Immunological Aspects of the Renal System Flashcards
1
Q
What is the functional criteria and structural criteria for no kidney disease (NKD)?
A
Functional criteria:
GFR>=60 mL/min per 1.73 m^2
Stable SCr (serum creatinine)
Structural criteria:
No damage
2
Q
What is the functional criteria and structural criteria for acute kidney injury (AKI)?
A
functional criteria:
increase in SCr (serum creatinine) by 50% within 7 days, or increase in SCr by 0.3 mg/dL within 2 days, or Oliguria
structural criteria:
no criteria
3
Q
What is the functional criteria and structural criteria for chronic kidney disease (CKD)?
A
functional criteria:
GFR<60 ml/min per 1.73 m^2 for >3 months
structural criteria:
kidney damage for > 3 months
4
Q
Risk factors for kidney disease
A
age race or ethnic groups genetic factors hypertension diabetes melliuts metabolic syndrome
5
Q
kidney disease modifiers
A
severity of acute kidney injury stage of chronic kidney disease number of episodes duration of acute kidney injury proteinuria
6
Q
outcomes of kidney injury/disease
A
cardiovascular events kidney events ESRD (end stage renal disease) disability diminished quality of life death
7
Q
What is the major filtering organ?
A
kidneys
8
Q
How much human body mass are the kidneys?
A
0.5%
9
Q
How much CO do the kidneys receive?
A
20% of total CO
about 1L/ml
more than any other organ in the body
10
Q
What is the high oxygen demand in the kidneys associated with?
A
tubular oxygen consumption necessary for solute reabsorption
11
Q
What does AKI stand for?
A
ischemic acute kidney injury
12
Q
What does AKI lead to?
A
metabolic acidosis and ATP depletion
major cause of acute renal failure (ARF)
13
Q
What does ARF stand for?
A
acute renal failure
14
Q
What is ARF?
A
abrupt decrease in kidney function
15
Q
What is the incidence of AKI?
A
5% of hospitalized patients
30% of critically ill patients
16
Q
What are the causes of kidney hypoperfusion and AKI?
A
- intravascular volume depletion and hypotension
- hepatorenal syndrome
- renal vascular disease
- sepsis
- medications
- decreased effective intravascular volume
All lead to hypoxia and acute kidney injury
17
Q
How can intravascular volume deplesion and hypotension occur?
A
GI tract losses
renal losses
dermal losses
hemorrhage
18
Q
What are causes of renal vascular disease?
A
Large vessel
- renal artery thrombosis
- arterial occlusion during surgery
- renal artery stenosis
Small vessel
- vasculitis
- arthroembolism
- hemolytic uremic syndrome/thrombotic thrombocytopenic purpura
- malignant hypertension
- scleroderma
- preeclampsia
- sickle cell anemia
- hypercalcemia
- transplant rejection
19
Q
What are medications that cause AKI?
A
- cyclosproin A
- tacrolimus
- angiotensin-converting enzyme inhibitors
- nonsteroidal antiinflammatory drugs
- radiocontrast agents
- amphotericin
20
Q
What causes decreased effective intravascular volume?
A
- congestive heart failure
- cirrhosis
- nephrosis
- peritonitis
21
Q
What is the cause of AKI in most cases?
A
STERILE INFLAMMATION;
not infection
22
Q
What is sterile inflammation induced by?
A
intrinsic damage-associated molecular patterns (DAMPs)
23
Q
Where are DAMPs released?
A
dying parenchymal kidney cells
24
Q
When are DAMPs generated?
A
during ECM degredation and remodeling
25
What are DAMPs?
molecular patterns (alarmins) are endogenous intracellular molecular structures:
- HMGB1 (nucleolus protein)
- uric acid
- HSPs (exosomes)
- S100 protein (cytoplasm)
- hyaluronans in ECM
26
What is the function of C reactive protein (CRP)?
- has 5 subunits
| - can bind to DAMPs and activate complement via classical pathway
27
How do immune cells recognize DAMPs?
toll-like receptors
28
Once DAMPs bind to TLRs and become activated, what do they induce?
innate immune responses and renal inflammation
29
What are the inducers for innate immunity and homeostatic inflammation?
```
innate:
pathogens (bacteria and virus)
-PAMPs (exogenous ligands)
-nucleic acid (CpG and dsRNA)
-lipid (lipid A)
-protein (PGN)
```
```
homeostatic inflammation:
cell/ECM derived molecules
-DAMPs (endogenous ligands)
-nucleic acid (ATP)
-lipid (oxLDL and saturated fatty acids)
-protein (HSP and HMGB1)
```
30
What are the sensors for PAMPs and DAMPs?
toll-like receptors
NOD-like receptors
C-type lectin
31
What are the mediators for PAMPs and DAMPs?
TNF alpha
IL-6
IL-1 beta
32
What are the functions of dendritic cells? What disease are they present in?
functions:
- antigen presentation
- migration
- Type 1 IFNs, CXCL2, IL-1beta and IL-12
Acute kidney injury and infections
33
What do resident renal cells activate when they sense DAMPs?
dendritic cells
macrophages
endothelial cells
34
What are macrophages associated with? Disease?
ROS, IL-1beta, TNF, IL-6 and chemokines
| most kidney diseases
35
What are endothelial cells associated with? diseases?
TNF, IL-6, chemokines, and IFNalpha
IC-GN (ischemia induced glomerulonephritis)
diabetes
sepsis
36
What cells are activated during inflammation? What happens next?
```
WBC recruitment
neutrophils
macrophages
lymphocytes
dendritic cell activation
```
```
leukocyte activation
cytokine release
margination
tissue migration
reduced flow
```
37
What are the pro inflammatory responses in the development of acute kidney injury?
DC --> increase Th1 and Th17 differentiation
macrophage --> M1 increased TNF alpha, increased IL-6
T cell --> increased CD4 Th1 response, increased IFN-gamma, increased IL-6, decreased IL-4
38
What are the anti inflammatory responses and tissue repair for macrophages and T cells?
macrophage --> M2 increased clearance of early apoptotic cells, increased arginase-1, increased IL-10
T cell --> decreased antigen specific T cell expansion
39
What are immune responses mediated by in early stages? late stages?
```
early = Th17 cells
late = Th1 cells
```
40
What macrophages play a key role in AKI?
M1
41
What macrophages play a key role in tissue repair?
M2
42
Describe the classically activated M1 macrophage pathway
- induced by PAMPs and DAMPs through binding to TRLs and other PRRs
- IFN-gamma and proinflammatory cytokines promote differentiation of M1 macrophages
- cytokines produced by M1 macrophages perpetuate the acute phase of inflammation in kidney
43
Describe the alternatively activated M2 macrophage pathway
- induced by IL-4 and IL-13 produced by T cells
| - M2 macrophages are important in tissue repair and renal fibrosis which both are controlled by IL-10 and TGF-beta
44
Which macrophage is involved in presentation of antigens to T cells?
M1
| using IL-12 and IL-23
45
What initiates macrophage reprogramming?
CSF-1, IL-10
46
What cytokine(s) promote Th1 cells?
IL-12
47
What cytokine(s) are secreted by Th1 cells?
IFN gamma
48
What is the function of Th1 cells?
antigen presentation and cellular immunity
49
What cytokine(s) promote Th2 cells?
IL-4
50
What cytokine(s) are secreted by Th2 cells?
IL-4
IL-5
IL-13
51
What is the function of Th2 cells?
humoral immunity and allergy
52
What cytokine(s) promote Th17 cells?
IL-6
| TGF beta
53
What cytokine(s) do Th17 cells secrete?
IL-17
54
What is the function of Th17 cells?
tissue inflammation
55
What does IL-17 stimulate?
stimulates resident renal cells to produce chemokines and other inflammatory mediators
56
What do the chemokines initiated by IL-17 recruit?
recruitment of neutrophils
57
What do Th17 cells secrete besides IL-17? What might be its function?
CCL20 also called macrophage inflammatory protein-3 (MIP-3)
facilitate the infiltration of monocytes, Th1 cells, and Th17 cells
58
What does recruitment of pro-inflammatory leukocyte subsets lead to in the kidney?
immune-mediated kidney damage
59
What is the function of Treg cells in AKI?
```
antiinflammatory
inhibits B lymphocytes
inhibits T lymphocytes
promote TGF beta and IL-10
inhibits neutrophils and monocytes
```
60
Who is likely to have complement proteins in biopsies of the kidney?
- glomerulonephritis
| - various kidney disease
61
Where does complement activation occur in acute kidney injury?
downstream of immune complex deposition (type III)
| downstream of antibody-mediated injury (type II)
62
What are the immune reactant of type II hypersensistivity?
immune reactant: IgG or IgM
63
immune reactant of type III hypersensistivity?
immune reactant: IgG and IgM
64
type II hypersensitivity antigen form
antigen form: cell-bound antigen
65
type II hypersensitivity mechanism of activation
mechanism of activation: IgG or IgM antibody binds to cellular antigen, leading to complement activation and cell lysis
66
type II hypersensitivity example
example: patients with anti-glomerular basement membrane (GBM) antibody mediated GN
67
antigen form type III hypersensitivity
antigen form: soluble antigen
68
mechanism of activation of type III hypersensitivity
mechanism of activation: antigen-antibody complexes are deposited in tissues. complement activation provides inflammatory mediators and recruits neutrophils. enzymes released from neutrophils damage tissue.
69
examples of type III hypersensitivity
post-streptococcal glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus
70
What is the treatment for end stage renal disease?
kidney transplantation
71
What is the barrier to transplantation?
genetic incompatibility of the donor and recipient
72
What are the methods used for preventing graft rejection?
HLA matching
| immunosuppression
73
What causes transplant rejection?
host versus graft responses
74
What are the targets of rejection?
histocompatibility antigens
75
What is a hyperacute rejection?
immediate reaction caused by antibody
76
What is acute rejection?
occurs days to weeks after transplantation and caused by T cells
77
What is chronic rejection?
seen months or years after transplantation and caused by vascular trauma, inflammatory products of T cells
78
What are graft versus host rejections?
donor lymphocytes attack the graft recipient
| mechanism of GVHD can be acute or chronic
79
What does successful organ transplantation depend on?
immunosuppressive drugs
80
What are autografts?
grafts exchanged from one part to another part of the same individual
81
What are isografts?
grafts exchanged between different individuals of identical genetic constitutions (identical twins)
82
What are allografts?
grafts exchanged between nonidentical members of the same species
83
What are xenografts?
graft exchanged between members of different species
84
What classification of grafts are particularly susceptible to rapid attack by naturally occurring antibodies and complement?
xenografts
85
What increases the chances of successful survival in xenografts?
insertion of human genes into the genomes of the donor animals (miniature swine)
86
What variables determine transplant outcome?
1. condition of the allograft
2. donor-host antigenic disparity
3. strength of host anti-donor response
4. immunosuppressive regimen
87
What are non-immunological factors?
- mechanical trauma and ischemia-reperfusion injury to the graft tissues
- mediators are released which trigger several biochemical cascades leading to immediate tissue damage
88
What does the clotting cascade generate?
fibrin and fibrinopeptides
89
What do fibrinopeptides do?
increase local vascular permeability and serve as chemoattractant for neutrophils and macrophages
90
What does the kinin cascade produce? what does it cause?
bradykinin causes vasodilation, smooth muscle contraction, increased vascular permeability
91
What results from uncontrolled early proinflammatory responses?
hyperacute allograft rejection
92
What does intensified immunosuppression and immunological understanding prevent?
hyperacute rejection related to ABO incompatible kidney transplantation (ABOi-KT) for patients with end-stage kidney disease
93
What is the major blood group system?
ABO
94
Are ABO antigens expressed on other tissues?
yes
95
What is ABO matching NOT important for?
corneal transplantation, heart valve transplantation, bone and tendon grafts (nonvascularized tissues)
96
Is ABO incompatibility a contraindication to stem cell transplantation?
No
97
Blood type A
antibodies?
antigens?
donor?
antibodies: B
antigens: A
donor: A or O
98
Blood type B
antibodies?
antigens?
donor?
antibodies: A
antigens: B
donor: B or O
99
Blood type AB
antibodies?
antigens?
donor?
antibodies: none
antigens: A/B
donor: A, B, AB, O
100
Blood type O
antibodies?
antigens?
donor?
antibodies: A/B
antigens: none
donor: O
101
What are the steps for testing for pre-existing anti-class I/II HLA abs? What is the test called?
"Microcytotoxicity Test for Preformed Abs"
1. recipient serum is added to donor cells
2. complement is added
3. dye is added
4. preformed antibodies are present
102
What is the success of transplantation dependent on?
HLA Ags
103
What are HLA Ags encoded by?
major histocompatibility complex: HLA class-I and class-II
104
Why is HLA compatibility between donor and recipient required?
extreme polymorphism of HLA
105
How many allelic forms are there of HLA molecules?
hundreds
106
How many HLA alleles per person?
10-12
107
How are HLA Ags expressed?
co-dominantly
108
What are strong barriers to transplantation?
class I HLA Ags (HLA-A and HLA-B)
109
What are the 3 most important pairs of the class II HLA Ags for transplantation?
HLA-DR
HLA-DP
HLA-DQ
110
What are convenient sources of lymphocytes for HLA typing?
- spleen and lymph node (cadaver)
| - peripheral blood (RBCs and platelets removed)
111
Where are HLA antisera obtained?
multiparous women or from planned immunization of volunteers
112
What does antisera contain? How does antisera work?
antibodies to HLA Ags;
Abs bind to HLA Ag on the surface of lymphocytes, Ag-Ab complex formed activate classical complement cascade resulting in lymphocyte lysis. lymphocyte lysis can be detected by staining the cells with acridine orange, ethidium bromide, or hematoxylin stain
113
What are the steps in testing for class I HLA compatibility?
1. Abs are added
2. Complement is added
3. Dye is added
Result in recipient: complement forms pores in the cells, dye is accumulated in cells if HLA Ag are identical
114
What are the steps for testing for class II HLA compatibility? What is this test called?
"Mixed lymphocyte response"
1. donor cells don't proliferate due to the radiation treatment, but can serve as APCs
2. mix with recipient cells + 3H-thymidine
3. proliferation of recipient cells occur, radioactivity is incorporated in DNA that allows quantify cell proliferation
result: recipient cells do not share class II MHC of donor
3. radioactivity is NOT incorporated in DNA, no reaction/no radioactivity
result: recipient cells share class II MHC of donor
115
What are two types of immune responses in transplantation?
host versus-graft disease: kidney is transplanted the recipient's T cells attack the transplant
graft versus host disease: bone marrow is transplanted the T cells in the transplant attack the recipient's tissues
116
What are the immune events in allograft rejection?
1. APCs trigger CD4+ and CD8+ T cells
2. both a local and systemic immune response develop
3. cytokines recruit and activate immune cells
4. development of specific T cells, NK cells, or macrophages mediated cytotoxicity
5. allograft rejection
117
What is host versus graft response?
- host immune system attacks the donor tissue
- adaptive immune response against the graft
- immune response is more vigorous and strong than against a pathogen
- higher frequency of T cells that recognize the graft as foreign
- if a second graft is perfomed from the same donor, it is rejected more rapidly
118
What is direct allorecognition?
T cell recognizes unprocessed (intact) allogenic MHC molecules on the surface of donor antigen-presenting cells (APCs) in the graft
119
What is indirect allorecognition?
T cell recognizes processed peptide of allogenic MHC molecule bound to self MHC molecule on host APC
120
What is host versus graft response?
- up to 2% of the host T cells are capable of recognizing and responding to single foreign MHC
- nonimmune injury of the graft (DangerSignals, DAMPs) activates endothelial cells and T cells enter the allograft
- Ag specific T cells interact with APC and become stimulated
- inflammatory cytokine/chemokine field is created and causes further activation of APC, endothelium and leukocyte traffic
121
What are the effector mechanisms of graft rejection?
humoral rejection Th2 (IL-4, IL-5, IL-10)
| cellular rejection Th1 (IL-2, IFN-gamma)
122
What does hyperacute rejection trigger?
complement activation, endothelial damage, inflammation, and thrombosis (preexisting antibodies and complement)
123
What does acute rejection trigger?
parenchymal cell damage, interstitial inflammation (primary activation of T cells Th1 cells and CTLs)
124
What does chronic rejection trigger?
chronic DTH reaction in vessel wall, intimal smooth muscle cell proliferation, vessel occlusion (M2 macrophages and T cells)
125
What type of hypersensitivities are hyperacute, acute, and chronic rejections? When is the onset?
hyperacute: II, immediate
acute: IV, days to weeks
chronic: IV, months to years
126
What is the mechanism and vessel histology of hyperacute rejection?
preformed antibodies directed against the donor tissue caused by accidental ABO blood type incompatibility (very rare).
presents while still in surgery with thrombosis and occlusion of graft vessels.
127
What is the mechanism and vessel histology of acute rejection?
T cell mediated immune response directed against the foreign MHC.
inflammation and leukocyte infiltration of graft vessels results. MOST COMMON type.
128
What is the mechanism and vessel histology of chronic rejection?
T cell mediated process resulting from the foreign MHC "looking like" a self MHC carrying an antigen.
results in intimal thickening and fibrosis of graft vessels as well as graft atrophy.
129
When is hyperacute graft rejection more likely to occur?
- ABO blood group incompatibility
| - recipient sensitized to donor MHC by previous transplants, multiple blood transfusions, or pregnancy
130
What does classical complement activation lead to?
death of the endothelium
131
What cells play an important role in triggering acute rejection?
donor DCs, also called passenger leukocytes
- donor DCs migrate to the lymph nodes draining the organ and stimulate a primary recipient response
- activated T cells migrate to the organ and lead to tissue damage by generation of cytotoxic T cells and induction of delayed-type hypersensitivity reactions
132
What T cells can cause graft rejection: CD4+ or CD8+?
Both
133
What are non-immunologic factors in chronic rejection?
- ischemia-reperfusion damage
- recurrence of the disease
- nephrotoxic drugs
134
What type of rejection does not respond to immunosuppressive therapy?
chronic rejection
135
What is graft versus host disease (GVHD)?
- caused by reaction of grafted mature T cells in the marrow inoculums with allo-Ags of the host.
- reaction directed against minor H Ags of the recipient
136
Who gets GVHD?
immunocompromised recipients because their immune system is unable to reject the allogenic cells in the graft;
transplants of small bowel, lung, or liver (naturally contain lots of T cells)
137
How is GVHD classified?
acute or chronic
138
What is acute GVHD?
epithelial cell death in the skin, liver, and GI
| symptoms: rash, jaundice, diarrhea, and GI hemorrhage
139
What is chronic GVHD?
fibrosis and atrophy of affected organ
clinically: may lead to complete dysfunction of the affected organ (or two of the same)
may produce obliteration of small airways
140
What type of hypersensitivity is GVHD?
type IV
141
What is the mechanism of GVHD?
donor APCs activate donor CD8+ T cells by cross presenting recipient antigens on MHC class I molecules
142
What are the two effector mechanism of GVHD?
Fas-FasL
| Perforin/granzyme
143
What cytokines signal myocytes to become M1 or M2?
M1: microbial TLR ligands, IFN gamma
M2: IL-13, IL-4
144
What are the functions of M1 macrophages? M2?
M1: microbicidial actions: phagocytosis and killing of bacteria and fungi; inflammation
M2: antiinflammatory effects; wound repair, fibrosis
