Nichols: Glomerular Disease Flashcards

Question

What do you see? When might you see this?

Answer 1

- _Granular cast_ - Seen when there is tubular damage from any cause, such as acute tubular necrosis (ATN)

Answer 2

- _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

Answer 3

- _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

Answer 4

- _Asymptomatic_: only abnormality will be found in lab tests, such as mild proteinuria or hematuria

Answer 5

- _Macroscopic hematuria_ -\> IgA nephropathy - Hematuria can be present intermittently; have flares, often with upper respiratory infections, but recover spontaneously

Answer 6

- _Nephrotic syndrome_: membranous nephropathy, FSGS, MCD - Large proteinuria

Answer 7

- _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

Answer 8

- _Rapidly progressive glomerulonephritis_: lupus nephritis, ANCA vasculitis

Answer 9

- _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

Answer 10

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

Answer 11

- Nature of the antigen involved - Site of immune complex deposition

Answer 12

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)

Answer 13

- _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

Answer 14

- _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

Answer 15

- _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

Answer 16

- Oval fat bodies - Commonly seen in nephrotic syndrome

Answer 17

- Maltese cross - Oval fat bodies under polarized light - Commonly seen in nephrotic syndrome

Answer 18

- Xanthelasma -\> nephrotic syndrome

Answer 19

- Hematuria - Proteinuria - Edema - HTN

Answer 20

- Nephrotic: abnormal filter WITHOUT inflammation - Nephritic: abnormal filter WITH inflammation

Answer 21

- _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_

Answer 22

- _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

Answer 23

Minimal change disease (also seen with FSGS) on EM

Answer 24

Membranous nephropathy on EM

Answer 25

Post-infectious (commonly strep) glomerulonephritis on EM

Answer 26

Membranoproliferative glomerulonephritis

Answer 27

Alport syndrome

Answer 28

Lupus nephritis

Answer 29

Hypertensive nephropathy (arterioles) or Scleroderma (larger vessels)

Answer 30

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

Answer 31

- **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**

Answer 32

- 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

Answer 33

- 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_

Answer 34

- 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

Answer 35

- **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_

Answer 36

- 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_

Answer 37

- **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

Answer 38

- _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

Answer 39

- _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)

Answer 40

- _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

Answer 41

- _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)

Answer 42

- Edema - Heavy proteinuria - Hypoalbuminemia - Hyperlipidemia - Inactive urinary sediment - _Mechanism_: non-inflammatory injury to glomerular capillary wall

Answer 43

- Active urinary sediment - Dysmorphic RBCs - RBC casts - _Mechanism_: inflammatory injury to the glomerular capillary wall

Answer 44

- 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)

Answer 45

Minimal change disease Focal segmental glomerulosclerosis

Answer 46

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

Answer 47

- 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

Answer 48

- _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

Answer 49

Minimal change disease -\> minimal pathology

Answer 50

Minimal change disease -\> minimal pathology

Answer 51

- Blue: effacement/fusion (obliterating slit diaphragm openings) - Red: detachment of foot processes

Answer 52

Effacement/fusion of the foot processes (MCD)

Answer 53

- _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

Answer 54

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

Answer 55

- 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)

Answer 56

- **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_

Answer 57

- **_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)

Answer 58

- 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

Answer 59

- 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)

Answer 60

- 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

Answer 61

- 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

Answer 62

- FSGS: **hyalinosis** -\> accumulation of leaked plasma proteins and lipids - Green: large accumulation - Black: small accumulations

Answer 63

- FSGS: **adhesion** of involved segment to Bowman's capsule - **Hyalonisis** at the bottom right

Answer 64

- _FSGS_: foot process effacement - Looks very similar to MCD on EM

Answer 65

- _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%

Answer 66

- _Collapsing type FSGS_: highlight of collapsed BM and 2 adhesions - Silver stain - May have collapsed sequentially -\> still segments

Answer 67

- _Collapsing type FSGS_: highlight of collapsed BM - Electron microscopy

Answer 68

- 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)

Answer 69

- **_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

Answer 70

- _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)

Answer 71

- 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_ 2^o 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_

Answer 72

- 1 = post-infectious glomerulonephritis - 2 = membranous nephropathy

Answer 73

- **_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)

Answer 74

- 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

Answer 75

- Recent study: 70% of pts w/idiopathic, but not 2^oMN 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_

Answer 76

- **_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

Answer 77

- 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

Answer 78

- 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

Answer 79

- _MN_: light microscopy showing thickened BM w/o increased cellularity - _PAS stain_: particularly helpful for membranous and membranoproliferative

Answer 80

- _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

Answer 81

- _MN_: low power electron microscopy -\> diffusely thickened BM with sub-epi deposits separated by spikes of new GBM (**SPIKE AND DOME PATTERN**)

Answer 82

- _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

Answer 83

- _MN_: high power EM -\> thickened BM with subepi deposits (colored blue here) separated by spikes of new GBM - Spike and dome pattern

Answer 84

- 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

Answer 85

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

Answer 86

- 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

Answer 87

- _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

Answer 88

- 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%)

Answer 89

- _Post-streptococcal glomerulonephritis_: light microscopy -\> diffuse endocapillary proliferation and infiltration by numerous neutrophils (polys)

Answer 90

- _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

Answer 91

- _Post-streptococcal glomerulonephritis_: EM of dome-shaped subepithelial humps (colored blue here)

Answer 92

- **_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

Answer 93

- 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

Answer 94

- _Solubility factor_: suPAR may be involved in etiology of 1^o FSGS - Reduced nephron mass assoc with 2^o 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

Answer 95

- 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

Answer 96

- 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

Answer 97

- Podocyte disorders 1. Minimal change disease 2. Focal segmental glomerulosclerosis

Answer 98

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

Answer 99

- _Glomerular basement membrane disease_: 1. Anti-glomerular basement membrane disease (Goodpasture’s: when lungs involved) 2. Alport’s syndrome 3. Thin basement membrane

Answer 100

- _Vascular injury syndromes_: 1. ANCA-associated glomerulonephritis/pauci-immune glomerulonephritis 2. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)

Answer 101

- 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)

Answer 102

- 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

Answer 103

- _Green_: membranoproliferative glomerulonephritis (subendothelial deposits) - _Blue_: IgA nephropathy (mesangial deposits)

Answer 104

- 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_

Answer 105

Membranoproliferative glomerulonephritis

Answer 106

- **_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

Answer 107

- _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)

Answer 108

- 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 - _2^ocauses_: infections (bac, viral: hep B, C, HIV, fungal, protozoal), autoimm (SLE), paraproteinemias, neoplasia (leukemia, lymphoma, neuroblastoma)

Answer 109

- _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)

Answer 110

- 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

Answer 111

- 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

Answer 112

- **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)

Answer 113

- **Membranoproliferative glomerulonephritis** - Highlighting abundant _increased cellularity_ on the left - Normal on the right for comparison

Answer 114

- **Membranoproliferative glomerulonephritis** - Highlighting abundant _increased mesangial matrix_ on the left - Normal on the right for comparison

Answer 115

- **Membranoproliferative glomerulonephritis** - _Silver stain_ highlighting thickened split double contour BM's due to new membrane formation & debris deposited within BM -\> **tram tracks**

Answer 116

- **MPGN** - _EM_ showing _deposits_ (within the BM, so not sub-epi or sub-endo)

Answer 117

- **_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

Answer 118

- 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)

Answer 119

- 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_)

Answer 120

- **Dense deposit disease** - _EM_: ribbons of dense dark material in GBMs 1. Not lumpy, not granules, not humps 2. Thick, continuous ribbon

Answer 121

- **Dense deposit disease** - _EM_: ribbons of dense dark material in GBMs 1. Not lumpy, not granules, not humps 2. Thick, continuous ribbon

Answer 122

- **Dense deposit disease** - _EM_: ribbons of dense dark material in GBMs 1. Not lumpy, not granules, not humps 2. Thick, continuous ribbon

Answer 123

- **Dense deposit disease** - _EM_: ribbons of dense dark material in GBMs 1. Not lumpy, not granules, not humps 2. Thick, continuous ribbon

Answer 124

- 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_

Answer 125

- Aka, “Berger’s Disease;” primary or secondary - _Most common 1^o 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_

Answer 126

- 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)

Answer 127

- _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)

Answer 128

- _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

Answer 129

- _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

Answer 130

- _Top_: O-linked glycans - _Bottom_: N-linked glycans

Answer 131

- **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

Answer 132

- **IgA nephropathy** - IF on left, EM on right - RBC going through the capillary on the EM

Answer 133

- **IgA mesangial deposits** - Deposits labeled D - MC = mesangial cell

Answer 134

Anti-GBM disease

Answer 135

- 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

Answer 136

- 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)

Answer 137

- **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

Answer 138

- **Anti-GBM/Goodpasture's** - IF: **linear** IgG deposits (deposits in most other diseases are granular)

Answer 139

- 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

Answer 140

- _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

Answer 141

- Rapidly progressive (crescentic) glomerulonephritis (can be seen in anti-GBM/Goodpasture's) - Proliferating parietal epi cells on the right

Answer 142

Rapidly progressive cresentic glomerulonephritis (pauci-immune)

Answer 143

- Top: linear - Bottom: granular

Answer 144

- **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

Answer 145

- **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)

Answer 146

- **_IMPORTANT CONCEPT_** - NOT a medical emergency, but it certainly does require prompt diagnosis and treatment to prevent severe permanent renal damage and failure

Answer 147

- 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

Answer 148

- **_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

Answer 149

- It results from embryologic fusion of epithelial basement membrane (green) & endothelial basement membrane (blue)

Answer 150

- Hereditary nephritis -\> **Alport Syndrome** (basket-weave appearance of GBM)

Answer 151

- Hereditary Nephritis/Alport Syndrome - Basket weave pattern basement membrane

Answer 152

- 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

Answer 153

- 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

Answer 154

- Most common 1^o 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

Answer 155

- 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

Answer 156

- 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**”

Answer 157

- 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

Answer 158

- ANCA-associated disease (pauci-immune glomerulonephritis) - Thrombotic microangiopathy - Lupus nephritis - Scleroderma

Answer 159

- Diabetic nephropathy - Sickle cell nephropathy - Amyloidosis - Light chain disease

Answer 160

- HIV-associated nephropathy - Cryoglobulinemia

Answer 161

1. Inflammation of blood vessels as in vasculitides or 2. Loss of thromboresistance as in the thrombotic microangiopathies

Answer 162

- **_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 +)

Answer 163

- 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

Answer 164

- **_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

Answer 165

- Aneurysm - Renal arteriogram of patient with polyarteritis nodosa in the kidney (segmental, transmural, necrotizing)

Answer 166

- _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

Answer 167

- _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

Answer 168

- **_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

Answer 169

- Left: C-ANCA - Right: P-ANCA

Answer 170

- 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 1^o target in sm vessel vasculitis - ANCAs play a significant role in disease genesis - _Important for making the diagnosis AND causing the disease_

Answer 171

- _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

Answer 172

- _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

Answer 173

- **_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

Answer 174

- Vascular necrosis & thrombosis of **_granulomatosis with polyangiitis_** - Former blood vessel

Answer 175

- Crescentic glomerulonephritis of **_granulomatosis with polyangiitis_**

Answer 176

- Glomerular damage of **_granulomatosis with polyangiitis_** - Don’t be too literal about the word crescent -\> may also be all the way around the glomerulus

Answer 177

- _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

Answer 178

- _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)

Answer 179

- 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)

Answer 180

- Thrombotic microangiopathy in a glomerulus (thrombosed capillary) - Decreased resistance to thrombosis

Answer 181

- Thrombotic microangiopathy (thrombosed arteriole) - Decreased resistance to thrombosis

Answer 182

- Verotoxin producing _E. coli H7:O157_ may cause cytotoxic antiendothelial antibodies - _Chemotherapeutic agents_: cyclosporine, gemcitabine, bleomycin/cisplatin - _Radiation_: bone marrow transplant patients

Answer 183

- Multiple pathways - Low levels or Abs to ADAMST13 -\> auto-Ab pts can benefit from plasmapharesis - SLE

Answer 184

- 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

Answer 185

- 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

Answer 186

Systemic lupus erythematosus (SLE) Renal biopsy

Answer 187

- “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

Answer 188

- 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)

Answer 189

- 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

Answer 190

- Lupus nephritis class II: mesangial proliferative - Mild - Increased # of mesangial cells

Answer 191

- Lupus nephritis class III: focal proliferative - Moderate - FSGS would be in the differential here

Answer 192

- 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)

Answer 193

- _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)

Answer 194

- _Lupus nephritis class IV_: diffuse proliferative - Damaged glomerulus, crescent formation, and lots of excess cells of various types - SEVERE - Can have crescents

Answer 195

- Lupus nephritis class V: membranous - Nephrotic

Answer 196

- Lupus nephritis EM: subendothelial and mesangial deposits

Answer 197

- Lupus nephritis EM: subendothelial and mesangial deposits

Answer 198

- Lupus nephritis EM: subendothelial and mesangial deposits

Answer 199

- 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**

Answer 200

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

Answer 201

- _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**

Answer 202

- 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

Answer 203

- **_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

Answer 204

- _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)

Answer 205

- 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

Answer 206

- 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

Answer 207

- Aka, Wegener’s granulomatosis - _Sinopulmonary renal_ disease (classic) - _Pauci-immune_ glomerulonephritis: negative IF staining - Associated with C-ANCA (**PR3-ANCA**) positivity

Answer 208

- _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)

Answer 209

- _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