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 for primary FSGS/MCD
A circulating factor (suPAR, CLCF1 or microRNA’s) cause injury to podocytes
MCD benign end and FSGS is severe with progressive CKD and ESKD
Rate correlates with degree of proteinuria
Circulating factor results in recurrence post transplant often fulminantly. This is why FSGS can recur quickly after transplant
Describe causes of of membraneous nephropathy
primary as a result of foot process antibody (90%)
Secondary: lupus, medications (eg NSAIDS, anti TNF, immune Cp inh et al), infection (hep B, hep C, syphilis), malignancy (prostate, lung, breast, bladder or GI)
What is the most common medication causes membranoproliferative glomerulonephritis?
immune checkpoints
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)
What is the management of membranous nephropathy?
5-30% get spontaneous complete remission
standard proteinic kidney disease management
immunosuppression
What is the final pathology of CKD?
Glomerular sclerosis (2* to FSGS) with associated proteinuria
Action of angiotensin II in the kidney
-↑ IGP by efferent arteriole vasoconstriction
- Alters podocyte function causing proteinuria
– Stimulates proliferation of smooth muscle cells and cytokine release
- stimulates sympathetic NS
Role of mRA when added to RAS blockage in CKD?
further reduction in proteinuria
reduced progression to ESRD
some evidence of cardiovascular benefit
Role of finererone in CKD
It is a type of non-steroidal mRA (steroidal mRA include spironolactone and eplerenone) and has been shown to reduce cardiovascular and kidney failure outcomes in patients with T2DM
S/E- slight drop in BP, no sexual side effects, hyperkalaemia
S/E of SGLT2
euglycaemic DKA
Glycosuria- increased UDI and increased topical candidiasis
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.
Is there a role for lipids in CKD?
*No mortality benefit when on haemodialysis
* reduction in atherosclerotic endpoints in dialysis patients
What are the three parameters we use to assess bone pathology (TMV) in CKD?
Turnover, Mineralisation, Volume
What are the major patterns of bone disease in CKD
*Osteitis fibrosa cystica- high turnover mediated by PTH
*Adynamic bone disease- low turnover
*Osteomalacia- low turnover with abnormal mineralisation
*Mixed
Describe fibroblast growth factor 23
Circulating 32kDA peptide- derived from bone: klotho- co-receptor, expressed in kidney and parathyroid
Secreted by osteocytes and osteoblasts
reduced phosphate, vit D, PTH secretion
Describe phosphate regulation in CKD
3 feedback loops
– FGF23 -↓ renal reabsorption, ↓ 1, 25 Vit D hydroxylation ↓ PTH release
– PTH -↓ renal reabsorption, ↑ bone turnover, ↑FGF23 and ↑ 1, 25 Vit D hydroxylation (↑PO4)
– 1, 25 Vit D -↑ renal reabsorption and gut absorption, ↑ FGF23 production and ↓ PTH release
Describe calcium regulation in CKD
Decreased in response to increase phosphate, reduced 1,25 vit D, resistance to PTH induced release from bone
How to treat high PTH in CKD
1) 1,25 Vit D or analogue supplementation
2) calcimemtics
3) surgery
What Is hungry bone syndrome?
profound life threatening hypocalcaemia post PTHectomy
associated low phosphate and magnesium
What is the value of correcting anaemia in CKD?
quality of life
dont correct too much! Hb >125-130 is associated with increase cardiovascular mortality and stroke
What did the IDEAL trial show regarding CKD?
No benefit in starting dialysis early- wait until become symptomatic
What is the role of PLA2R Ab in membranous nephropathy?
High level of PLA2R Ab associated with risk of progression and a low/negative or reducing level with remission
Describe histology of membranoproliferative glomerulonephritis disease
Describe the pathology of membranopoliferative glomerulonephritis
Immune complex monoclonal Ig mediated
*Infections (hep C (with EMC), hep B, chronic bacterial, fungal or schistosomal)
* Autoimmune (lupus (fullhouse IF), Sjogren’s or RA)
* Monoclonal gammopathies
Complement mediated (described 2007)
*C3 or C4 glomerulopathy
* C3 nephritic factor
No Ig or complement deposition
* Pattern may occur in the healing phase of multiple causes of acute glomerular injury
C3 glomerulonephritis and post-strep glomerulonephritis are different.
Yes but hard to tell the difference
both result in low C3
A common pathology is due to abnormal regulation of the alternative complement pathway.
What are eplets?
Eplets are small configurations of polymorphic amino acid residues on human leukocyte antigen (HLA) molecules
The same eplet may be on multiple HLA antigens and this is way exposure to one HLA antigen may generate ABs against multiple HLA types
What is the immunosuppression for a renal transplant?
Induction therapy:
- IL 2 monoclonal (Basiliximab)
- Polyclonal (antithymocyte globulin)
Maintenance therapy
- Calcineurin inhibitor (cyclosporin or tacrolimus)
- antimetabolite (mycophenolate or azathioprine)
- steroid (prednisone)
Acute allograft dysfunction by timing: Immediate, 1-12 weeks, >3 months
What is found on the biopsy of a acute rejection kidney?
T lymphocytic infiltration
What is the role of donor derived cell free DNA?
goes higher in acute rejection
What is the treatment of acute rejection?
Methylprednisone 500g-1g daily for 3 doses
rescue dose MMF
modify CNI- change CyA to Tac
ATG
if antibody mediated Rituximab/PEx/IVIG
What is the most common infection following a renal transplant?
urinary tract!
even later strep pneumonia is common
What is the most common opportunistic infection post renal transplant?
CMV
When do you have most risk of CMV infection in renal transplant?
Donor positive to recipient negative (give 6 months of prophylaxis)
if recipient positive and degree of immunosuppression
How to treat CMV infection in renal transplant?
IV ganciclovir
if mild- oral valganciclovir, letermovir, or maribavir
treat until PCR negative and then suppressive therapy
reduce immunpsupression
What is the reason for valganciclovir resistance? Maribavir, letermovir?
Valganciclovir due to variants in U54 and U97 genes
Maribavir u97 variants
Letermovir due to U56 variants
What are symptoms of BK virus infection in renal transplant?
– Tubulointerstitial nephritis with allograft dysfunction
– Ureteric stenosis
– Haemorrhagic cystitis
– Systemic vasculopathy
thought to occur due to the injury in the renal tract during transplant process to influence virus reactivation
described as viral inclusions
RISKS: degree of immunosuppression, use of tacrolimus, donor age, ureteral stent, viral co-infection and others
Monitoring: monthly plasma viral load to 9 months and 3 monthly to 2 years.
can consider IVIG if reducing immunosuppression doesn’t work
What is the prophylaxis for EBV in renal transplant?
Valganciclovir , reduce inmunosupresión
What conditions can commonly occur after renal transplant?
FSGS
HUS
Membranoproliferative GN
Common cause of late graft loss?
patient death
chronic rejection
recurrent GN
typical histological appearance: transplant glomerulopathy and interstitial fibrosis
What is the most common cancer in patients with renal transplant?
SCC cancer
Post-transplant lymphoproliferative disorder
b-cell monoclonal proliferation
frequently extra nodal
EBV associated
may reflect over immunosuppression
What is the rate of post-transplant diabetes?
incidence of 10-15% at 1 year
What immunosuppressive agents are diabetogenic?
Tacrolimus/cyclosporin direct islet cell toxicity
sirolimus diabetogenic
steroids insulin resistance
Managing diabetes post-transplant?
aggressive insulin therapy early so we can prevent loss of islet cells. if later on then manage as you would normally with diabetes
Describe electrolyte disturbance post transplant
hypomagnesemia as a result of CNI renal wasting
hypophosphataemia as a result of diuresis, increase PTH or a circulating factor which increases renal phosphate excretion now almost certainly identified as FGF 23
A 35 year old male has chronic hepatitis, managed with tenofovir. Dipstick urinalysis show glycosuria and proteinuria. Which of the following findings are most consistent with tenofovir-induced Fanconi syndrome?
A. Hypocalcaemia
B. Hypomagnesaemia
C. Hypophosphataemia
D. Hypouricaemia
C. Hypophosphataemia
proximal tubule dysfunction
can also cause hypomagnesaemia
