JC78 (Medicine) - Glomerular, Tubulo-interstitial diseases and AKI Flashcards
3 standard histopathological tests for kidney biopsies
Light microscopy with staining
Immunofluorescence
Electron microscopy
List all staining techniques for light microscopy exam of kidney biopsy
Haematoxylin and eosin (H&E, for nuclei and cytoplasm)
Periodic acid-Schiff (for basement membrane and PAS-positive material)
Period acid silver- methenamine
Masson Trichome (for fibrosis, deposits)
Congo red (for amyloidosis)
Enzyme techniques
Masson-Trichrome stain
- Usage and color changes when binding to different molecules?
Kidney fibrosis - blue
Kidney deposits - orange to red
List all primary glomerular diseases
Categorize into non-proliferative and proliferative
Non-proliferative:
- Minimal change nephrotic syndrome
- Membranous nephropathy
- Focal segmental glomerulosclerosis
- Thin membrane disease
Proliferative:
- IgA Nephropathy
- Membranoproliferative GN
- Crescentic GN
- IgM Nephropathy
List secondary glomerular diseases
Categorize into proliferate and non-proliferative causes
Non-proliferative
- Diabetic nephropathy
- Hypertensive nephrosclerosis
- Amyloidosis
- Light/heavy chain deposition disease
- Alport’s syndrome
- Infection-related membranous glomerulopathy
- HIV nephropathy (FSGS or collapsing glomerulopathy)
- Drug-induced glomerulopathy
- Malignancy-associated nephropathy
- Reflux nephropathy
Proliferative:
- Lupus nephritis
- Post-streptococcal GN
- Hepatitis B or C- related membranoproliferative GN
- Systemic vasculitis
- Goodpasture syndrome
6 general presentations of glomerulonephritis
- Asymptomatic microscopic hematuria/ proteinuria
- Macroscopic hematuria
- Acute nephritic syndrome
- Nephrotic syndrome
- Rapidly progressive glomerulonephritis
- Chronic glomerulonephritis/ CKD
Asymptomatic hematuria
- Presentation
- Severity of proteinuria
- Classical histopathological feature
Incidental finding of macroscopically/ microscopically detected RBC in urine, usually dysmorphic RBC
Normal GFR, no systemic disease
Proteinuria: variable, usually <1g/day
Feature:
Dysmorphic RBC/ Acanthocytes with ring-formed cell bodies + multiple blebs
RBC casts
Macroscopic haematuria
- Presentation
- D/dx
Presentation:
Episodic, painless, macroscopic hematuria
Glomerular disease - brown/ smoky urine with no clots
D/dx:
- Urological: Stones/ tumor
- Renal: Glomerulonephritis, Acute interstitial nephritis, Polycystic kidney disease
- Infection: Cystitis, TB, Schistosomiasis
- Glomerular causes: IgA Nephropathy, Alport’s syndrome, Thin Membrane Disease (benign familial hematuria)
Alport syndrome
- Inheritance
- Pathogenesis
- Presentation
Inheritance: X-linked dominant
Pathogenesis: Mutation in type IV collagen genes, affect auditory sensory cells and glomeruli
Presentation:
- High tone deafness*
- Macroscopic Hematuria
- Renal failure
How to differentiate 3 glomerular causes of macroscopic hematuria?
- Any gross hematuria?
- Common in IgA Nephropathy and Alport syndrome
- Rare in Thin basement membrane disease - Family history of CKD:
- Alport syndrome: Renal failure, high-tone deafness in male (X-link dominance)
- IgA Nephropathy: Runs in family, no clear inheritance pattern
First-line investigations for hematuria
Basic:
- Renal function test
- Urine culture, AFB
- Urine cytology
- Urinalysis
Imaging:
- X-ray or CT KUB
- USG/ Doppler ultrasound
- Cystoscopy
- IV pyelogram/ retrograde pyelogram
- CT urogram
D/dx tests:
- Pure tone audiometry for Alport’s syndrome
- Kidney biopsy for significant proteinuria (>1g/day)
First-line investigations/ evaluations for proteinuria
- Dipstix - screening for proteinuria
- Spot urine quantitative analysis: Urine protein- creatinine ratio
- Timed urine (24h)
Dipstick for screening
Quantitative analysis for monitoring and further Ix of positive dipstick
Standard urinary dipstick
- Mechanism
- Cut-offs for 5 different levels of positive dipstix for albumin
Mechanism:
- Measures albumin concentration via colorimetric reaction between albumin and tetrabromophenol blue
- Different shades of green for concentrations of albumin
Cut-offs: (mg/dL)
- Negative
- Trace: 15-30
- 1+ = 30-100
- 2+ = 100-300
- 3+ = 300-1000
- 4+ = >1000
Urine protein to creatinine Cut-off for nephrotic proteinuria
> 3.5mg/mg = nephrotic
Causes of false positive proteinuria
Strenuous exercise in 24h (myoglobinuria)
Concomitant systemic infection or UTI
High output state: Fever, pregnancy, hypertension
Haematuria
Orthostatic proteinuria
- Define
- Severity of proteinuria
- Diagnostic test
Increased protein excretion in upright position. No proteinuria in supine position
Usu. <1g/day, may exceed 3g/day
Split urine collection (no proteinuria over night when supine, proteinuria during daytime when upright)
Acute nephritic syndrome
- Presentation
- Severity of proteinuria
- Most common cause
Abrupt onset of macroscopic hematuria
Oligouria
Acute renal failure
Fluid retention - edema, hypertension
Urinary protein <3g/day
Most common cause:
- Post-streptococcal GN
Post-streptococcal GN
- Typical demographic
- Pathogenesis
- Presentation
- Ix
- Tx
Demographic: Usu. children between age 2-10
Pathogenesis: Streptococcal antigen deposit in glomerulus during infection, with delayed host immune response
Presentation:
- Gross hematuria, Oligouria, HT, edema develop 7 days to 12 weeks after streptococcal infection (throat/ skin)
- Spontaneous resolution: diuresis within 1-2weeks, normal renal function within 4 weeks
Ix:
- Total hemolytic complement activity, C3 concentrations (low)
- Antibodies against Streptolysin O
Tx:
Penicilin, supportive therapy, temporary dialysis
D/dx acute nephritic syndrome with low C3 complement concentration
Post-streptococcal GN
Lupus nephritis
Membranoproliferative glomerulonephritis
Nephrotic syndrome
- Severity of proteinuria
- Presentation
Massive proteinuria >3.5g/day
Presentation:
Generalized edema - Periorbital edema, ankle edema
Hypoalbuminemia (<30g/dL) - Muehrcke’s bands in fingers
Hyperlipidemia and lipiduria, Xanthelesma
Massive proteinuria - Frothy urine
Primary kidney diseases asso. with nephrotic syndrome
Primary non proliferative:
Focal segmental glomerulonephritis
Membranous glomerulopathy
Minimal change disease
Primary Proliferative:
Membranoproliferative glomerulonephritis
IgA nephropathy (sometimes)
~~~
Systemic causes of Nephrotic syndrome
DM
SLE
Amyloidosis
Secondary membranous nephropathy:
- Infection: HBV, HCV, HIV, Malaria, Syphillis
- Malignancy: lymphoma, adenocarcinoma, myeloma
- Drugs: penicillamine, gold, mercury, NSAIDs, Probenecid
First-line investigations for nephrotic syndrome
Generic Tx
Blood:
- CBC with differential
- Renal function test
- Urine protein analysis - urine protein: creatinine ratio >3.5
D/dx cause:
- Fasting glucose for DM
- Ig pattern for SLE, amyloidosis
- Secondary membranous nephropathy:
HBsAg, Anti-HCV, Anti-HIV,
Tumor screening with CXR, FOBT, tumor markers
- Idiopathic membranous nephropathy - Anti-PLA2R
Tx:
Corticosteroids, Calcineurin inhibitors for refractory cases
Diagnostic marker for idiopathic membranous nephropathy
Anti-PLA2R
M-type Phospholipase A2 receptor used as target antigen
Glomerular diseases/ diseases that do not require kidney biopsy before dx
Children (<12) with steroid-sensitive nephrotic syndrome or Post-streptococcal GN
Idiopathic membranous nephropathy (PLA2R +ve)
ANCA vasculitis (MPO or PR3 +ve)
Anti-glomerular basement membrane disease
Alport disease, Fabry disease
Familial focal and segmental glomerulosclerosis
SLE
Rapidly progressive glomerulonephritis (RPGN)
- Presentation
- ## Histopathological feature
Presentation:
- Glomerulonephritis: hematuria, proteinuria, RBC casts
- Rapid kidney failure in days to weeks
- Other organs: e.g. Pulmonary hemorrhage in Goodpasture’s, Hepatic failure in leptospirosis
Histological feature:
Cellular crescents - Glomerulus periphery is replaced by circumferential layer of fibro-cellular proliferation/ Crescent
RPGN
- Underlying etiologies
Renal: Pauci-immune GN (systemic vasculitis) Anti-GBM disease/ Goodpastrue syndrome Crescentic IgA Nephropathy Acute post-infectious GN
Multisystem diseases:
- Systemic vasculitides
- Cryoglobulinemia
- SLE
RPGN
First-line investigations
Basic: CBC with differentials RFT, electrolytes Urine protein quantification Urine sediments
Underlying cause:
- Autoimmune markers:
ANCA, Anti-GBM, ANA, Anti-dsDNA, C3/C4 concentration
- CXR and DLCO for pulmonary involvement in Goodpasture’s
RPGN
Generic Tx
Systemic corticosteroids +/- immunosuppressants
Plasmapheresis for Anti-GBM Ab removal
Chronic glomerulonephritis
- Presentation
- 1 major etiology
Progressive kidney function loss with glomerular inflammation
Proteinuria, hematuria, hypertension
Kidney atrophy
Etiology: Tubulointerstitial diseases
Chronic glomerulonephritis
- First-line Ix with typical findings
- Tx
Ix:
CBC - NcNc anaemia
Renal: High serum urea, creatinine, PO4
Hypocalcemia, Hyperkalemia, Metabolic acidosis
USG - Kidney atrophy
Urine protein quantification - Proteinuria
Tx:
Supportive
RRT if CKD stage 5
Tubulointerstitial diseases
- Presentation
- Major entities/ types
Presentation: due to interstitial inflammation and tubular dysfunction
- Loss of renal function
- Abnormal urine sediment (WBC, Protein)
- Electrolyte disturbance
- Acid-base disorders
Entities:
- Acute interstitial nephritis
- Chronic interstitial nephritis
- Potassium-wasting tubular disorders
- Renal tubular acidosis
First-line investigations for AKI
- Visual: Color/ Turbidity/ Volume
- Chemical (Urine dipstick): pH/ Special gravity/ Glucose/ Protein/ Ketones/ Blood/ Leukocyte esterase/ Nitrite/ Bilirubin/ Urobilinogen
- Microscopic (Urine sediment): RBC/ WBC/ Epithelial cells/ Microorganisms/ Casts/ Crystals
Renal function test (RFT)
• Plasma creatinine level
• Plasma urea level / Blood urea nitrogen (BUN)
• Plasma Urea: Creatinine ratio / BUN: Creatinine ratio
• Glomerular filtration rate (GFR)
Urine albumin-to-creatinine ratio (ACR)/ Urine albumin/ Urine total protein
Clinical/ Biochemical definitions of AKI
Acute kidney injury (AKI) is defined by any of the following
- Increase in serum creatinine ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 hours (OR)
- Increase in serum creatinine to ≥ 1.5x from baseline which is known or presumed to have occurred within the prior 7 days (OR)
- Urine volume < 0.5 mL/kg/hr for 6 hours
Risk factors of AKI
Pre-existing CKD Age >50 Diabetic nephropathy Heart failure Hypovolemia Liver disease Sepsis, Trauma, Post-op Cancer
AKI
Categorize etiologies into 3 anatomical groups
Pre-renal (>50%)
Intrinsic: Tubular necrosis, Interstitial nephritis, Acute GN/ RPGN
Post-renal (<10%): obstructive pathologies
List pre-renal causes of AKI
Hypovolemia
• Hemorrhage
• Vomiting/ Diarrhea
• Diuretics
Hypervolemia but low effective circulating volume
• Heart failure with reduced ejection fraction (HFrEF)
(Cardiorenal syndrome)
• Decompensated liver disease with portal hypertension (Hepatorenal syndrome)
Low Afferent arteriole vasodilatation
• NSAIDs: Inhibits COX enzymes and thus decreased synthesis of prostaglandins (PG)
• ACEI/ ARB
• Cyclosporine
List intrinsic/ renal causes of AKI
Small vessel diseases: Thrombotic microangiopathy, renal atheroembolism, small vessel vasculitis
Large vessel vasculitides:
• Renal artery embolism/ aneurysm/ dissection
• Rena vein thrombosis
• Systemic thromboembolism
Glomerular diseases:
Proliferative glomerulonephritis (Nephritic pattern)
Non-proliferative glomerulonephritis (Nephrotic pattern)
Tubular and interstitial disease:
Acute tubular necrosis
Acute interstitial nephritis
Acute urate nephropathy (TLS)
List post-renal causes of AKI
Obstructive diseases:
- Bladder outlet obstruction
- Tumors
- Renal calculi
- Papillary necrosis
- Retroperitoneal fibrosis
Management plan for AKI
- Accurate Dx and reverse underlying cause
- Treatment
Fluid overload - IV Loop or thiazide diuretics
Hyperkalemia
• Restriction of dietary K+ intake, discontinuation of ACEI/ARB and loop diuretics to promote urinary K+ loss
Hypocalcemia
• Restriction of dietary PO43- intake + Calcium carbonate or calcium gluconate if symptomatic
Hyperphosphatemia
• PO4 binding agents
Metabolic acidosis
• Administration of sodium bicarbonate
Acute dialysis: Central vascular access hemodialysis
Causes of acute tubular necrosis
- Ischemia
- Sepsis or shock
- Endogenous nephrotoxin: Rhabdomyolysis/ Hemolysis/ Multiple myeloma
- Exogenous nephrotoxin: Contrast nephropathy/ Aminoglycosides/ Cisplatin/ Amphotericin B
Causes of acute interstitial nephritis
- Myeloma cast nephropathy
* Drug-induced nephrotoxicity: NSAIDs/ Penicillin/ Rifampicin/ Allopurinol
Compare the urinalysis results for proliferative vs non-proliferative glomerular disease
Proteinuria + Hematuria + Dysmorphic RBC + RBC casts
o Proliferative glomerular disease (Nephritic pattern)
Heavy proteinuria + NO hematuria
o Non-proliferative glomerular disease (Nephrotic pattern)/ DM nephropathy/ Amyloidosis
Ddx high plasma urea-to-creatinine ratio/ high plasma BUN-to-creatinine ratio
Ddx LOW plasma urea-to-creatinine ratio/ high plasma BUN-to-creatinine ratio
AKI
S/S and pathogenesis
Edema
• ↓ Plasma oncotic pressure due to hypoalbuminemia
• Renal Na+ and water retention in collecting tubules - drop in plasma volume due to interstitial edema»_space; compensatory increase RAAS activation
Hypertension
• Renal Na+ and water retention in collecting tubules - drop in plasma volume due to interstitial edema»_space; compensatory increase RAAS activation
Oliguria/ Anuria
Typical electrolyte profile in AKI and pathogenesis
Hyponatremia (↓) - Inability to excrete free water
Hyperkalemia (↑): Occurs due to presence of metabolic acidosis
- Excess H+ are buffered in the cells and electroneutrality is maintained in part by the movement of intracellular K+ into the extracellular fluid
- Impaired cellular uptake of K+ due to diminished Na+-K+-ATPase pump also contributes to hyperkalemia
Hypocalcemia (↓)
- Hyperphosphatemia leading to hypocalcemia
- ↓ Synthesis of calcitriol (1,25-(OH)2D3) in kidneys**
Hyperphosphatemia (↑)
o ↓ Renal excretion of PO43-
Typical arterial blood gas profile in AKI
Metabolic acidosis + ↑ Anion gap
o Excretion of acid and regeneration of HCO3-is impaired in low GFR
- Impaired H+ and NH4+ excretion due to decreased in number of functioning nephrons in renal failure
o ↑ H+ production in lactic acid or ketoacids in sepsis and trauma
o ↓ HCO3- due to loss from diarrhea or renal tubular acidosis
