Day 2 reading - Robbins page 914-922 Nephrotic Syndrome Flashcards
A derangement in glomerular capillary walls resulting in increased permeability to plasma proteins is called?
Nephrotic syndrome
What are the manifestations of neprotic syndrome? Give levels where appropriate.
(4)
- Massive proteinuria - daily loss of 3.5 gm or more of protein (less in kids)
- Hypoalbuminemia - plasma levels below 3 gm/dl
- generalized edema
- hyperlipidemia and lipiduria
What is the edema seen in nephrotic syndrome a direct consequence of? What further aggravates this?
decreased intravascular colloid osmotic pressure. The edema is further aggravated by water and sodium retention
The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria.
What does a highly selective proteinuria consist of?
Mostly low-moleculaar-weight proteins (albumin, 70kD, transferrin, 76 kD)
What does a poorly selective proteinuria consist of?
Higher molecular weight globulins in addition to albumin
Nephrotic patients are especially vulnerable to infection by what agents?
Staphylococcal and pneumococcal infections
What impact does nephrotic syndrome have on the coagulation cascade? What consequence do some of these patients encounter as a result?
Causes loss of endogenous anticoagulants (antithrombin III in particular) in the urine. This can lead to thrombotic and thromboembolic complications.
What are the three most common systemic causes of nephrotic syndrome?
- Diabetes
- Amyloidosis
- SLE
What are the most important causes of primary glomerular lesions?
- Minimal change disease
- membranous glomerulopathy
- focal segmental glomerulosclerosis
In what population is minimal change disease most common?
Children in N. america
In what population is membranous glomerulopathy most common?
Adults
Who do we see focal segmental glomerulosclerosis in?
Older adults
What is membranous nephropathy characterized by?
Thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the subepithelial side of the basement membrane.
What percent of membranous nephropathy cases are primary?
~75%
What are the notable associations with secondary membranous nephropathy?
- Drugs
- Underlying malignant tumors
- SLE
- Infections
- Thyroiditis (and other autoimmune disorders)
Name four drugs associated with secondary glomerulonephritis!
- penicillamine
- captopril
- gold
- NSAIDs
What underlying malignant tumors are associated wtih secondary membranous glomerulonephritis?
Carcinomas of the lung, colon and melanoma
What are 5 infections that are associated with secondary membranous glomerulonephritis?
- Chronic hepatitis B
- Hepatitis C
- Syphilis
- Schistosomiasis
- Malaria
Primary membranous nephropathy, AKA idiopathic nephropathy, is considered to be what kind of disease?
Autoimmune, linked to HLA alleles such as HLA-DQA1 and caused in most cases by antibodies to a renal autoantigen.
What is most often the autoantigen in primary membranous nephropathy?
The renal phospholipase A2 receptor
How does the glomerular capillary wall become leaky in membranous nephropathy?
It seems that the Crb-C9 membrane attack complex activates glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which injur the capillary cell wall and increase protein leakage.
By light microscopy, the glomeruli in membranous glomerular nephropathy either appear normal in the early stages of the disease, or exhibit…?
Uniform, diffuse thickening of the glomerular capillary wall
Shown is a silvel methenamine stained glomerulus. What is the condition we see here?
What does the arrow in the top left image reveal?
Membranous glomerulo nephropathy
Arrow indicates prominent “spikes” of silver staining matrix projecting from the basement membrane lamina densa towards the urinary space. These seperate and surround deposited immune complexes that lack affinity for the silver stain.
How does membranous nephropathy typically present clinically?
Insidious onset of nephrotic syndrome, or in 15% of patients, with nonnephrotic proteinuria.
Hematuria and mild HTN are present in 15% to 35% of cases.
What are the odds of complete or partial remission in a membranous nephropathy patient?
up to 40%
Antibodies to what receptor may be a useful marker of membranous nephropathy?
PLA2 receptor
What is minimal change disease characterized by?
diffuse effacement of foot processes of visceral epitheliar cells (podocytes), detectable only by electron microscopy, in glomeruli that appear virtually normal by light microscopy
When do we see the peak incidence in nephrotic syndrome? (age)
2 to 6 years of age/
Minimal change disease may arise following what two situations?
Routine prophylactic immunization
a previous respiratory infection
Although the absence of immune deposits in the glomerulus excludes classic immune complex mechanisms, several features of the disease point to an immunological basis. What are they? (5)
- association with respiratory infections and immunizations
- responds to corticosteroroids and other immunosuppressive therapies.
- associated with other atopic disorders like eczema and rhinitis
- association of some HLA haplotypes in min. change patients with atopy
- increased incidence of minimal-change disease in patients with Hodgkin lymphoma
The exact mechanism of minimal change damage is somewhat of a mystery.
What do the ultrastructural changes seen in patients point to?
What do animal models suggest?
Ultrastructural changes indicate primary visceral epithelial cell injury (podocytopathy) and studies in animal models suggest the loss of glomerular polyanions.
What is the principal lesion in minimal-change disease?
The visceral epithelial cells (podocytes) show a uniform and diffuse effacement of foot processes, being reduced to a rim of cytoplasm with loss of recognizable intervening slit diaphragms.
Foot process effacement is also present in other proteinuris states such as membranous nephropathy and diabetic nephropathy; what is required to make a diagnosis of minimal-change disease?
The effacement of the podocytes must be visible by light microscopy.
In minimal change disease do immunoflourescence studies show Ig or complement deposits?
Nope
In the attached image, identify the following…
- CL
- P
- M
- That which the arrows are the top of the image are indicating
What is this disease?
- capillary lumen
- Podocyte cell body
- mesangium
- Effacement of foot processes
Minimal change disease
What is the selectivity of proteinuria associated with minimal change disease?
Highly selective, with most of the protein being albumin
What is a characteristic therapeutic feature of minimal change disease?
Its usually dramatic response to corticosteroid therapy
What is the most common cause of nephrotic syndrome in adults in the US?
Primary focal segmental glomerulosclerosis
Primary focal segmental glomerulosclerosis is sometimes considered a primary disorder of what?
Podocytes, like minimal-change disease
Primary focal segmental glomerulosclerosis is frequently manifest clinically by the acute or subacute onset of nephrotic syndrome or nonnephrotic proteinuria. What are some commonly associates presentations when first clinically recognized?
- HTN
- Microscopic hematuria
- some degree of azotemia
Primary focal segmental glomerulosclerosis occurs in what settings?
- As a primary disease
- In association with other diseases
- HIV
- heroin addiction
- sickle-cell disease
- massive obesity
- As a secondary event, reflecting scarring of previously active necrotizing lesions. (e.g. IgA nephropathy)
- as a component of the adaptive response to loss of renal tissue
- In uncommon inherited forms of nephrotic syndrome
- genes encoding proteins localized to the slit diaphragm
- podocin
- Alpha-actinin 4
- TRPC6
- genes encoding proteins localized to the slit diaphragm
How do the clinical signs of idiopathic focal segmental glomerulosclerosis differ from minimal-change disease?
- Higher incidense of…
- hematuria
- decreased GFR
- HTN
- Proteinuria is more often nonselective
- poor response to corticosteroid therapy
- progression Chronic kidney disease with at least 50% developing ESRD in 10 years
The discovery of a genetic basis for some cases of FSGS and other causes of the nephrotic syndrome has improved the understanding of the pathogenesis of proteinuria in the nephrotic syndrome and has provided new methods for diagnosis and prognosis of affected patients. Leading examples of this include?
- NPHS1 - 19q13: Encodes the protein nephrin (key component of the slit diaphragm)
- NPHS2 - 1q25-q31: Encodes podocin (also localized to slit diaphragm)
- Gene for actin binding alpha-actinin 4
- Gene encoding TRPC6
What are the four proteins that are impacted in FSGS?
Podocin
Nephrin
Alpha-actinin 4
TRPC6
Renal ablation FSGS, a secondary form of FSGS, occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue. Particularly striking examples where this occurs are?
- Reflux nephropathy
- Unilateral Agenesis
What might you see in FSGS on light microscopy?
Focal and segmental lesions may involve only a minority of the glomeruli and may be missed if the biopsy contains an insufficient number of glomeruli.
What will you see in the sclerotic segments in FSGS?
Collapse of capillary loops, increased matrix and segmental deposition of plasma proteins along the capillary wall (hyalinosis) which can even occlude capillary lumens.
Lipid droplets and foam cells are often present.
Glomeruli that do not show segmental lesions usually appear normal in FSGS on light microscopy, but…
may show increased mesangial matrix
What happens if FSGS progresses?
Increased numbers of glomeruli become involved and sclerosis spreads within each glomerulus. In time this leads to total (global) sclerosis of glomeruli with pronounced tubular atrophy and interstitial fibrosis.
In the photo on the left, what do you see going on?
The right most glomerulus shows segmental sclerosis.
In the image at right, what do you see going on?
Hyalin insudation (arrow) and lipid (small vacuoles) in sclerotic area``
What is collapsing glomerulopathy characterized by?
Retraction and/or collapse of the entire glomerular tuft
What is the most characteristic lesion of HIV-associated nephropathy?
proliferation and hypertrophy of glomerular visceral epithelial cells.
Collapsing glomerulopathy is typically associated with prominent tubular injury with formation of what? What is the prognosis?
Microcysts
Particularly poor prognosis
What type of glomerulonephritis is best considered a pattern of immune mediated injury rather than a specific disease?
Membranoproliferative glomerulonephritis (MPGN)
MPGN is classified in two types. What is type one characterised by?
Type I - deposition of immune complexes containing IgG and complement
What is the most important factor in type II MPGN?
What group of disorders do these belong to?
Activation of complement is the most important factor (dense deposit disease)
C3 glomerulopathies
What is MPGN characterized by histologically?
- Alterations in GBM
- Proliferation of glomerular cells
- leukocyte infiltration
- deposits in mesandial regions and capillary walls
How are the deposits different between type I and II MPGN?
Type I - composed of immune complexes
Type II - deposits are unknown material, and C3 is not found in them. Rather it is found on the GBM.
In most cases of type I MPGN there is evidence of what?
Immune complexes in the glomerulus and activation of both classical and alternative complement pathways.
What do the glomeruli look like in MPGN?
Large and hypercellular with a “lobular” appearance due to the proliferating mesangial cells and increased mesangial matrix.
In MPGN the GBM is thickened and shows a double-countour or tram-track appearance. What is this caused by?
Duplication of the basement membrane - commonly referred to as splitting.
What disease is shown here? How do you know?
Membranoproliferative glomerulonephritis
- presence of mesangial cell proliferation
- increased mesangial matrix
- basement membrane thickening with segmental splitting
- accentuation of lobular architecture
- swelling of cells lining peripheral capillaries
- influx of leukocytes
What disease is shown here?
What is indicated by the blue arrows?
What does the red dashed arrow show?
Type II MPGN
Markedly dense homogenous deposits in GBM (blue)
Large disruption in basement membrane = hematuria
What is the typical outcome of primary MPGN?
Few remissions occur, sith most cases progressing inexorably to crescents and a clinical picture of RPGN. ~50% develop chronic renal failure in 10 years.
Treatments with steroids, immunosuppressants and antiplatelet drugs are innefective.
Secondary MPGN (invariably type I) is more common in adults and arises in what settings?
- Chronic immune complex disorders - SLE, Hep B and C infections, etc.
- Alpha-1 antitrypsin deficiency
- malignant diseases - lymphoid tumors like chronic lymphocytic leukemia
What do most patients with dense deposit disease (formerly type II MPGN) have abnormalities with?
Excessive activation of the alternative complement pathway
Patients with dense deposit disease consistenly present with decreased serum levels of what?
C3, Factor B and properdin
What do more than 70% of Dense deposit disease patients have?
C3 nephritic factor - binds the alternative pathway convertase and prevents its inactivation.
What is the defining histologic feature of dense deposit disease?
On electron microscopy, the permeation of the lamina densa of the GBM by a ribbon-like, homogeneous, extremely electron dense material of unknown composition.
What is the prognosis of dense deposit disease?
Poor, ~50 progress to ESRD. There is a high incidence of recurrence in transplant recipients, with dense deposits recurring in 90% of such patients. Though renal failure in the allograft is much less common.
