Pathology Renal Master

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Nephrotic Syndrome vs Nephritic Creatinine levels

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nephrotic-mild elevation
nephritic-very elevated

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Nephrotic vs Nephritic, Hypertension.

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Hypertension in Nephritic;
Nephrotic-no hypertension bc of hypoalbuminemia.

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Nephrotic syndrome cell.

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podocyte.

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nephritic syndrome

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endothelial cell

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Nephrotic sydromes: Podocyte injury

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Minimal Change disease, focal segmental GN

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nephrotic subepithelial disease

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membranous nephropathy

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glomerular cap wall deposition disease

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amyloidosis, light chain deposit disease, diabetic nephropathy

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Nephritic syndromes: subendothelial space/mesangial

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Post infectious GN
IgA nephropathy
Lupus nephritis

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Nephritic syndrome GBM

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anti-GBM disease

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Nephritc syndrome: inflammat of vascular, Glomerular cappilarry wall

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ANCA disease

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Rapidly progressive GN

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-renal failure over days to wks, hematuria, RBC casts

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Nephrotic: Immune Complex mediated diseases; SUBEPITHELIAL DEPOSITS

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1)Membraneous Nephropathy
2)Post-infectious GN: seen in late course of disease

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Nephritic: Immune Complex mediated diseases, Subendothelial and Mesangial deposits

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1)Focal or Diffuse Proliferative Lupus
2)Post infectious GN-early phase
3)IgA Nephropathy: with prominent IgA in mesangium

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Anti GBM basement membrane disease, Immune Complex Mediated

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-usually nephritic w cresentic GN

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if there's generalized edema;

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evaluate for proteinuria

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Xanthelasma in nephrotic syndrome indicates

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hyperlipidemia

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Kidney biopsy Purposes:

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Diagnosis, Prognosis, Guide therapy

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Kidney Biopsy Slide Preps

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LM, Immunoflu, EM

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Foot process effacement

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Minimal change disease

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Spike and dome

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Membranous nephropathy

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Subepithelial humps

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post-infectious GN

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Tram Tracks

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Membranoproliferative GN

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Basketweave

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Alport syndrome

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Wire loops

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Lupus nephritis

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onion-skin

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hypertensive nephropathy or scleroderma

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Glomerular Filtration Barrier

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Based on charge, size(4nm), shape

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Actinin 4 associated w; podocyte problem

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dominant FSGS

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Nephrin 1 associated w

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autorecessive finnish type focal segmental sclerosis

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TRPC6 associated w

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autosomal dominant FSGS

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podocin associated w

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autosomal ressive steriod resistant FSGS

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IgG-Big doesn't pass thru glomerulus,"",,"", B2 microglobulin-Low molecular weight protein

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epithelial cell defects

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protein can pass thru

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Types of Proteinuria:

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1)Glomerular, common you think of, associated w any glomerulonephritis, albunin is dominant proteine
2)Tubular-secondary to tubulointerstitial disease LMW proteins
3)Overflow-Produc and hence filtration exceeds reabsorb capacity, multiple myeloma

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urine dipstick protein it measures

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albumin

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How much too much protein?

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150mg/day uppler limit normal; urine dipstick only picks up over 300mg/day

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how to measure urine protein

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1urine dipstick 2)24 hr urine collection 3)spot urine protein creatinine ratio

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Primary Nephrotic syndrome management

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decrease proteinuria by
1)controlling hypertension thru low salt, angio enzyme inhib (ACEI), Angio receptor blocker (ARB)
2)Steroids and Immunosuppressive drugs

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Secondary Nephrotic management

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decrease proteinuria by 1)Control hypertension 2)treat the cause
-doesn't respond to steroids or immunosuppressives

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nephrotic + nephritic urinary sediment

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inactive urinary sed-Nephrotic;;active urinary sed-Nephritic

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The urinary sediment in nephrotic syndrome can have hyaline casts, granular casts, fatty casts and (white blood cells casts).

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fat oval bodies, maltese cross

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nephrotic

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HUGEEEEEE

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the course of post-infectious glomerulonephritis in general and post-streptococcal glomerulonephritis in particular, the immune complexes tend to be deposited in a subendothelial location, but late in the course of disease, they tend to be deposited in a subepithelial location.

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post infect GM- more common in kids, biospy not big deal ;;;;;;lupus-more common in adults, biopsy big deal

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immune complex trapped bc

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1)high plasma flow rate 2)high intraglom pressure 3)high hydraulic conductivity

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IMPORTANT CONCEPT 5: Microalbuminuria is the earliest clinical manifestation of diabetic nephropathy on the road to end-stage kidney disease

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IMPORTANT CONCEPT 6: Nephrotic range proteinuria is >3.5 grams/day, which correlates with a urine protein/creatinine ratio of >3.5.

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podocytopathies

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minimal change disease, focal segmental Glomerulosclerosis

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minimal change disease

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-most common nephrotic syndrome in children
-pathogenesis not clear-maybe Tcells damage podocytes
-Steroids work for disease; are slow acting
-Recurrence common

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minimal change disease

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effacement and detachment of foot processes

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FSGS

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-hypertension might be high
-scar tissue that forms on glomerulus
-50% of FSGS pts develop end stage kidney disease wi 10 yrs

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FSGS pathogenesis

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Supra
-goes to glomerulus, binds to Beta 3 integrin, messes up attachment and protein escape
-nephrin protein mutations involved

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FSGS caused by gene gene

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APOL1 on chrom 22-increased risk of FSGS and renal failure in African Americans

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focal segmental GS; has hyalinosis, what is hyalinosis

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accum of leaked plasma proteins and lipids

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Are subtypes of FSGS

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Tx of FSGS

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1)steroid and immunosuppressive
2)Response to steroids poor
3)others:calcineurin inhibitors

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Steroids w Minimal Change D and FSGS

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Steroids cause proteinuria to go away in Minimal cd; good
-proteinuria still there FSGS BAD

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Membranous nephropathy

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-antibody antigen complex accumulating in subepithelial space
-70% have autoantibodies to M type phospholipase A2 receptor (PLA2R)
-if antigen goes down; represents good prognosis

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Secondary Membranous Nephropathy

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-can be caused by infection, autoimmune, drugs, malignancy (Cancers)

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Membranous Nephropathy

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-most common cause of nephrotic syndrome in caucasian adults
-predominant 50yr Male
-Spontaneous resolut 30%, Progressive Renal Failure 40%, Persistent proteinuria w/ variable renal dysfunc 30%

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Risk factors for loss of renal function, MN

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Male, proteinuria, hypertension, azotemia, Glomerulosclerosis

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Membran Nephr LM

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thickened basement memb wo increased cellularity

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Membranous Neph Immuno

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have IgG deposits; this is way to different but diabetic nephrop and MN bc diabetic won't have this

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membran nephrop

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-is nephrotic so no inflammati as complement activated
-if disease secondary-resolut of subepithelial deposits is slow

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-retract and effacement of foot processes occurs in presence of subepith deposits
-likely complement dependent process mediated by membrane attack complex;;;; C3 and C5a washed out in urine

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Post infectious GN

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-associated w recent infection; i.e sepsis or streptococcus
-hematuria-tea colored urine
-Low C3, normal C4 (alternative pthy activation)
-Elevated antistreptolysin O (ASO) titers if preceded by throat infection
-Elevated Anti-DNAse B titers if preceded by skin infection
-positive blood culture in sepsis

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Post infectious GN

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-LM::::polys look like ants
-Immunoflouresce:see C3 deposits

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BIG

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Post streptococcal GM: late course in subepithelial, short course of disease- can have subendothilial deposition

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Tx of PIGN

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Supportive measures:
-Control hypertension:antihypertensives, diuretics
-renal replacement therapy if severe kidney dysfunc
Tx of infection:
-good prognosis w/ resolutio of hypertens 3 wks, C3 resolut 6wks, hematuria 12months

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FSGS

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less likely to remit w steroids
-secondary FSGS associated w/ reduced nephron mass

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Membranous nephropathy usually presents with nephrotic syndrome (edema due to proteinuria), but post-infectious glomerulonephritis usually presents with nephritic syndrome (hematuria).

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IMPORTANT CONCEPT 1: Minimal change disease is classically the insidious onset of nephrotic syndrome in a child, with a good response to steroid therapy.

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IMPORTANT CONCEPT 3: The collapsing glomerulopathy type of focal segmental glomerulosclerosis has a rapid onset of nephrotic syndrome with rapid progression to renal failure.

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: 85% of membranous nephropathy cases are primary

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IMPORTANT CONCEPT 5: Autoimmunity with immune complexes formed in situ from the binding of filtered autoantibody to podocyte M-type phospholipase A2 receptor (PLA2R) is probably the pathogenic mechanism causing most primary membranous nephropathy.

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IMPORTANT CONCEPT 7: Post-streptococcal glomerulonephritis is classically the acute onset of nephritic syndrome in a child, with a good prognosis for spontaneous recovery.

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Nephritic immune complex formation; subendothelial/messangial deposits

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-membranoproliferave GN
-IgA nephropathy

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podocyte injury: MCD, FSGS
Immune: Membraneous nephropathy (sub epi), PIGN(sub epi)
Membranopolifiverate GN(sub endo), IgA nephro(mesangial)
GBM disease: Anti GBM disease, Alport's syndrome, Thin basement memb
Vascular Injury: ANCA/pauci, hemolytic uremic syndrome, TTP

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lupus, PIGN- also associated w subendo/mesang immune

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endothelial damage

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-cytokine and autacoids along w/ complent damage endothelial cell, inflammation, hematuria

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Membranoproliferative GN types

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Type 1:most common form, Type 2:Dense Deposit disease
Type 3 rare

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MPGN type 1

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-hypercellular at glomerulus
-hypertrophy in mesangium
-capill wall changes in double contour to GBM, duplication of basement membrane, TRAM TRACK

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MPGN type 1 multiple presentations

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--can present like rapidly progressive GN along w other stuff
- Often associated w HEPATITIS C

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Membranoprolif GN

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-no consensus tx
-rare cases-remission
-usually SLOW progress to end stage renal disease

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Dense Deposit(Type 2 MPGN)

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-similar in presentat to MPGN1
-low C3
-may be assosc w deposits in eyes or partial liodystrophy(loss of subjQ fat in upper half of body)
-EM shows characteristic electron dense deposits in the GBM

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Type 1 MPGN (immune-complex mediated type)

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-CLASSICAL PATHWAY
-damage to endothelial cells, then repair of cells and effacement

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Type 2 MPGN (complement mediated type)
-kind of look same as MPGN1 on microscope

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-ALTERNATIVE PATHWAY
-damage to endothelial cells, then repair of cells and effacement

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IgA nephropathy aka Berger's disease

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-Most common primary glomerulonephritis worldwide
• Characterized by deposition of IgA-containing immune complexes predominantly in the mesangium
• May be primary or secondary
• Secondary IgAN
– Henoch-Schonlein Purpura
– Ankylosing spondylitis
– Dermatitis herpetiformis
– Celiac disease
– Inflammatory bowel disease
– Cirrhosis
– Psoriasis

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IgA nephropathy

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• Typically triggered by an infection of the upper
respiratory or gastrointestinal tract
-"synpharyngitic" – nephritic sediment within 1 to 2
days of infection
-if see this and sore throat: think IgA nephrophrathy
• Galactose deficient IgA1 is produced and forms
immune complexes in the circulation

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Variable Presentat of IgA nephro

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-nephritic syndrome
-assymptomatic
-rapidly progressive GN

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• Risk factors for loss of renal function:

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– Heavy proteinuria
– Decreased GFR at onset
– Older age at onset
– Uncontrolled hypertension
– Crescents and/or tubulointerstitial fibrosis/ atrophy
– Familial forms

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IgA nephropathy pathogenesis

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• Related to under galactosylation of O-linked
glycans in the hinge region of IgA1
• IgG or IgA1 antibodies recognize O-linked
glycans that terminate with Nacetylgalactosamine
instead of galactose
• Circulating immune complexes are formed and
deposit in the mesangium

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GBM Diseases

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1)Anti GBM disease2)hereditary nephritis

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Anti-GBM Disease

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• Results from the formation of autoantibodies against
a noncollagenous portion of the α-3 subunit of type
IV collagen
• Anti-GBM antibodies bind in
a relatively uniform manner leading to a LINEAR (not
granular) appearance on immunofluorescence
• Rapid development of kidney failure due to focal
glomerular necrosis and crescent formation
• Rapidly progressive glomerulonephritis

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Goodpasture's disease (systemic version of Anti GBM)

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• Cough, dyspnea, crackles, hemoptysis may precede or
coincide with renal dysfunction
• Pulmonary hemorrhage exacerbated by exposures to tobacco smoke, influenza, volatile hydrocarbons
• Rapidly progressive renal failure with azotemia at
presentation in 50 to 70% of cases
• Anemia out of proportion to renal insufficiency
• Arthritis/arthralgias common
•• Treated with CORTICOSTEROIDS, PLASMAPHARESIS, and cytotoxic agents

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Cresents

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• The accumulation and proliferation of cells outside
the glomerular tuft which can result in compression
of the tuft with rapid progression to renal failure
• Referred to as diffuse crescentic glomerulonephritis
if >50% glomeruli involved under light microscopy
• Initially characterized by segmental proliferative and
necrotizing lesions - cellular crescents -
fibrocellular crescents - fibrous crescents

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Pathogenesis of crescents

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• Not well characterized
• May be due to severe damage to capillary walls
which tear and necrose the GBM
• Entry of red blood cells, white blood cells, fibrinogen,
and plasma constit enter Bowman's space and cause
cause proliferation of mononuclear cells and parietal
epithelial cells
• Both antibody and cell-mediated processes may be
involved.

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IMPORTANT CONCEPT: Rapidly
progressive glomerulonephritis is not
a medical emergency, but it certainly
does require prompt diagnosis and
treatment to prevent severe
permanent renal damage and failure.

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Alport Syndrome aka Hereditary nephritis
-GBM disease

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-damage to tiny blood vessels in kidney
• X-linked inheritance (defects in α-5 collagen type IV; COL4A5)
in 80% of cases\
• Heterozygous females may have hematuria and thin
basement membranes
• Affected males have persistent hematuria, progressive
proteinuria, and ultimately end stage renal disease
• Associated with sensorineural hearing loss, lens
abnormalities, and platelet defects; rarely esophageal
leiomyomas
• Biopsy shows abnormally thin basement membranes with
splintering of the lamina densa causing a BASKET WEAVE appearence

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GBM

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-results from fusion of endo BM and Epi BM

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Thin basement membrane disease

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• Usually benign as long as heterozygous (NOT
homozygous or compound)
• Associated with defects in α-3 or α-4 collagen
type IV
• GBM thickness is uniformly reduced and
about ½ normal

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Alpha 5 Type 4 Collagen

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Alports

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Alpha 3 Type 4 Collagen

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Goodpastures

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the immune complexes are thought to be usually preformed outside the glomeruli and trapped there in the process of filtration, but in post-infectious glomerulonephritis, some, maybe most, maybe all may be formed in situ in the glomeruli with antigens and antibodies arriving separately.

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Endothelial cell injury, can - in turn – lead to thrombus formation in glomerular capillaries. So glomerular endothelial cell injury and capillary luminal thrombus formation can be a feature, a complication, of nephritic syndrome.

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IMPORTANT CONCEPT 2: Membranoproliferative glomerulonephritis is an uncommon disease that commonly has features of both the nephritic syndrome and the nephrotic syndrome.

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type 2 MPGN

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2 hit mutation disease

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What differentiates type II from type I even more is the presence of the dense deposits in the basement membrane visualized by electron microscopy. These dense deposits in the glomerular basement membrane are often seen separating or “splitting” it into two layers. Type II membranoproliferative glomerulonephritis features ribbons of dense dark material deposited within the glomerular basement membranes on electron microscopy

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IMPORTANT CONCEPT 4: IgA nephropathy is a common cause of nephritic syndrome, and is most common in children, especially east Asians.

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IgA nephropathy differs from post-streptococcal glomerulonephritis in being “synpharyngitic” because the glomerulonephritis, with nephritic urinary sediment occurs within 1 or 2 days of infection.

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, anti-GBM disease is a crescentic necrotizing glomerulonephritis

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Patients with exclusive renal involvement are said to have anti-GBM disease, while those patients with both renal and pulmonary involvement are said to have Goodpasture syndrome.

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IMPORTANT CONCEPT 6: Anti-GBM disease is rare, but significantly more common in men, (especially young men, [especially whites, {particularly those who smoke}]).

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Rapidly progressive (crescentic) glomerulonephritis can be classified by the type of glomerular deposits:

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Type I Linear: anti GBM disease, Goodpastures
Type 2 granular (Immune complex):Primary and Secondary renal disease
Type 3 None (Pauci immune): ANCA Associated or drug induced idiopathic

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Type 2 rapid progressive GN: Plasmapheresis is usually NOT helpful in these patients

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). Those with ANCA in a peri-nuclear distribution (“P-ANCA”) tend to have microscopic polyangiitis with involvement of skin (especially) and other organs besides kidney. Those with ANCA in a diffuse cytoplasmic pattern (“C-ANCA” [yes, it would have made a lot more sense to use the “D” in “diffuse” since they are all cytoplasmic]) tend to have granulomatosis with polyangiitis (Wegener’s), which is characterized by granulomatous vasculitis in 3 places: kidney, lung and upper respiratory tract (nose, mouth and throat).

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IMPORTANT CONCEPT 7: Rapidly progressive glomerulonephritis is not a medical emergency, but it certainly does require prompt diagnosis and treatment to prevent severe permanent renal damage and failure.

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Rapidly progressive glomerulonephritis is a clinical syndrome that can result from any one of several different diseases. Rapidly progressive glomerulonephritis is characterized by nephritic syndrome with rapid loss of renal function, oliguria and, if untreated, death in weeks or months.

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Mutations in the alpha5 chain results in defective heterotrimer assembly and defective basement membranes. This collagen chain is crucial in the formation of the lens, cochlea, and glomeruli; therefore, affected patients have nephritis, nerve deafness, and lens disorders.

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5-Alports,"",,"",3Goodpastures

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IMPORTANT CONCEPT 8: Alport syndrome consists of slowly progressive nephritis, deafness and lens disease due to mutation in the gene for the alpha5 chain of type IV collagen.

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