Disorders Of Glomerular Function

Question 1

Azotemia definition

Answer 1

Elevation of BUN and creatinine levels in blood

Almost always means decreased GFR

Question 2

Prerenal vs postrenal azotemia

Answer 2

Prerenal = usually means hypoperfusion of the kidneys due to reduced ECF (ischemia)

Postrenal = urine outflow is obstructed

Question 3

Uremia definition

Answer 3

Azotemia + clincial manifestations and biochemical abnormalities
- includes but not limited to: dehydration, edema, metabolic acidosis, anemia, HTN, CHF, N/V, myopathy, bleeding, esophagitis, puritis /dermatitis

failure of renewal excretory function and metabolic functions

Question 4

Classic presentation of nephrotic syndrome

Answer 4

Proteinuria (>3.5g daily protein loss)

Hypoalbuminemia (<3g/dL)

Generalized edema

Hyperlipidemia

numerous causes but all share in a derangement in capillary walls of the glomeruli that results in increased permeability to proteins

Question 5

Why does nephrotic syndrome sometimes lead to anasarca (generalized widespread edema)?

Answer 5

Decreased intravascular volume causes renin release in JG cells and triggers the RAAS pathway.
- RAAS pathway results in salt and water retention

Also long standing proteinuria eventually leads to hypoalbuminemia which secondarily casues water to move out of extracellular fluid and into interstitial space = edema/anasarca

Question 6

Nephritic syndrome classic presentation

Answer 6

Hematuria

Proteinuria (<3.5g/dL)

Azotemia

Hypertension

may present with or without edema

caused by inflammatory lesions of glomeruli which leads to infiltration of leukocytes into the glomerulus. This inflammation allows RBCs to pass through the glomerulus and reduce GFR

Question 7

Why does nephritic syndrome show HTN?

Answer 7

A combo of fluid retention and RAAS pathway activation

Question 8

Rapidly progressing glomerulonephritis

Answer 8

Rapid loss of renal function within a few days- 2 weeks
- almost always accompanied by nephritic syndrome and is not a specific etiology itself.

histology shows crescentic Glomerulonephritis

causes renal failure within months if not treated

Question 9

Chronic kidney disease

Answer 9

Results form any process that induces progressive scarring of the kidney

Almost always presents with

• hyperphosphatemia
• dyslipidemia
• metabolic acidosis
• uremia

Question 10

What two mechanisms of antibody deposition in the glomerulus is known to occur?

Answer 10

1) deposition of circulating Ag-Ab complexes in the glomerular capillary wall

2) antibodies reacting in situ within the glomerulus either with themselves of other extrinsic molecules
- endogenous = SLE
(Shows linear pattern of staining in IF microscopy of the GBM)

• exogenous = Hep B/parasites, spirochete infections
  (Shows granular pattern of staining in IF microscopy of the GB)

Question 11

Mediating immune pathway to glomerular injury

Answer 11

complement activation and recruitment of leukocytes
- complement is activated via the classical pathway and leads to generation of chemotactic agents (C5a) for neutrophils and monocytes

Question 12

Does primary or secondary glomerular diseases more often cause nephrotic syndrome?

Answer 12

Children = primary

Adults = secondary

Question 13

Minimal-change disease

Answer 13

Is the most frequent cause of nephrotic syndrome in children
- especially in ages 1-7yrs

Shows glomeruli that have a normal apperance by light microscopy with only diffuse effacement of the foot processes of the podocytes

Is relatively benign outside of clinical manifestations of nephrotic syndrome and easily treatable

Question 14

Minimal change disease treatment and clincial features

Answer 14

Usually only shows selective proteinuria for albumin with abrupt nephrotic syndrome
- NO HTN and decreased renal function

90% if children respond to short course of corticosteroid therapy
- 66% however show recurrence of proteinuria

5% develop CKD after 25 years (believed to be due to hidden underlying focal segmental glomerulosclerosis

adults respond also to steroids but response is slower and relapses are more common

Question 15

Focal segmental glomerulosclerosis (FSGS)

Answer 15

Sclerosis of some but not all glomeruli that involves only a part of each affected glomerulus

Can be primary or secondary
- primary = HIV infections, heroin abuse, IgA nephropathy, inherited disorders

is the most common primary cause of nephrotic syndrome in adults (35%)

is believed that minimal-charge disease can transform into FSGS overtime, but both are still independent entities

Question 16

FSGS clinical course and treatment

Answer 16

FSGS and minimal change disease look very identical
- HOWEVER, FSGS has high hematuria and HTN rates with non selective proteinuria

Responds poor to corticosteroid therapy

50% of patients with FSGS develop end-stage renal disease

Question 17

Membranous nephropathy

Answer 17

Subepithelial immunoglobulin containing deposits along the glomerular basement membrane

Light microscopy shows diffuse thickening of the capillary wall with deposits

only really shows up in adults between ages 30-60

• 80% of cases are primary and caused by auto-antibodies against podocyte antigens*
• other 20% are secondary to infections, autoimmune diseases, exposure to inorganic salts and medications

Question 18

Pathogenesis of membranous nephropathy

Answer 18

Chronic immune complex glomerulonephritis induced by antibodies reacting in situ
- most frequent one is podocyte antigen phospholipase A2 receptor

Immune complex leads to spontaneous MAC compliment formation and causes podocyte injury with non selective proteinuria

Question 19

Membranous nephropathy morphology

Answer 19

Diffuse thickening of the capillary walls with subepithelial deposits in the GBM with spike like protrusions
- forms a “spike and dome” pattern

Question 20

Membranous nephropathy clincial features

Answer 20

Sudden onset full-blown nephrotic syndrome
- nonselctive proteinuria that is less then 3.5 g/dL

Falls steroid therapy almost always and usually requires treatment of the secondary cause ( if present)

Question 21

Membranoproliferative glomerulonephritis (MPGN)

Answer 21

Alterations in the GBM and proliferation of the actual glomeruli cells

• accounts for 10% of all nephrotic syndrome cases
• can show non-nephrotic proteinuria or a combined nephrotic-nephritic symptoms
• *there are two types, with MPGN type 1 being far more common (80%)**
• type 1 = idiopathic immune complex deposition with unknown antigen

Poor prognosis with 50% of cases a showing nephrotic syndrome

Question 22

C3 glomerulopathy

Answer 22

Encompasses two conditions, dense deposit disease and C3 glomerulonephritis

Super rare and only differs based on electron microscopy

Can show nephrotic or nephritic syndrome and varying levels of protienuria

Both has very poor prognosis with post-translation rates of up to 85%

Question 23

Pathogenesis of C3 glomerulopathy

Answer 23

Acquired or hereditary abnormalities of the alternative pathway of complement activation is the cause of both dense deposit disease and C3 glomerulonephritis

most patients present with an autoantibody against C3 convertase (C3NeF). This causes uncontrolled cleavage of C3 and activation of the alternative complement pathway

Question 24

Acute postinfectious glomerulonephritis

Answer 24

Caused by glomerular deposition of immune complexes after an infection. Develops linear IgG and complement immune complexes and damages cells in the glomerulus

• most common is streptococcal species (usually have to be B-hemolytic)
• others include: pneumococcal, mumps/measles/hep B/C

Typical case develops 1-4 weeks after recovering from a group A streptococcal infection

Question 25

Clincial presentation of acute postinfectious glomerulonephritis

Answer 25

Acute nephritic syndrome is most common - presents with red cell casts - mild proteinuria (<1 gm/day) - low serum compliment levels Symptoms - malaise - fever - nausea - oligouria - hematuria (“cola colored urine”) - periorbital edema - mild HTN **also shows elevated anti-steptolysin O antibodies**

Question 26

IgA nephropathy

Answer 26

* *most common cause of recurrent microscopy or gross hematuria** - most common glomerular disease revealed in renal biopsy worldwide Usually affects children and young adults after a nonspecific upper-respiratory tract infection - begins 1-2 days after the upper-respiratory infection as a episode of gross hematuria - usually goes away after several days but can recur periodically in the setting of a viral infection ***all mark is deposition of IgA in the mesangium only, henoch-Schonlein purpura is systemic IgA deposition ***

Question 27

Pathology of IgA nephropathy

Answer 27

Abnormally Glycosylated IgA1 immunoglobulin Elicits autoimmune responses to self cells and forms large immune complexes with circulating IgA **the presence of C3 complement and the absence of C1q/C4 complement in IgA nephropathy signifies this is a alternative complement pathway**

Question 28

Clincial features of IgA nephropathy

Answer 28

Gross hematuria after unspecified upper respiratory infection - sometimes can be UTI or GI infection. But it’s rare Symptoms: (highly variable amoung patients) - flank pain - mild proteinuria - red blood cell casts

Question 29

Hereditary nephritis

Answer 29

A group of glomerular diseases caused by mutations in the BGM proteins Contains alport syndrome and thin basement membrane disease Most of them affect type 4 collagen

Question 30

Alport syndrome

Answer 30

When fully developed, shows grooms hematuria with red blood cell casts and progression to chronic renal failure - also shows deafness and sight disorders (lens dislocation, cataracts, etc.) - symptoms start to appear at 5-20yrs of age Is an X-linked disease - males almost always express fully developed, where as females usually just present with hematuria **90% of males progress to end stage renal disease before 40 yrs**

Question 31

Alport syndrome pathogenesis

Answer 31

Manifestations are due to mutations in one of the collagen type 4 genes seen on chromosome 2 or 13 - there are more than 500 different mutations Always results in defective ensemble and shows loose poorly defined collagen type 4 - defects in GBM, lenses and the cochlea are seen because of this Shows really irregular basement membranes in GBM (basket-weave appearance)

Question 32

Thin basement membrane disease | Benign familial hematuria

Answer 32

Very common hereditary issue that presents with asymptomatic hematuria - can show proteinuria also but renal function is not affected and prognosis is excellent Shows diffuse thinking of the GBM (150-225nm)

Question 33

pathology of thin basement membrane disease

Answer 33

Mutations in a3/a4 chains of type 4 collagen Almost always autosomal inheritance and familial heterozygous is most commonly seen

Question 34

Rapidly progressing glomerulonephritis | Crescentic glomerulonephritis

Answer 34

*always shows crescentic glomerulonephritis* Characterized by rapid loss of renal function, severe oligouria, azotemia and nephritic syndrome - if untreated rapidly presents to renal failure - prognosis is based on fraction of involved glomeruli (<80% = good prognosis) Is associated with: - good posture syndrome type-1 - immune complex mediated type-2 (IgA nephropathy, poststrep GN, henoch-Schonlein purpura, etc.) - pauci-immune type-3 (ANCA disorders, idiopathic, Wegener, microscopic polyangitis )

Question 35

Goodpasture syndrome

Answer 35

Linear deposits of IgG/C3 complexes and development of anti-GBM antibodies - develops pulmonary hemorrhages w/ hemoptysis and renal failure overtime Requires plasmapheresis to cure

Question 36

Chronic glomerulonephritis

Answer 36

End-stage glomerular disease that has a variety of features and reasons it develops Shows diffuse scarring of glomeruli that stains blue and/or acellular eosinophilic masses on H and E sections Symptoms: - proteinuria - HTN - azotemia - non specific symptoms: anemia/vomiting/fatigue - edema ***MUST receive wither dialysis or renal transplant or the patient will die***

Question 37

What are the 6 patterns of glomerular disease seen in SLE?

Answer 37

Class 1 = minimal mesangial lupus nephritis - **least common pattern** Class 2 = mesangial proliferative lupus nephritis Class 3 = focal lupus nephritis - ** <50% of glomeruli are in involved - mild hematuria and proteinuria with red blood cell casts - often progresses to diffuse without treatment Class 4 = diffuse lupus nephritis - **most common pattern** - also most severe other than class 6 - >50% of glomeruli affected Class 5 = membranous lupus nephritis - idiopathic immune complexes forms Class 6 = advanced sclerosing lupus nephritis - **90% of more glomeruli are sclerotic and begins end stage renal failure

Question 38

Diabetes mellitus

Answer 38

Group of metabolic disorders that all share hyperglycemia as an effect - can be defects in insulin secretion ro inability to respond to insulin Secondary damage is seen in the following organs: - kidneys - eyes - nerves - blood vessels **is the leading cause of end-stage renal disease, adult-onset blindness and atraumatic lower extremity amputations**

Question 39

What are the 3 lesions in kidneys affected by diabetes nephropathy

Answer 39

1) glomerular lesions - most important is capillary basement membrane thickening 2) renal vascular lesions via arteriolosclerosis 3) pyelonephritis/ necrotizing papillitis

Question 40

Diabetes mellitus pathology related to kidney

Answer 40

*if glomerulosclerosis is present, often develop nephrotic syndrome* Pathology = almost always shows diffuse GBM thickening and Nodular glomerulosclerosis (kimmelstiel-Wilson lesion) - both result in scarring of kidneys and ischemia of the kidneys