Renal Flashcards
Definition nephrotic syndrome and consequences
proteinuria >3.5 gram/day
hypoalbuminemia
Edema
Hyperlipidemia
Hypercoagulability, lipiduria, increased susceptibility to infections
What are the primarily glomerular pathology and systemic diseases causes nephrotic syndrome
Primarily glomerular - Minimum change disease - Focal segmental glomerulosclerosis Membranous nephropathy Membranoproliferative (MPGN) / Mesangiocapillary (MCGN)
Systemic
Diabetes
Amyloidosis
What is the pathology of Minimal change disease?
foot process effacement on EM (normal LM and IF)
What is the pathology of focal segmental glomerulosclerosis
LM shows sclerosis in parts (segmental) of some (focal) glomeruli with EM showing foot process effacement
What is the pathology of Membranous Nephropathy
Thickened GBM with no cellular proliferationl LM and EM show subepithelial deposits (spikes and domes with thickened GBM) and IF shows IgG
Mesangium characteristically noraml and no sub-endothelial deposits
What is the pathology of Membranoproliferateive (MPGN) / Mesangiocapillary (MCGN)
increased mesangial and endocapillary cellularity (difficult to visualise capllaries as full of cells) with thickened GBM leading to double contour (tram track) appearance of capillary walls
-IF may show Ig or only complement depending on the type (immune vs complement mediated MCGN)
What is the commonest cause of nephrotic syndrom in caucasians?
Membranous nephropathy
What is the commonest cause of nephrotic syndrom worldwide and in Africa?
FSGS
What is the differential for FSGS and MCD if there is just foot prrocess effacement on EM
SUPAR in FSGS (commonest cause of nephrotic worldwide is FSGS -> its fucking shit (FS) worldwide, but everyone thinks its SUPAR)
CD80 overexpression on podocytes in MCD but not FSGS (MCD is the commest cause of AKI out of the nephrotic GN’s, but doesnt get CKD)
What is the pathogenesis of MCD
Primarily a podocyte abnormality
Activated T cells secrete increased IL-13
IL-13 leads to CD 80 expression on podocytes
CD90 leads to decreased expression of nephrin
NEPHRIN is the major negative protein on the filtration barrier
Treatment of MCD?
ACEi low Na diet Statins Corticosteroids second line cyclophosphamide/cyclosporine 3rd line Rituximab
What is the pathophys of Membranous nephropathy?
Commest in caucasians
GBM thickening with no cellular proliferation or infiltration
Immune deposits beneath podocytes (subepithelial) / No hypercellulairty / no mesangial involvement
2/3rd are primary membranous
1/3 associated with other diseases
What are the causes of secondary Membranous nephropathy?
Connective Tissue: SLE (commonest), Rheumatoid
Infections: Hepatitis B (commonest), hepatitis, schistosomiasis, malaria
Drugs: penicillamine, gold, captopril, NSAIDS, anti-TNF (Infliximab)
Tumours (in>65) prostate carcinoma
In primary membranous nephropathy what are the antibodies tested/responsible?
Antibody to phospholipase A2 receptor (anti-PLA2R) seen in 70% of primary MN but not in secondary
PLA2R expressed on podocytes, hence the subepithelial deposit
Thrombospondin type-1 domain containing 7A (THSD7A) is the responsiblke podocyte antigen in 10% of cases of primary MS that are anti-PLA2R negative
Pathogenesis of MN?
IGG antibodies pass across GBM to antigens on podocyte foot process e.g. PLA2R
Resultant antigen-antibody coimplex activates complement
C5-9 enters podocytes and the complement mediated podocyte injury leads to two changes
- proteinuria due to loss of slit diaphragm integrity
- GBM expansion by the overproduction of type IV collagen
What is the prognosis of MN?
Related to proteinuria
<4 good
4-8 intermediate, 50% CKD
>8g/day 75% CKD
What is the treatment of MN?
ACEi, statin, salt restriction, BP control
Treatment of underlying disease in secondary MN (SLE, hepatitis B, offending drug (infliximab), prostate carcinoma)
Prophylactic anti-coagulation if albumin <20 - as you lose antithrombin III
Membranous nephropathy has the highest risk of of VTE out of the nephrotic syndromes
What about immunosuppression?
If low risk <4g no immunosuppression
if medium risk and then decreases to 4g/day after 6 months then nothing
if >4g at 6 months, or if high risk to begin with then treat
-> corticosteroids, cyclophosphamide
MMF, rituximab
What is the ponticelli regimen?
alternating prednisolone and cyclophosphamide monthly for 6 months
What are the different disease states associated with nephrotic syndromes?
HIV = FSGS (cuz its fucking shit and it happens in Africa)
hepatitis B = membranous nephropathy (caucasian, B memorable, also the commonest nephrotic Sx related to solid organ malignancies)
hepatitis C = membranoproliferative/mesangiocapillary (Hep C= MCGN
What is the patho of FSGS?
sclerosis in parts (segmental) of some (focal) glomeruli
commonest cause worldwide and in africa
the non sclerotic flomeruli show foot process effacement
90% of FSGS are primary, and most of these have an elevated plasma soluble urokinase type plasminogen activator receptor (suPAR)
SUPAR leads ti integrin activit which leads to foot process effacement and proteinuria
What is the association between SUPAR and recurrence?
increased levels of SUPAR before renal transplant is associated with an increased risk of recurrent disease in the allograft
FSGS recurs in approximately 30% of transplanted kidneys and may lead to graft loss
Plasmapheresis after transplant in recurrent FSGS leads to decreased SUPAR and improvement in proteinuria
What are some secondary causes of FSGS?
HIV Lithium Sirolimus Calcineurin inhibitors Heroin Interferon
What the fuck is APOL1?
polymorphism in the apolipoprotein L1 (APOL1) gene on chromosome 22 has association with FSGS in people of african origin.
APOL1 provides innate immunity against typanosomiasis (sleeping sickness)
Which type of histological classification of FSGS has the worst prognosis?
Collapsing FSGS secondary to HIV
What is the treatment of FSGS?
Prednisolone achieves 40-60% partial to complete remission inprimary
Calcineurin inhibitor
What is Membrano proliferative GN / mesangiocapillary GN?
characterised by increased mesangial and endocapillary cellularity (proliferative lesions) with thickened GBM leading to a double contour appearance of glomerular capillary walls
Immune complex mediated MCGN
Hepatitis C (70-90% of all patients), cryoglob HBV, HIV, IE, malaria, SLE, Myeloma
Complement mediated
Associated with C3nef
Inherited mutation of Factor H
Monoclonal gammopathies
Immune complex mediated MCGN?
chronic antigenemia and classical pathway
subendothelial and mesangial immune deposit
glomerular deposition of immune complexes in the sub-endothelial and mesangial region leading to activation of the classical pathway and low C3 and C4 levels
Complement mediated MCGN
Persistent activation of the alternative pathway
C mediated MPGN ie either dense deposit disease (DDD) or C4GN may result from antibodies to C3 convertase by preventing its degradation by factor H, or by genetic mutation in factor H
Excessive activation of the alternate complement pathway: continuous overactivation so low C3 but normal C2 and 4
What is the spectrum of MCGN/MPGN?
microscopic haematuria with non-nephortic proteinuria (35%)
nephrotic syndrome with minimall depressed GFR (34%)
chronic progressive GN (20%)
rapidly progressive GN (10%)
What is the treatment of MPGN/MCGN?
supportive therapy: ACEi, statin, anticoag, low Na diet
identify and treat precipitant e.g. HIV
idiopathic cases treated with prednisolone and cyclophosphamide
Complement mediated MCGN
- C3Nef disease: PLEX, rituximab, eculizumab
- For Factor H deficiency: FFP
What are secondary causes of HTN?
Renovascular HTN Primary aldosteronism Cushings disease Pheochromocytoma Drugs: OCP, NSAIDs, Glucocorticoids, Decongestants, Cyclosporine, Tacrolimus, Erythropoeitin, Primary renal disease Coarctation of Aorta Polyarteritis Nodosa Liddle Syndrome Chronic liquorice ingestion Apparent mineralocorticoid excess Glucocorticoid remediable hypertension
when do you suspect reno vascular HTN?
Elevation in serum creatine by >30% within 1 week of starting ACEi/ARB
Sever hypertension with an unexplained atrophic kidney or asymmetry >1.5cm
Onset of severe HTN 180/120 after age 55
A systolic-diastolic abdominal bruit that literalists to one side
Flash pulmonary oedema
What is primary hyperaldosteronism and causes?
Hypokalaemia and metabolic alkalosis (potassium normal in 50% cases)
May be as high as 10% in HTN population
Bilateral idiopathic hyperplasia (60%)
Unilateral aldosterone producing adenoma or Conns syndrome (30-40%)
What are the bloods tests for primary hyperaldosteronism?
aldosterone/renin activity ratio >20 strongly predictive
confirm with oral sodium or IV saline infusion test - 2 litres/8hours
In normal people urinary and plasma aldosterone should fall
Adrenal Ct scan
Adrenal vein sampling to differentiate adenoma from hyperplasia
What is the commonest cause of cushing syndrome?
Cushing disease (pituitary source of increased ACTH) 68%
Ectopic ACTH 12%
Adrenal adenoma 10%
Adrenal carcinoma 8%
Cushing syndrome workup?
mid night salivary cortisol
24-hour urinary cortisol
low-dose dexamethasone suppression test
if 2/3 positive
-> serum ACTH
low ACTH: CT scan adrenal gland
high ACTH: high dose dex suppression, pituitary MRI, petrosal vein sampling
Phaeochromocytoma
Catecholamine secreting tumours that arise from chromatin cells of the adrenal medulla and the sympathetic ganglia
10% extra-adrenal, multiple, malignant
Tria of presenting Sx: episodic headache, sweating, tachycardia
Urinary fractionated metanephrines and catecholamines has highest sensitivity and specificity at 98%
What are predisposing conditions for Phae?
Von Hippel Lindau
Multiple endocrine neoplasia type 2
Neurofibromatosis type 1
Whats the deal with Polyarteritis Nodosa?
Vasculitis that typically affects medium-sized muscular arteries with new onset HTN seen in 35%
Kidneys, skin, joints, muscles, nerves, and GO tract most commonly affected
20% of patients are positive for Hep B
Necrosis of arterial wall with disruption of the elastic lamina leads to characteristic development of aneurysmal dilatations and constrictions
Commonest symptoms in PAN?
systemic features 80%
neuropathy 75%
Arthralgias 60%
Skin: lived reticularis, purpura, ulcers 50%
Renal failure but no GN 50%
GI 40%
New onset HTN 35%
Orchitis 20%
Hep B 20%
What is Liddle Syndrome?
Autosomal dominant condition with mutation in ENAC channel in collecting duct (under control of aldosterone) rendering it resistant to normal degradation
Persistent sodium reabsorption and resultant hypertension
Presentation at young age and may develop hypokalaemia with metabolic alkalosis
What is apparent mineralocorticoid excess?
Cortisol avidly binds aldosterone receptor. In kidney 11-beta-hydroxysteroid dehydrogenase enzyme type 2 converts cortisol to cortisone.
Deficiency in this 11-beta-HSD2 leads to elevated levels of cortisol in the kidneys which stimulates hyperaldosteronism
plasma renin and aldo will be low
urinary cortisol will be high
chronic liquorice ingestion also causes this picture
