (platelet consumption)
  • Thrombotic thrombocytopenic purpura
    1. Features of HUS +/- fever and neurologic dysfunction (e.g. seizures)
236
Q

SLE and scleroderma summaries

A
  • Systemic lupus erythematosus
    1. Poor renal survival associated with diffuse proliferative disease (Class IV)
  • Scleroderma (systemic sclerosis)
    1. Scleroderma renal crisis: new onset of accelerated arterial hypertension and/or rapidly progressive oliguric renal failure

Renal (15 decks)

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