Dunedin-Renal Flashcards
When investigating vasculitis, which tissue biopsy has the highest yield?
Kidney
Discuss relapse rates of renal vasculitis PR3 vs MPO.
PRs 2 fold > than MPO
risk of relapse: prior relapse, lung disease, upper airways disease, persistently positive ANCA (PR3), bacterial and viral infection may trigger relapse
rising ANCA titres is not diagnostic of relapse
What is the management for renal vasculitis?
Induction therapy: cyclophosphamide and rituximab (for fertility preservation, malignancy risk and cumulative cycle exposure)
Steroids
Plasma exchange- debatable, use if advanced kidney injury or pulmonary haemorrhage
Avacopan: complement C5a receptor inhibitor.
Maintenance: rituximab, azathioprine, methotrexate and mycophenolate
What is the pathogenesis behind anti-GBM disease?
Anti body against NC1 domain of the alpha 3 chain of type 4 collagen
also recognise alpha 5 and 4 chains
rarely purely against alpha 4
autoantibodies activate the complement (alternative and classical) and T cell systems leading to damage
What does a biopsy show in anti-GBM?
Crescenteric proliferative GN with linear IgG basement membrane staining
What is the management of anti-GBM disease?
Basically the same as renal vasculitis
Plasmapheresis and immunosuppressive therapy
pulse methylpred, cyclophosphamide
What is de-novo anti-GBM disease?
Happens post transplant in patients with genetic COL4 abnormalities (thin basement membrane/alports syndrome)
What is the typical timing of post-strep GN?
1-3 weeks after a sore throat
1-6 weeks after other infective sites
What is the symptoms of post-step GN?
can be asymptomatic or symptomatic
in those symptomatic
- haematuria (macroscopic coke coloured)
- proteinuria (may be nephrotic range)
- HTN
- often profound swelling
- acute kidney injury
How to diagnose post-strep GP?
confirmed strep infection or consistent serology (streptozyme measures all 5)
- Anti-streptolysin (ASO), anti-hyaluronidase (AHase), anti-streptokinase (ASKase), Anti-nicotinamide-adenine dinucleotidase (anti-NAD) or Anti-DNase B antibodies
- acute nephritic syndrome
- C3 is low (due to activation of the alternate pathway) C4 normal
What is the treatment of post-strep GN?
treat infection, supportive therapy, Mx HTN (with loop diuretics), RAAS blockade if needed, dialysis if required
Causes of glomerular ischaemia
TMA
HUS
TTP
Hypertensive renal crisis
scleroderma renal crisis
pre-eclampsia
Pathophysiology of TMA/MAHA?
Endothelial injury/exposure –> platelet/fibrin clots –> mechanical damage to passing red cells –> capillary occlusion due to fibrin/platelet clot results in end organ injury –> platelet consumed –> passing red cells are broken into fragments or distorted into sperocytes (smaller hence microangiopathic)
alternative pathway constantly turning over and requirements active regulation to prevent injury to tissue
regulatory factors are complement factor H, CFI, membrane cofactor protein MCP (CD46) and others
Describe mechanisms of endothelial injury in HUS, TTP, Hypertensive, scleroderma and pre-eclampsia
HUS- shiga toxin mediated injury or abnormal regulation of the alternative complement pathway
TTP- von willebrand factor multimers causing endothelial injury
Hypertensive- ?direct pressure injury
Scleroderma- not clear what initiated injury but associated with other markers of disease severity and steroid exposure
Pre-eclampsia- likely placental derived factor (?sFLT-1)
Describe pathophysiology of complement mediated HUS
Loss of function variants in CFH, CFI or CD46 (regulatory) or gain of function variants in CFB or C3 (effector) results in over activity of alt pathway and endothelial injury (~60% of adult HUS)
Antibodies against the regulatory proteins can cause the same process (8-10% of adult HUS)
Generally a two hit phenomena where something else triggers TMA (this is a proportion of ST – HUS)
Describe pathophysiology of TTP
Deficient ADAMTS13 activity — TTP is caused by severely deficient activity of the ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) protease, typically described as an activity level <10 percent
* Cleaves vWF multimers
* In the absence ultra large multimers accumulate which accumulate on the endothelial surface and result in platelets attaching
Criteria to perform renal biopsy
*>1g proteinuria (may not if has been stable for a long time)
*Reduced eGFR
*Apparent hereditary disease if no gene test
*if the patient really wants to know
What is the most common type of GN?
IgA nephropathy
Describe the pathogenesis of IgA nephropathy
Abnormal circulating IgA is produced (the IgA is abnormal in that the hinge regions are poorly glycosylated) –> not able to be effectively cleared by the liver –> abnormal IgA is preferentially deposited in the mesangial cell –> these mesangial cells are transformed into a pro-inflammatory phenotype –> mesangial processes induce a abnormal podocyte response and local complement pathways are activated
Treatment of IgA
most of the time supportive
RAAS blockade
SGLT2 inhibition
immunosuppression (doesnt work in advanced fibrotic disease, can use steroids, targeted release budesonide, or mycophenolate)
What is non-specific mesangial proliferative GN?
Presents like IgA
biopsy looks like IgA without IgA
general therapy the same
role of immunosuppression is not defined
Genetic abnormalities in Alport syndrome?
disease-causing variants in genes encoding the alpha-3, alpha-4, and alpha-5 chains of collagen IV
These collagen IV alpha chains are normally located in various basement membranes of the kidney, cochlea, and eye
What is the mode of inheritance of alport syndrome?
majority X-linked
some autosomal recessive, autosomal dominant
COL4A3,4,5
How to diagnose alport syndrome
Genetic testing or renal biopsy
thin basement membrane disease
Is there haematuria in nephrotic syndrome?
Typically no, apart from FSGS
What is the most common cause of nephrotic syndrome?
Diabetic nephropathy
Newly diagnosed albuminuria in patient with T2DM?
If haven’t had DM for long, have no retinopathy or have haematuria then likely another cause and would consider biopsy
duration is more important than control
Management of nephrotic syndrome?
RAAS blockage- dual with MRA
Salt restriction
SGLT2 inhibition
loop diuretics to control swelling often at high dose
What are some causes of secondary FSGS?
Result of hyperfiltrative injury
*low nephron endowment/ CAKUT/prematurity of nephron loss
*Obesity
*Hypertensive injury
*Prior glomerular injury (Vasculitis)
Direct injury
*infection (HIVAN, parvovirus, HepC)
* Medications (heroin, interferon, bisphosphonates, anabolic steroids)
Describe Minimal change disease
Presentation: acute onset with heavy nephrotic syndrome
BP low, albumin low
may have history of atopy
note- pure MCD doesnt cause progressive CKD
Describe treatment of minimal change disease
Steroids
if steroid dependent or relapsing disease
- cyclophospamide
- cyclosporin/tacrolimus
- rituximab
- mycophenolate
- azathioprine
Describe pathogenesis of membranous nephropathy
1) Phospholipase A2 receptor antibodies (high expressed on podocytes, unknown with triggers Ab formation), antibodies move through the GBM to deposit at the target antigen on the podocyte
Other antigens: neural epidermal growth factor-like 1 (NELL1) the most common
thrombospondin type 1-1 domain-containing 7a (THSD7A)
Role of semalutide in CKD and T2DM?
When used with SGLT2 Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease.
Describe histology of membranoproliferative glomerulonephritis disease
Acute allograft dysfunction by timing: Immediate, 1-12 weeks, >3 months
What is the most common infection following a renal transplant?
urinary tract!
even later strep pneumonia is common
