Nephrology Cards Flashcards
Nephrotic Syndrome
Proteinuria >3.5g/24hrs
Hypoalbuminaemia
Generalised oedema
Hyperlipidaemia
Nephritic Syndrome
Haematuria with RBC casts and dysmorphic RBCs
Often some degree of oliguria with hypertension and progressive reduction in GFR
Commonest glomerular disease worldwide
IgA nephropathy
Goodpasteur disease
Characterised by antibody against alpha-3 chain of collagen type IV (anti-GBM antibody)
Alport syndrome
Results from mutations in genes encoding the alpha 3, 4 and 5 chains of type IV collagen
Proximal Convoluted Tubule
65-70% sodium reabsorption by apical Na-H exchanger protein.
Linked to regeneration of HCO3- (carbonic anyhydrase involved) -> Acetozolamide will interfere with this.
Sodium reabsorption coupled to reabsorption of glucose via SGLUT -> SGLT2 inhibitors work here (prevent reabsorption of both glucose and sodium).
Fanconi Syndrome
Defect in the proximal tubule - leading to inefficient regeneration of HCO3- and hence proximal renal tubular acidosis. Reabsorption of glucose, amino acids, phosphate and uric acid are affected.
Thick Ascending Limb of LOH
Na-K-2Cl transporter absorbs 1 Na and K each along with 2 Cl ions.
Frusemide inhibits the Na-K-2Cl transporter (NKCC2)
Bartter syndrome
Due to a defect in Na reabsorption in thick ascending limb of LOH (so same as being on Frusemide) - 5 types depending on the mutation in protein involved.
Effect of Frusemide on Calcium
Frusemide by inhibiting NaK2Cl co-transporter in TAL inhibits all downstream events including paracellular reabsorption of Ca and Mg.
Effect of Thiazides on Calcium
Blocking the DTC with thiazides causes upregulation of other portions of the renal tubules - upregulation of NaK2Cl in TAL causes increased Ca reabsorption.
Countercurrent mechanism LOH
The descending limb is highly permeable to water but the thick ascending limb is impermeable to water.
CaSR
Found in basolateral membrane of cells of thick ascending limb of LOH (as well as parathyroid gland).
Net result of renal CaSR stimulation by plasma calcium = decrease in paracellular calcium and magnesium absorption and increased urinary calcium loss.
FHH = caused by inactivating mutations of CaSR.
Mild hypercalcaemia, hypocalciuria, inappropriately normal to high PTH and high-normal to elevated serum magnesium levels.
Benign condition that does not require parathyroidectomy.
Distal Convoluted Tubule
Sodium is reabsorbed by the apical NaCl co-transporter (NCCT).
Inhibition of NCCT by thiazide diuretics lead to volume contraction, leading to increased TAL reabsorption of sodum which in turn leads to increased paracellular reabsorption of calcium.
Gitelman Syndrome
Characterised by impaired NCCT (so same as being on thiazide diuretics).
Hypokalaemia, metabolic alkalosis and hypomagnesaemia with lowish BP.
Collecting Duct
Principal cells contain aquaporin 2 (AQP 2) which reabsorb water.
Vasopressin (ADH) via V2 receptor moves AQP2 to the luminal surface.
DI results when there is a vasopressin deficiency (central DI) or when the kidneys fail to respond to the hormone (nephrogenic DI).
Lithium causes a nephrogenic DI by causing decreased expression of AQP 2.
Aldosterone
Produced by zone glomerulosa of adrenal cortex.
Sodium reabsorption.
K and H excretion.
RTAs
Disorders of the tubule characterised by:
a) Normal anion gap (hyperchloraemic) metabolic acidosis.
b) Despite a relatively well-preserved GFR with either
c) Hypokalaemia (types 1 and 2) or hyperkalaemia (type 4).
Defect in distal H+ leads to distal (type 1) RTA.
Defect in HCO3- reabsorption leads to proximal (type 2) RTA.
Type 4 RTA (commonest) is characterised by decreased production of aldosterone or diminished responsiveness of the cortical duct to aldosterone.
Type 1 and 2 RTA
Type 1 RTA (Distal RTA)
- Inability to secrete H+
- Urine pH >5.5 (no H+ in the urine)
- Proximal tubules reabsorb all alkali (including citrate) which normally keeps Ca in urine soluble, so nephrolithiasis and nephrocalcinosis.
- No Fanconi syndrome.
- Sjogren’s syndrome, SLE, PBC, autoimmune hepatitis.
- Treat with alkali and K+ replacement.
Type 2 RTA (Proximal RTA)
- Inability to reabsorb HCO3-
- Urine pH <5.5 (distal tubules secrete the excess H+ as in any acidosis)
- No renal stones
- Fanconi syndrome: glycosuria, phosphaturia, uricaciduria and aminoaciduria.
- Myeloma, drugs - tenofovir, acetazolamide.
- Same treatment, needs bigger doses of alkali though.
Type 4 RTA
Decreased production or diminished responsiveness to aldosterone.
Associated with DM (commonest), NSAIDs, ACE-I, calcineurin inhibitors (cyclosporine or tacrolimus), K-sparing diuretics and high-dose heparin.
In those not hypertensive or volume overloaded, synthetic mineralocorticoid such as fludrocortisone may help.
In patients with hypertension or fluid overload, a thiazide or loop diuretic may help by increasing distal delivery of Na and consequently increase urinary secretion of H and K.
Initial trigger for hyperparathyroidism in CKD
Phosphate retention
ATN
Defined by histologic changes - necrosis of the tubular epithelium and occlusion of the tubular lumen by casts and cell debris.
3 major causes of ATN:
- Renal ischaemia: all causes of severe pre-renal AKI particularly hypotension, shock and surgery.
- Sepsis: usually associated with hypotension.
- Nephrotoxins: aminoglycosides, vancomycin, cisplatin, radiocontrast material, cidofovir.
AIN
Caused by inflammatory infiltrate in the renal interstitium (glomeruli normal).
Drugs: NSAIDs, penicillins, cephalosporins, ciprofloxacin, PPIs, diuretics. 70-75%.
Systemic disease: Sarcoidosis, sjogren’s syndrome, SLE and others 10-15%.
Indications for dialysis in AKI
- Refractory hyperkalaemia especially with ECG changes.
- Pulmonary oedema.
- Acidosis (pH <7.15)
- Uraemic encephalopathy
- Uraemic pericarditis
CKD Aetiologies
Diabetic nephropathy.
Glomerulonephritis.
Hypertension.
Autosomal dominant polycystic kidney disease.
Others e.g. cystic disease, reflux nephropathy.
Dialysis-related amyloidosis (DRA)
Tissue deposition of amyloid, particularly in bone, articular cartilage, synovium, muscle, tendons and ligaments.
Derived primarily from beta-2 microglobulin.
Present with shoulder pain or carpal tunnel syndrome.
XR show multiple bone cysts that enlarge over time.
Treatment of Calciphylaxis
Sodium thiosulphate given 3 times weekly during dialysis.
Cease warfarin.
Treat hyperphosphataemia and avoid non-calcium-containing phosphate binder.
When to call it nephrotic syndrome?
Proteinuria >3.5g/24hrs
Hypoalbuminaemia
Oedema
Frequently observed:
Hyperlipidaemia
Hypercoaguability and thrombotic events (8 times more likely of arterial and venous thrombosis; more in MN)
Differential Diagnosis of Nephrotic Syndrome
Primary Glomerular Pathology - Minimum change disease (MCD) - FSGS - Membranous nephropathy (MN) - MPGN/MCGN Systemic diseases (30% in adults) - DM - Amyloidosis - Lupus (usually causes membranous nephropathy)
Minimal Change Disease
Cause of nephrotic syndrome in >90% children <10yrs
Among adults: more acute, more likely to present with AKI.
EM - effacement of podocyte foot processes.
Mostly unknown aetiology.
Associations:
- Drugs: NSAIDs, IFN-a, ampicillin, rifampicin, cephalosporins, lithium.
- Neoplasm: HL and less commonly NHL and leukaemia.
- Allergy: atopy/eczema/asthma.
Tx:
- Good response to corticosteroids.
Membranous Nephropathy
Commonest glomerular cause of NS in Caucasians.
GBM thickening with no cellular proliferation or infiltration.
Antibodies to phospholipase A2 receptor (Anti-PLA2R) seen in 70% of primary cases and has a strong associated with prognosis.
Tx:
1. Usual: angiotensin inhibition and BP control, diuresis, lipid lowering, salt restriction.
2. Treat underlying disease in secondary MN.
3. Prophylactic anticoagulation if serum albumin <20 and with RFs.
4. If moderate risk of progression or > -> immunosuppression (Cyclophosphamide or pred with abnormal initial kidney function; rituximab or calcineurin inhibitor and pred for those with stable kidney function).
FSGS
A histologic lesion defined as sclerosis in parts (segmental) of some (focal) glomeruli.
Foot process effacement seen.
>80% idiopathic and most in this group have elevated plasma ‘soluble urokinase type plasminogen activator receptor suPAR’ elevated.
Best prognosis: tip variant
Worse prognosis: collapsing variant
MPGN or MCGN
Characterised by increased mesangial and endocapillary cellularity (proliferative lesions) with thickened GBM leading to a double-contour appearance.
Immune-complex mediated MCGN
- Associated with chronic antigenaemia and/or circulating immune complexes (chronic infections such as hep B, hepC, autoimmune diseases and monoclonal gammopathies)
- Glomerular deposition of immune complexes leads to activation of classical pathway (normal or mildly low C3 and low C4 levels)
Complement-mediated MCGN
- Excessive activation of alternate complement pathway (so low serum C3 but normal C4)
Staphylococcal GN vs. Post-streptococcal GN
Staphylococcal GN
- simultaneously
- In elderly and especially diabetics, alcoholics, malignancy
- Associated infections: skin, lung, endocarditis, deep abscess, UTI.
- Often IgA dominance or co-dominance.
- Up to half develop CKD or ESRD.
Post-streptococcal GN
- Up to 2 weeks after infection
- Common in children
- Follows throat (ASO, anti-DNase B, anti-NAD, AHase titres high) or skin infections (anti-DNase B, AHase high).
- On IF C3 dominant.
- Renal recovery in >90% especially children
Treat cause.
No role for immunosuppressive therapy.
IgA nephropathy
Commonest cause of GN worldwide.
Characterised by mesangial proliferation and deposition of IgA.
Associated diseases: coeliac disease, RA, AS, reiter syndrome, cirrhosis, NASH, hepatitis B and C, sarcoidosis, HIV.
Features:
- Episodic macroscopic haematuria 40-50% (often within 24-48hrs of URTI).
- Microscopic haematuria in 30-40%
- Nephrotic syndrome in 5%
- Rapidly progressive GN in 5%
LM: diffuse mesangial proliferation and hypercellularity.
EM: electron dense deposits in mesangium.
Depends on proteinuria/HTN/renal fx.
Initially ACE-I or ARB; then add pred.
Anti-GBM antibody
Goodpasture Disease
Directed against alpha 3 chain of type IV collagen
Bx: diffuse proliferative GN often with crescents on LM/EM and characteristic linear deposition of IgG along the GBM on IF.
10-40% may also be MPO ANCA +ve
Tx: Plasma exchange up to 2 weeks + pred and cyclophosphamide up to 3 months.
Followed by pred alone or low-dose pred and aza for 6-9 months.
Alport Syndrome
Autosomal dominant heterozygous mutation of A3 or A4 of type IV collagen leading to asymptomatic haematuria through to progressive GN.
More than 80% X-linked so usually males have worse prognosis.
Primary Aldosteronism (Conn’s Syndrome)
Hypokalaemia and metabolic alkalosis.
Types:
Bilateral idiopathic hyperaldosteronism (60-70%)
Unilateral aldosterone-producing adenoma (30-40%)
Less common:
Unilateral adrenal hyperplasia; aldosterone-producing adrenocortical carcinoma
Dx:
Plasma aldosterone:renin ratio >30 strongly predictive (denominator dependent).
Confirm with oral sodium loading or saline infusion test
Adrenal CT scan.
Adrenal vein sampling to differentiate adenoma vs. hyperplasia may be needed.
Renovascular Hypertension
Two types:
- FMD in 10-15%. Commoner in women <50 and unrelated to lipid status.
- RAS (atherosclerotic renal artery stenosis) usually after 50yr and cholesterol plaque obstructs renal artery.
Suspect with elevation of serum Cr by >30% within a week of starting ACE-I or ARB.
Think about bilateral RAS in recurrent presentations with flash APO and refractory heart failure.
Cushing Syndrome work-up
Initial screen (need at least 2 positive)
- Midnight salivary cortisol
- 24hr urinary cortisol
- Low-dose dexamethasone suppression test
If +ve, follow-up with serum ACTH levels (ACTH dependent vs. independent).
If ACTH low -> CT scan of adrenal gland.
If ACTH normal to high:
- High-dose (8mg) dexamethasone suppression test
- > will suppress ACTH in Cushing’s disease (pituitary-derived ACTH) and will not in ectopic ACTH.
- > if positive -> MRI pituitary
- > in equivocal cases, petrosal venous sinus sampling may be required to establish central-to-peripheral ACTH gradient.
If suspect ectopic ACTH -> CT, MRI, PET or octreotide scintigraphy.
Phaeochromocytoma
Rule of 10: 10% extra-adrenal, multiple, malignant. Genetic syndromes: - Von Hippel-Lindau (VHL) syndrome - MEN2 - NF1 Plasma fractionated metanephrines 24hr urinary fractionated metanephrines
Liddle Syndrome
Autosomal dominant condition with mutation in the ENAC channel, rendering it resistant to normal degradation.
Persistent sodium reabsorption and resultant hypertension.
May develop hypokalaemia with metabolic alkalosis.
Hypokalaemia associated with metabolic alkalosis
High BP
- Primary hyperaldosteronism (commonest)
- Liddle syndrome
- Chronic liquorice ingestion
- Apparent mineralocorticoid excess
- Familial hyperaldosteronism (including glucocorticoid-remediable hyperaldosteronism)
Low-normal BP
1. Bartter syndrome
Due to a defect in Na reabsorption in thick ascending limb of LOH (so same as being on Frusemide) - 5 types depending on the mutation in protein involved.
Usually presents in childhood.
2. Gitelman syndrome (milder disease and commoner in adult population)
Mostly a disorder of adulthood with hypomagnesaemia a striking feature.
Characterised by impaired NCCT (so same as being on thiazide diuretics).
Hypokalaemia, metabolic alkalosis and hypomagnesaemia with lowish BP.
Urine Anion Gap (UAG)
Positive in type 1 RTA and negative in metabolic acidosis due to any other cause including diarrhoea.
ENAs
SSA (Ro), SSB (La) and Ro 52 - SLE or Sjogren’s syndrome
Sm (Smith) - highly specific for SLE
RNP positive in MCTD
Scl-70 - systemic sclerosis
Jo-1 - dermatomyositis, anti-synthetase syndrome
Lupus Nephritis Biopsy (Renal)
Presence of IgG/A/M, C3 and C1q (“full house”) in a mesangiocapillary pattern of the glomerulus
Vasculitis by Classification
Large Vessel
- Takayasu arteritis
- Giant cell arteritis
Medium-sized vessel
- Polyarteritis nodosa (PAN)
- Kawasaki disease
Small-vessel vasculitis
a. Pauci-immune:
1. Granulomatosis with polyangiitis (Wegener’s, GPA)
2. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA)
3. Microscopic polyangiitis
b. Immune-complex mediated
1. Cryoglobulinaemic vasculitis
2. IgA nephropathy/HSP
3. Anti-glomerular basement membrane (anti-GBM) disease
PAN
Systemic necrotising transmural vasculitis that typically affects medium-sized muscular arteries.
No GN, no lung involvement, no ANCA, no involvement of arterioles/capillaries/veins and no granuloma on biopsy.
ANCA-associated small vessel vasculitis
GPA (Wegener’s) - 90% ANCA, mostly PR3
MPA - 70% ANCA, mostly MPO
EGPA (Churg-Strauss) - 50% ANCA, MPO slightly > PR3
C-ANCA (PR3 antigen)
P-ANCA (MPO antigen)
Beware:
10-40% of anti-GBM antibody disease ANCA + (mostly MPO)
Drug-associated ANCA vasculitis
Most commonly: anti-thyroid drugs, minocycline, hydralazine, cocaine, penicillamine, clozapine and isoniazid.
Pauci-immune vasculitis
Preceded by fever, malaise, anorexia and weight loss for weeks to months.
Wegener’s (GPA) - granulomatous inflammation affecting upper and lower respiratory tracts with GN.
MPA - necrotising inflammation causing GN, pulmonary capillaritis, but NO asthma/eosinophilia/granulomas.
EGPA - asthma, eosinophilia and necrotising granulomatous inflammation involving respiratory tract, renal involvement less common.
Renal biopsy show segmental necrotising glomerulonephritis often with crescents, no granulomas/IF negative.
GPA
Lung involvement in 90% - pulmonary haemorrhage, nodular or cavitating lesions radiologically
ENT involvement in 90% - sinusitis, rhinitis, ocular inflammation
Kidney involvement in 80% - GN with/without proteinuria and renal failure, RPGN
Cutaneous manifestations in 40% - leukocytoclastic angiitis causing purpura, ulceration and necrosis
Less commonly GIT, heart, neurological abnormalities.
Diagnosis: ANCA + in 90% (mostly commonly C-ANCA, PR3)
MPA
Kidney involvement in 80% - GN with/without proteinuria and renal failure, RPGN.
Lung involvement in 40%, GI in 40%, ENT in 35% and neurologic in 30%.
MPO/P-ANCA in more than 80%
Renal biopsy same as Wegener’s but NO granuloma.
EGPA
Characterised by asthma and peripheral + tissue eosinophilia with vasculitis and extravascular granulomas.
Mean age 40.
Prodromal phase: 2nd-3rd decade with atopic disease/asthma.
Eosinophilic phase: pulmonary opacities, asthma and peripheral eosinophilia with infiltration of lungs and GIT.
Vasculitic phase: 3rd-4th decade with vascular/extravascular granulomatosis with fever, weight loss, malaise.
Solid organ malignancy is most commonly associated with:
Membranous nephropathy.
Associated with positive anti-PLA2 receptor antibodies.
IgA nephropathy histology
Histological features include mesangial hypercellularity and positive immunofluorescence for IgA & C3
Differentiating between IgA nephropathy and post-streptococcal glomerulonephritis:
- post-streptococcal glomerulonephritis is associated with low complement levels
- main symptom in post-streptococcal glomerulonephritis is proteinuria (although haematuria can occur)
- there is typically an interval between URTI and the onset of renal problems in poststreptococcal glomerulonephritis
Lupus Nephritis
Nephrotic syndrome is associated with lupus nephritis not nephritic.
Clinical features of lupus nephritis:
1) Acute renal impairment
2) Microscopic hematuria
3) Proteinuria
4) Nephrotic syndrome
5) Lupus serology ( DsDNA, C3,C4)
Lupus Nephritis Stages
Stage I: Minimal mesangial lupus nephritis(LN)
Stage II: Mesangial proliferative LN
Stage III: Focal LN <50% gloms involved.
Stage IV: Diffuse LN >50% gloms involved.
Stage V: Pure membranous LN
Stage VI: Advanced sclerosing LN >90% gloms involved.
Cyclophosphamide toxicity includes:
1) Infertility secondary to gonadal toxicity
2) Malignancy
3) Bladder toxicity
4) Myelosuppression
5) Herpes zoster
6) Major infection
What is the drug of choice for refractory, relapsing lupus nephritis?
Rituximab is a human monoclonal antibody which is anti-CD20 and causes B cell depletion.
RPGN Treatment
Induction:
cyclophosphamide and IV methylprednisone
Maintenance therapy:
Azathioprine
For severe cases:
Plasma exchange
Other agents:
MMF (promising but no RCT)
Methotrexate-induction and maintenance
Rituximab
Bactrim
IVIG
The use of ACE inhibitors/ARBs in diabetic patients who are normoalbuminuric and normotensive are protective against which complication?
Diabetic retinopathy
Which of the following is the main site of potassium reabsorption in the nephron?
Proximal convoluted tubule
Drugs that can be cleared by hemodialysis
“BLAST”
Barbiturate
Lithium
Alcohol(methanol,ethylene glycol)
Salicylates
Theophyllines
Causes of primary aldosteronism:
- bilateral adrenal hyperplasia (most common)
- adrenal adenoma
- familial hyperaldosteronism
- unilateral adrenal hyperplasia
- adrenal carcinoma
- ectopic aldosterone production (rare)
Diuretics and Lithium
Diuretics that act at the distal renal tubule(hydrochlorothiazide, spironolactone, triamterene) increases blood concentrations of lithium.
Diuretics that act at the proximal tubule, Acetazolamide reduces blood concentrations of lithium.
Thiazide diuretics (may cause a paradoxical antidiuretic effect resulting in possible water retention and lithium intoxication)
Erythropoietin is predominantly made from which type of cell in the kidney?
Peritubular cells
MAHA
Haemolytic anaemia due to intravascular RBC fragmentation and is characteristically Coomb’s negative.
MOSTLY caused due to abnormalities in arteries and capillaries when it is termed TMA BUT can also be due to intravascular devices such as prosthetic heart valves.
Characteristic laboratory findings:
1. Haemolytic anaemia (low haptoglobin, high reticulocytes, raised LDH and indirect Br)
2. Negative Coomb’s test
3. Schistocytes (fragmented RBCs) on peripheral blood film
Not all MAHA is caused by TMA, but nearly all TMAs cause MAHA.
TMA
Thrombotic microangiopathy.
Microvascular thrombosis due to abnormalities in the vessel walls.
Injury to endothelial cells is the central pathophysiology.
Clinically, TMA presents with:
a) MAHA AND thrombocytopaenia.
b) Variable signs of organ injury due to platelet thrombosis e.g. AKI, neurological involvement.
TMA is a histological diagnosis characterised by platelet microthrombi within small arterioles and capillaries.
TMA Differential
Primary TMA Syndromes
- TTP
- ST-HUS
- Complement-mediated TMA (previously termed atypical HUS)
- Drug-induced TMA
- Disorders of vitamin B12 metabolism mediated TMA
Secondary causes of MAHA with thrombocytopaenia:
- Pregnancy associated
- Autoimmune disorders (SLE, SS, APS)
- Severe HTN
- Systemic infections (bacterial endocarditis, HIV, CMV)
- DIC
- Haematopoieitc stem cell transplant or organ transplant
- Immunosuppressive drugs such as Calcineurin inhibitors
TTP
Previously healthy individual presents with MAHA and severe thrombocytopaenia.
Caused by severe deficiency of ADAMTS13 to typically <10%.
AKI usually is not severe and anuria is unlikely.
Severe thrombocytopaenia is very common.
Neurological dysfunction common ranging from headache to seizures, stroke and coma.
Classic textbook pentad (rare, <5%)
1. MAHA
2. Neurological abnormalities
3. Fever
4. Renal dysfunction
5. Thrombocytopaenia
ADAMTS13 deficiency is mostly acquired due to auto-antibody (>95%) formation rather than a primary genetic condition.
Renal biopsy in all cases of TMA show…
Platelet microthrombi within small arterioles and capillaries
Characteristically swollen endothelial cells and subendothelial space, along with vessel wall thickening.
Management of TTP
Plasma exchange with FFP; cease when PLT count normal for at least 2 days.
Prednisolone 1mg/kg daily; hastens recovery by reducing production of ADAMTS13 inhibitor.
Rituximab: reduces relapse rate from 40% to 13%.\
Severe cases: Caplacizumab (anti-vWF monoclonal antibody).
PLT count trend is most reliable measure of disease response.
ST-HUS
Simultaneous occurrence of MAHA, thrombocytopaenia and AKI with history of recent diarrhoea.
Commoner in children.
Shiga-toxin producing E. coli (mostly O157:H7).
1/2 to 2/3 require dialysis during the acute phase, but the overall renal prognosis is good.
Neurological signs in up to 25%.
Pancreatitis in up to 20%.
Clinical + lab diagnosis with eventual confirmation with stool PCR.
Supportive mx.
CM-TMA
Arises from dysfunction of the complement system - alternative pathway.
Need to rule out HUS and TTP before considering diagnosis:
- AKI usually severe in comparison to TTP.
- Thrombocytopaenia usually not as severe as TTP.
- No history of diarrhoeal illness.
- Association with pregnancy.
- Life-threatening syndrome requiring prompt initiation of therapy.
When to suspect:
- Known family or personal history of CM-TMA
- Presentation of significant AKI during pregnancy or post-partum.
- TMA with progressive deterioration in kidney function.
- No history of exposure to drugs associated with drug-induced TMA.
- ADAMTS13 not low.
Pathogenesis:
- Alternative pathway is constitutively active as a result of spontaneous hydrolysis of C3 to C3b.
- Either through loss or gain of function mutation.
- > 90% caused by genetic mutations (as opposed to TTP).
Management:
Treatment with either Eculizumab or Ravulizumab (monoclonal antibodies against the C5 complement component, blocks formation of MAC).
Drug-induced TMA
- Immune-mediated: quinine most common, others being quetiapine, oxaliplatin and gemcitabine.
- Metabolism-mediated: disorders of intracellular vitamin B12 metabolism can cause TMA.
FGF23
Secreted by osteocytes and osteoblasts in response to: increased PO4, increased 1,2-OH2-VitD, increased PTH and stimulates phosphaturia by down-regulating sodium phosphate co-transporters in the proximal tubule. Also reduces 1,25-vitD by directly inhibiting 1a hydroxylase (renal) and stimulating 24-hydroxylase (catabolic) as well as directly inhibiting PTH secretion.
AKI in Renal Tx
RIFLE R - rejection I - infection F - flow L - last disease (recurrence) E - elevated drug levels causing toxicity
Highest risk of graft failure is due to recurrence of:
IgA
Membranous nephropathy
Primary FSGS
Fabry’s disease
Cyclosporin SEs
Gum hyperplasia
Hirsutism
HTN
More renal toxic
Tacrolimus SEs
Neurotoxicity
Diabetes (islet cell toxicity)
Immunosuppression
Acute Allograft Dysfunction Timeline
Immediate
- ATN +/- rejection
- Hyper-acute or acute AMR
- Vascular
- Obstruction
1-12 weeks
- Rejection
- Drugs
- Obstruction
- Infection
- Recurrence of underlying GN
> 3 months
- Volume
- Drugs
- Rejection
- Obstruction
- Recurrence
- RAS
- De novo
Caused of Delayed Graft Function
Post-ischaemic ATN
ATN with superimposed rejection
Hyperacute and acute AMR
Ureteric leak/obstruction due to necrosis or haematoma
Atheroemboli or thrombosis of the renal artery or vein
Treatment for AR
Methylprednisolone Rescue dose MMF Modify CNI - change CyA to Tac ATG If antibody-mediated: Rituximab/PEx/IVIg
PTLD
B-cell monoclonal proliferation
EBV associated
Prophylaxis
Treatment: reduction in immunosuppression, anti-viral, Rituximab.
Infection Time Course in Transplantation
1-month
- Wound, urine, chest
1-6 months
- Viral opportunistic
> 6 months
- Standard community-acquired
Polyomavirus
BK virus
- Tubulointerstitial nephritis with allograft dysfunction, ureteric stenosis, haemorrhagic cystitis, systemic vasculopathy.
JC virus
- Progressive multifocal leukoencephalopathy
Risks: degree of immunosuppression, donor age, ureteral stent, viral co-infection.
Pre-emptively reduce immunosuppression with viraemia.
Biopsy if no clear viraemia or graft dysfunction.
Look for viral inclusion bodies.
Post-transplant erythrocytosis
4-22% develop persistently elevated haematocrit.
Angiotensin-mediated
Treatment ACE inhibitors or ARBs
Causes of membranous nephropathy:
1) SLE- Class V lupus nephritis
2) Drugs- NSAIDs,penicillamine, gold.
3) Hepatitis B and C
4) Malignancy- solid organ tumors
5) Hematopoetic stem cell transplant and graft versus host disease
6) Kidney transplant
7) Syphilis
Which of the following agent is least likely to be effective in the treatment of acute renal allograft rejection?
Cyclosporin has no role in the management of acute renal allograft rejection.
The use of sirolimus in renal transplant recipient is most likely to reduce which type of malignancy?
Kaposi’s sarcoma
Which of the following immunosuppressant is safe for use in pregnancy?
Cyclosporin and Azathioprine are safe for use in pregnancy.
Which of the following factor is responsible for causing insulin deficiency in New Onset Diabetes Mellitus After Transplant (NODAT)?
Tacrolimus causes insulin deficiency rather than insulin resistance and is responsible for NODAT.
Foot process effacement
Minimal change disease
Aldosterone stimulates which part of the renal tubule to reabsorb sodium?
Cortical collecting duct
ANP affects which part of the renal tubule to inhibit sodium reabsorption?
Medullary collecting duct
Which part is the site for excretion of trimethoprim?
Proximal convoluted tubule
Where is phosphate mainly reabsorbed after being filtered by the glomerulus?
Proximal convoluted tubule
In developed countries, which bone disorder is most frequent in patients receiving maintenance haemodialysis?
Adynamic bone disease because of suppression of PTH with calcium and potent vitamin D analogues.
Which GN is most likely to rapidly recur in a renal allograft?
FSGS
When a patient presents with nephrotic syndrome, which type of causative glomerulonephritis is associated with the greatest risk of a venous thrombotic event?
MN
Which glomerulonephritis is associated with selective COX-2 inhibitor use?
MCD
In which glomerulonephritis are anti-phospholipase A2 receptor (anti-PLA2R) antibodies commonly detected?
MN
