Nephrology Flashcards
1
Q
Which symptoms often occur with mebranous nephropathy? (4)
A
- Hypertension
- Oedema
- Proteinuria
- Erythrocytes
2
Q
What is the main problem in membranous nephropathy?
A
Inhibited podocyte function
3
Q
Which type(s) of casts can be found in a nephrotic syndrome?
A
Fatty casts
4
Q
Which type(s) of cast can be found in nephritic syndrome?
A
Erythrocyte casts
5
Q
Proteinuria occurs in case of [nephrotic/nephritic] syndrome
A
Proteinuria is characteristic for nephrotic syndrome
6
Q
What is the upper limit of proteinuria in nephritic syndrome?
A
3,5 g/day
7
Q
What is the lower limit of proteinuria in nephrotic syndrome?
A
3,5 g/day
8
Q
Haematuria is characteristic of [nephrotic syndrome/nephritic syndrome], but can also occur in [nephrotic syndrome/nephritic syndrome]
A
Characteristic of nephritic syndrome, can also occur in nephrotic syndrome
9
Q
Oedema is generally more extreme in [nephrotic syndrome/nephritic syndrome]
A
Nephrotic syndrome
10
Q
What are the clinical features of nephrotic syndrome? (3)
A
- Generalized oedema
- Periorbital oedema
- Hypertension
11
Q
What are the clinical features of nephritic syndrome? (2)
A
- Oedema
- Hypertension
12
Q
What is the most common aetiology of chronic kidney disease?
A
Diabetes (44%)
13
Q
What are the 5 most common aetiologies of chronic kidney disease?
A
- Diabetes (44%)
- Hypertension (29%)
- Other (18,4%)
- Glomerular disease (7%)
- Polycystic kidney disease (1,6%)
14
Q
Into which two major groups can glomerular kidney disease be divided?
A
- Primary: caused by processes inside the kidney
- Secondary: caused by processes outside the kidney
15
Q
What are primary glomerular diseases? (5)
A
- Minimal change disease
- Primary focal and segmental glomerulosclerosis (FSGS)
- Membranous nephropathy
- Membranoproliferative glomerulonephritis
- IgA nephropathy
16
Q
What are secondary glomerular diseases? (6)
A
- Lupus nephritis
- Anti-GBM disease
- Amyloidosis
- Infection-related glomerulonephritis
- ANCA-associated vasculitis
- Atypical HUS
17
Q
What are diagnostic blood tests for chronic kidney disease? (5)
A
- Anti-nuclear antibodies (ANA)
- Anti-neutrophil cytoplasmic antibodies (ANCA)
- Anti-GBM antibodies
- Complement C3/C4
- Biomarkers of underlying disease
18
Q
Which biomarkers of underlying disease should be checked in case of chronic kidney disease? (4)
A
- M-protein (haematological malignancy)
- Virology
- Anti-streptolysin titre
- Cryoglobulins
19
Q
What is the cause of decreased podocyte function in membranous nephropathy?
A
Subendothelial deposits of antibodies inside the GBM
20
Q
What is the causative antibody of primary membranous nephropathy?
A
anti-M-type phospholipase A2 receptor = PLA2R
21
Q
What is the function of the M-type phospholipase A2 receptor?
A
Lipid homeostasis of podocytes
22
Q
True or false: anti-PLA2R receptors always have affinity towards the same epitope
A
False; multiple parts of the receptor may raise a reaction
23
Q
What happens after deposition of subendothelial antibodies in membranous nephropathy?
A
- Activation of complement
- Podocyte damage -> disturbed filtration capacity -> proteinuria
24
Q
True or false: membranous nephropathy can only be caused by kidney-specific antibodies
A
False; secondary membranous nephropathy is caused by deposition of non-specific antibodies in the GBM
25
In which two ways can anti-PLA2R antibodies in membranous nephropathy be raised?
1. Autoreactive B-cells bind PLA2R, leading to B-cell activation, antigen internalization & presentation on MHCII
2. Endocytosis of PLA2R by professional APCs in the presence of microbial agents
26
Why is the presence of microbial agents key for APCs to be able to raise an auto-immune response after phagocytosing PLA2R?
Causes the APC to give pro-inflammatory costimulation to CD4+ T-cells
27
What happens after activation of CD4+ T-cells by B-cells/APCs in the raising of anti-PLA2R antibodies in membranous nephropathy?
Germinal centre reaction
28
Which processes happen in the germinal centre reaction of PLA2R-specific B-cells?
1. Affinity maturation
2. Class switch to IgG4
29
What is the most common isotype of anti-PLA2R antibodies in membranous nephropathy?
IgG4
30
Which steps in the raising of anti-PLA2R antibodies in membranous nephropathy may be blocked? (3)
1. DC activation/co-stimulation of T-cells
2. Clonal expansion of autoreactive B-cells
3. Production of auto-antibodies by plasmablasts
31
How is membranous nephropathy diagnosed?
Serology + kidney biopsy
32
How can a kidney biopsy confirm membranous nephropathy?
Anti-PLA2R antibodies concentrated on the GBM of the kidney
33
Why is kidney biopsy more sensitive for the diagnostics of membranous nephropathy than serology?
Anti-PLA2R titres in serum may be low, while these antibodies accumulate in the kidney due to their specificity
34
What is the 5-, 10- and 15-year prognosis of (primary) membranous nephropathy?
5-year: ~60% survival
10-year: ~40% survival
15-year: ~30% survival
35
What is the main treatment goal when treating membranous nephropathy?
Prevent kidney failure
36
True or false: membranous nephropathy can resolve itself through spontaneous remission
True
37
Which targets can be identified for the treatment of membranous nephropathy? (3)
1. T-cells & cytokines
2. B-cells
3. Complement
38
What is the most frequently used treatment for membranous nephropathy?
Rituximab (anti-CD20)
39
What is the second line treatment for membranous nephropathy (after rituximab failure)?
Cyclophosphamide
40
What are the side effects of treatment with cyclophosphamide? (2)
1. Infertility
2. Kaposi sarcoma
41
How can kidney failure be treated if it does occur in membranous nephropathy?
1. Dialysis (=bridging therapy)
2. Kidney transplant (=only permanent solution)
42
Which parameters are used to determine the treatment success of membranous nephropathy treatment? (5)
1. Proteinuria (filtration capacity)
2. eGFR (kidney function)
3. Creatinine (kidney function)
4. Serum albumin (filtration capacity)
5. Antibody titre
43
What are fragmentocytes in a blood sample indicative of?
Erythrocyte lysis
44
What is a low haptoglobin indicative of?
Erythrocyte lysis
45
What is the function of haptoglobin?
Binding of free haemoglobin in circulation
46
What are the three hallmarks of haemolytic uraemic syndrome?
1. Microangiopathic haemolytic anaemia
2. Thrombocytopenia
3. Acute kidney injury
47
Which to processes occur in microangiopathic haemolytic anaemia? (2)
1. Small vessel disease
2. Destruction of erythrocytes
48
How does erythrocyte destruction occur in microangiopathic haemolytic anaemia?
Fibrin sheaths in the small blood vessels lyse erythrocytes
49
How does acute kidney injury in haemolytic anaemic syndrome occur?
Narrowing & occlusion of renal arterioles by thrombi & erythrocytes
50
What is 'typical' HUS?
STEC-HUS -> caused by Shiga toxin-producing E. coli (STEC)
51
In which group does STEC-HUS most frequently occur?
Childeren <5 years (90%)
52
What is the incidence of STEC-HUS in children?
~3/100.000
53
What is the epidemiological pattern of STEC-HUS?
Outbreaks -> occurs in parallel with Shiga toxin-producing E. coli outbreaks
54
What is the most common trigger/cause of HUS in adults?
Coexisting disease
55
Which coexisting diseases can trigger HUS in adults? (7)
1. HSCT
2. Solid organ transplantation
3. Malignancy
4. Auto-immune diseases
5. Drugs
6. Malignant hypertension
7. Pre-existing nephropathy
56
What is atypical HUS?
Complement-mediated TMA
57
What is the incidence of atypical HUS? In which group does it mostly occur?
~7/million, mostly in children
58
What is TMA? (complement-mediated TMA = atypical HUS)
Thrombocytic microangiopathy
59
What is the cause of atypical HUS/anti-TMA syndrome? What are the underlying problems?
Dysregulation of the alternative complement pathway due to
1. Antibodies against complement factor H
2. Mutations in complement factor H
60
What is an important underlying principle of the complement system?
Depends on cleavage concepts of readily available proteins, which leads to rapid amplification of the response
61
What is the end stadium of all complement pathways?
Formation of membrane attack complexes (MAC)
62
Which two steps are central to all complement pathways?
1. C3 convertases
2. C5 convertases
63
How is the alternative complement pathway activated?
Continuous low-level deposition of C3 on all cells
64
How does the alternative complement pathway prevent attack on human cells?
Human cells express inhibitory proteins that block this complement pathway
65
Which two mechanisms do human cells use to inhibit the alternative complement pathway?
1. Prevention of association between C3b and Bb
2. Regulation of MAC-formation
66
How do self-cells prevent the association between C3b and Bb? (3)
1. Decay-associated factor prevents association between C3b and fB on the cell surface
2. CD46 stabilizes factor I on the surface -> inhibitory
3. Soluble factor H prevents factor B binding to C3 & promotes their dissociation
67
What is de CD number of decay-associated factor? What is its abbreviation?
CD55 = DAF
68
What is the precursor of factor Bb?
fB
69
What is the function of DAF in the regulation of the alternative complement pathway?
Prevents association between C3b and Bb fB on the cell surface -> stops early activation of the alternative complement pathway
70
What is the function of factor I in the regulation of the alternative complement pathway?
Stabilizes association of fH to C3b -> prevents C3b binding to fB
71
Which molecule do self-cells use to prevent MAC-formation on their surface?
CD59
72
What is the mechanism by which CD59 prevents MAC formation?
Prevents C8-C9 association
73
What happens when human cells cannot effectively regulate (the alternative) complement pathway(s)?
Complement attack on se-flcells
74
Which molecule inhibits the classical and mannose complement pathways?
C1-inh
75
What is the mechanism by which C1-inh prevents complement activation?
Irreversibly inactivates C1r/C1s (classical pathway) or MASP (mannose pathway)
76
What are the main complement factors that affect clotting?
1. C5a
2. MAC
77
Which effects does MAC have on clotting? (3)
1. Activates platelets
2. Induces erythrocyte lysis
3. Induces endothelial cell damage --> extra clotting surface
78
What effects does C5a have on clotting? (3)
1. Activates platelets
2. Expression of tissue factor
3. Plasminogen-activator inhibitor 1 (PA-I1)
79
Which major factors can disturb complement regulation? (2)
1. Gene mutations
2. Anti-fH antibodies
80
Which gene mutations can cause complement dysregulation? (4)
1. Factor H/factor I mutations
2. CD46/MCP defects
3. C3 mutations blocking fH-binding
4. Gain-of-function mutation of fB
81
Which strategies can be used for the treatment of aHUS? (4)
1. Plasmapheresis
2. Dialysis to replace kidney function
3. Kidney transplantation
4. Complement-targeting biologicals
82
What is the biggest determinant of aHUS disease recurrence after kidney transplantation?
Dependent on underlying mutation ->
-If mutation in soluble factor (fH, fI, C3, fB) -> not removed by replacing organ
-If mutation on cell surface (CD46) -> solved with donor organ
83
Which two drugs are currently commonly used for complement inhibition? Which protein do they target?
Eculizumab/ravulizumab -> target C5
84
Which 3 goals are the main research goals needed to improve treatment for aHUS?
1. Improved understanding of complement regulation
2. Discovery of new causative mutations/antibodies
3. Diagnosis of previously undiagnosed complement dysregulation
85
Why are there likely a high number of undiagnosed aHUS cases?
Often misdiagnosed as end-stage kidney disease due to hypertensive nephropathy -> underlying complement disorder missed
