Renal Flashcards
Hyperacute transplant rejection cause, pathology/histo and management
Due to pre-formed antibodies
Causes vascular thrombosis, PMNs, infarction
May need nephrectomy
Acute transplant rejection cause, pathology
7-10 days
Largely T cell mediated
Fever, oliguria, tender graft
Pathology: tubulitis, endotheliatis
Treatable
Chronic transplant rejection cause, pathology
Progressive decrease in eGFR, proteinuria, hypertension
Both immune and non-immune causes
No specific treatment
PathologyL glomerulopathy, chronic interstitial nephritis
Induction agents for solid organ transplant
Thymoglobulin
Basiliximab
Thymoglobulin MOA and issues
Target polyclonal T cells –> depletion
Lasts for days
Good for acute rejection treatment
Issues: CRS, LVF, meningitis, cytopaenias, neutralising antibodies, cancer, infection
Basiliximab MOA and issues
Target chimeric CD25 T cells + IL2R –> inactivation (rather than depletion)
Lasts for 2 months
Not as good for acute rejection as thyroglobulin
Minimal problems, expensive
Belatacept (CTLA4 Ig)
MOA
Benefits and risks
Blocks signal 2
Reduced renal toxicity compared to CSA
Increased EBV risk and PTLD
Decreased response to vaccines
Prevents CD28 mediated T-cell activation
Calcineurin inhibitors MOA
Cyclosporin and tacrolimus
Block signal 1
Block IL-2 generation
Tac more potent than CSA
CsA measure peak, tac measure trough
Nephrotoxic
MMF and aza in renal transplant
MMF more potent in first 12 months compared to Aza
MMF fairly leukocyte specific
MMF blocks IMPDH - prevents purine synthesis –> Cell G1 arrest
MMF absorbed more distally - less GI toxicity
Issues: Bone marrow suppression. Hepatoxocity/bone marrow suppression with Aza
mTOR inhibitors MOA, SE
Sirolimus/everolimus
Block signal 3
Bind to FKBP-12 to form complex and bind to mTOR. Inhibits IL-2/costimulatory triggered cell signalling
SE: Protineuria + oedema
mTOR for Kaposi sarcoma
Everolimus beneficial to treat kaposi’s sarcoma (HHV8 associated cancer)
MMF and cyclosporin
MMF levels are lower with CsA
Sirolimus and CNI
Increased risk of nephrotoxicity secondary to CNI (Sirolimus leads to overdosing of CNI)
Management of renal transplant acute rejection
Biopsy
IV Methylpred
Thymoglobulin if steroid resistant or vascular rejection
PLEX/IVIG if Ab mediated
Rescue therapy: High dose Tac or MMF
Number of episodes correlated with mortality
Key risk factor for CVS events after transplant
Diabetes
BK Polyomavirus
DNA virus
Primary infection in childhood
Asymptomatic - screen with serum PCR monthly
BK virus management
Reduce immunosuppression
Leflunomide if very high viral load
IV cedofovir alternative option
BK virus kidney biopsy histology
Intranuclear inclusions
IHC - SV40 antigen
Most common type of renal cancer
Clear cell
CD10 +ve
90% will have chromosome 3p abnormalities (VHL gene)
Renal oncocytoma cell of origin and IHC
Arise from intercalated cells
CD117, PAX-2 positive
Mitochondria rich
Renal chromophobe cancer can transform into:
Sarcoma
Von Hipped-Lindau syndrome
Autosomal dominant
Retinal angiomas, cerebellar and spinal angiomas, pheochromocytoma, pancreatic/renal cysts
Onset of tumours in adolescence
Birt-Hodd-Dube’ syndrome
Autosomal dominant
Risk of RCC and lung cysts
ADPKD genes
Autosomal dominant
PKD1 (85% - more severe) on chromosome 16.
PKD2 (15%) on chromosome 4
ADPKD systemic associations
Intracranial berry aneurysms
Liver (most common extra-renal manifestation) cysts, pancreatic cysts, cardiac LVH
PKD1 gene product and function
Produces polycystin 1 which regulates cell differentiation
Reduced levels correlated with disease severity
PKD2 gene product and function
Produces polycystin 2 which regulates intracellular calcium
When to screen for intra-cranial aneurysm in ADPKD
FHx
Undergoing major surgery
Symptoms or previous ICA
Occupation e.g. pilot
Patient concern
Type 2 RTA
Proximal RTA
Defect in bicarb reabsorption
Manifests with significant hypokalaemia and acidosis with bicarb >15
Urine pH <5.0 as collecting duct retains ability to reabsorb HCO3 in the setting of systemic acidosis, preventing a steep fall in the bicarb
Treat with alkali and K+ replacement
Type 1 RA
Distal RTA
Defect in H+ secretion in intercalated cells
Ammonia does not bind with H+ to form ammonium, less ammonium in urine
Urine pH >5.5
Treat with alkali and K+ replacement
Type 4 RTA
Most common
Type 4 RTA = aldosterone resistance
DM associated in 50% of cases (others NSAIDS, ACEi, CNI, K+ sparing diuretics and high dose heparin)
Treatment:
If hypertensive or overloaded: thiazide/loop diuretic
If hypotensive or not overloaded: fludrocortisone
Primary hyperaldosteronism cause and diagnosis
Most common cause of secondary hypertension
2/3 due to bilateral adrenal hyperplasia
1/3 due to unilateral adenoma
High A:R ratio
Saline loading test or fludrocortisone test - failure to suppress Aldosterone
Must correct K+ before testing
Drugs that suppress renin
BB, amlodipine, clonidine, NSAIDs
Drugs that stimulate renin
ACE/ARB, all diuretics
Neutral drugs for A:R testing
Verapamil
Hydralazine
Prazosin
Primary hyperaldosteronism treatment
MRA’s for hyperplasia
Adrenalectomy for unilateral adenoma
Renal artery stenosis causes
FMD and atherosclerosis
Fibromuscular dysplasia epidemiology, bloods, diagnosis and treatment
Young females with treatment resistant hypertension
High renin and aldosterone
May cause spontaneous dissection
Diagnose with renal DSA (100% sensitive and specific)
80% respond to angioplasty, small recurrence rate
Phaeochromocytoma
What is it
Presentation
Diagnosis
Management
Tumour of adrenal medulla
May occur along sympathetic chain (paraganglioma)
Present with sweating, anxiety, palpitations, weight loss, insomnia
Diagnose with fasting plasma metanephrines then confirm with 24 hour urine metanephrines/catecholamines
Avoid contrast
Alpha blocker before beta blocker
Surgery
IV contrast in phaeochromocytoma
May cause hypertensive crisis
Rare causes of hypertension and hypokalaemia
Apparent mineralocorticoid excess
Liddles syndrome
Licorice abuse
MHC function and genetic location
Helps the body distinguish between self proteins and those made by foreign substances
-Located on chromosome 6
Hepatorenal syndrome management
Stop diuretics, give fluid
Terlipressin
HDx then liver transplant (not kidney)
Contrast nephropathy time course and management
Onset 24-48 hours post contrast, peak 5-7 days, resolves 2 weeks
Non oliguric
IV fluid for prevention
NAC ONLY if severe HF preventing use of fluids
Minimal evidence for sodium bicarb
Causes of nephrotic syndrome
Minimal change disease - #1 in childhood
FSGS - African populations
Primary membranous - #1 primary cause
Diabetic nephropathy - #1 cause in whole population
Minimal change disease histology and management
Flattened podocytes on E.M
Steroids
-Poorer prognosis in adults
-Steroid refractory if no response at 16 weeks
FSGS variant with worst prognosis
Collapsing variant
FSGS management
Pred with wean over 3 months
Ritux
Cyclophosphamide
Primary membranous nephropathy presentation, histology and antibody
Presents with nephrotic range proteinuria, prone to thrombotic complications in first 2 years (higher risk with low albumin)
Histology: thickened GBM, intra-membranous Ig deposits, spikes
PLA2R antibody (podocyte antigen) - if positive do not need to do biopsy. Can be used to monitor response to therapy and post transplant recurrence
Causes of secondary membranous nephropathy
SLE
Hep B
Meds e.g. penicillamine
Membranous nephropathy management
RAAS blockade, statin, oedema management
30% will have spontaneous remission in first 1-2 years
Diabetic nephropathy histology and first change
Hyperfiltration is first
Thickening of GBM early on histology
Diabetic nephropathy management
If eGFR >30 and albuminuria >30mg.g - SLGT2
If CKD and additional CVD risk factors - GLP1
Nephritic syndrome causes
IgA nephropathy
Membranoproliferative GN
RPGN
Lupus nephritis
IgA nephropathy presentation, histology and prognosis
Asymptomatic haematuria - often synpharyngitic
Most common form of GN
Histology mesangial hypercellularity, matrix expansion, IgA positive
20% ESRF in 10 years, 30% reduced GFR
IgA pathophysiology
Caused by a defect in IgA producing cells causing increased serum levels of galactose deficient IgA1
Leads to antibody formation to galactose deficient IgA1 –> immune complex formation –> deposition in glomerulus
Secondary IgA causes
Liver disease/transplant
Coeliac disease
IgA nephropathy management
Supportive measures
Add immunosuppression if:
-Acute or rapid loss of GFR
-Very high proteinuria
IgA vasculitis (HSP) presentation
Systemic version of IgA nephropathy
Tetrad of:
1. Palpable purpura
2. Abdo pain
3. Kidney disease
4. Arthralgia
Membranoproliferative GN presentation, bloods, histology
Proteinuria + haematuria + low C3
Histo: reduplication of GBM - tram track sign
If C3 only - C3GN. If C + Ig - MPGN
Causes of secondary membranoproliferative GN
Hepatitis C
SLE
Management of membranoproliferative GN
Look for monoclonal band - treat myeloma
If familial - supportive care only
If C3GN - anti-complement e.g. eculizumab
If Hep C - treat Hep C first
Classical form of kidney involvement in Hep C
Immune-complex GN with or without cryoglobulinaemia
Causes of RPGN and presentation
Lupus nephritis
Anti-GBM
ANCA associated vasculitis
Present with oliguria and rapidly rising serum creatinine along with macro or microscopic haematuria
Lupus nephritis treatment
Treat class 3, 4, 5
Steroids + cyclophosphamide or MMF
If worsening in 3 months change therapy/repeat biopsy
Aza or MMF maintenance + pred
Anti-GBM disease epidemiology, presentation, histology
Bi-modal: young men, older women
50% present with RPGN and pulmonary haemorrhage
Haematuria, erythrocyte casts, proteinuria, mod-severe AKI, lung involvement (Goodpasture’s syndrome)
Histology: Crescentic GN, IgG staining along the glomerular capillaries (indicates antibodies against GBM)
Serum anti-GBM ab 60-100% sensitive so also need biopsy
Manage with plasmapheresis + pulsed IV steroids then PO
Cyclophosphamide
What do the Anti-GBM antibodies target
Alpha-3 chain of type IV collagen
ANCA-associated GN presentation
Vasculitic prodrome of malaise, arthralgia, myalgia
Flu-like symptoms
Dark brown/tea coloured urine
Lung involvement
Diagnose with serum ANCA and biopsy - no immune deposits (pauciimmune GN)
Treatment of ANCA-associated GN
High dose steroids with either cyclophosphamide or rituximab
Avacopan a new alternative
Indications for plasmapheresis in renal vasculitis
Anti-GBM disease
Pulmonary haemorrhage
Severe or rapidly progressive kidney disease
Alports syndrome presentation
Asymptomatic persistent haematuria in childhood, sensorineural hearing loss and ocular issues
Can also have leiomyomatosis - benign smooth muscle overgrowth tumours in GI, respiratory and female reproductive tract
Alport’s syndrome cause and management
Variants in genes encoding for alpha-3, alpha-4, alpha-5 chains (located in kidney, cochlear, eye) of type IV collagen
Can be x-linked, AD, AR
Manage with ACE-i and transplant
GPA vs MPA
GPA: leqkocytoclastic vasculitis + granulomas + PR3 pos
saddle nose (polychondritis)
MPA: Necrotising vasculitis + no granulomas + MPO pos
Much less ENT involvement in MPA
What can Sjogrens cause in the kidney?
Distal RTA
Renal stones
What can RA cause in the kidney?
Cryoglobulins
Amyloid
What can Gout cause in the kidney?
Progressive decline in eGFR due to hyperuricaemia
Stones
What can scleroderma cause in the kidney?
Renal crisis (hypertensive crisis)
Other than nephritis, what can lupus cause in the kidney?
Antiphospholipid syndrome –> microangiopathic renal injury
FHH pathophysiology
Autosomal dominant
Defect in CaSR in kidney and parathyroid
-Isn’t inhibited by high calcium so increased reabsorption on calcium
-High serum calcium low urine calcium
Lithium damages the CaSR in the kidney acting in a similar way
FGF23 secretion and function
Secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased Vit D
Increases in early stages of CKD leading to increased phosphate excretion and decreased 1a hydroxylase activity –> decreased Vit D formation –> increased PTH secretion
What is Klotho?
Co-receptor required for FGF23 signalling
Levels decrease as CKD progresses leading to decreased FGF23 responsiveness and inability to regulate phosphate levels
Effects of hyperphosphataemia
LVH
Faster CKD progression
Premature mortality
Stimulates osteoblast transformation of the vascular smooth muscle cell –> arterial calcification and stiffness
Secondary hyperparathyroidism
Due to hypocalcaemia
Tertiary hyperparathyroidism
Due to autonomous secretion of PTH by hypertrophied parathyroid gland in the setting of CKD
Increased PTH and calcium levels
May need parathyroidectomy
Calcimimetics mechanism of action
Increase the sensitivity of CaSR to calcium and can lower PTH secretion by directly inhibiting PTH gene expression
Renal osteodystrophy investigations
Bone biopsy gold standard but not practical
Monitor PTH and ALP levels
Management of secondary hyperparathyroidism
- Treat phosphate first
-Dietary restriction to <900mg/day
-Phosphate binders - Treat PTH
-Calcimimetics
-calcitriol or synthetic Vit D
-Treat vit D deficiency with cholecalciferol
Types of phosphate binders and preference
Calcium containing - calcium carbonate or calcium acetate
Non-calcium containing - sevelamer/lanthanum
First preference is non-calcium containing –> decrease mortality in CKD
Test to differentiate Barrter’s and Gittleman’s syndrome?
Urine prostaglandin E is elevated in Barrter’s
Which cells secrete EPO?
Peritubular
