Nephrology JC078: Glomerular And Tubulo-interstitial Diseases And Acute Kidney Injury Flashcards
***Renal parenchymal disease (GN)
Renal parenchyma:
- Functional tissue of kidney, consisting of ***Nephrons (basic unit)
Classification of glomerulonephritis by ***glomerular cellularity (Proliferative / Non-proliferative) in kidney biopsy
Primary glomerular diseases (i.e. no cause found)
- Proliferative
1. IgA nephropathy (IgAN)
2. Membranoproliferative GN (MPGN)
3. Crescentic GN
4. IgM nephropathy
- Non-proliferative
1. Minimal change nephrotic syndrome
2. Membranous nephropathy
3. Focal segmental glomerulosclerosis (FSGS)
4. Thin membrane disease (TBMD)
—> ALL above terms are ***morphological description under microscope
Secondary glomerular diseases
- Proliferative
1. Lupus nephritis
2. Post-streptococcal GN
3. Hep B / C-related MPGN
4. Systemic vasculitis
5. Goodpasture syndrome
- Non-proliferative
1. Diabetic nephropathy
2. Hypertensive nephrosclerosis
3. Amyloidosis
4. Light/Heavy chain deposition disease
5. Alport syndrome
6. Infection-related membranous glomerulopathy
7. HIV nephropathy (FSGS / Collapsing glomerulopathy)
8. Drug-induced glomerulopathy
9. Malignancy-associated nephropathy
10. Reflux nephropathy
Classification of Glomerular disease
Usually by different patterns of histologic injury seen on biopsy
NO single classification is ideal
- one histologic pattern can have **multiple etiologies (e.g. membranous pattern can be idiopathic / due to lupus / viral hepatitis infection)
- one etiology may produce a **variety of histologic patterns (e.g. lupus nephritis (class 1-6 with different morphological pattern), IgAN, HBV infection)
- one histologic pattern can have ***multiple clinical presentations (e.g. IgA nephropathy may present with asymptomatic microscopic haematuria / synpharyngitic gross haematuria / RPGN)
***Clinical features of Renal parenchymal disorders
Glomerulonephritis (present with 1 of 6 clinical syndromes):
1. Asymptomatic microscopic haematuria / proteinuria
2. Macroscopic haematuria
3. Acute nephritic syndrome
4. Nephrotic syndrome
5. Rapidly progressive glomerulonephritis
6. Chronic glomerulonephritis / CKD
- Asymptomatic haematuria
Features:
- Either Macroscopically / Microscopically (>2 RBC per high power field in spun urine) detected blood in urine, usually **dysmorphic
—> irregularities of RBC membrane
—> **acanthocytes (with ring-formed cell bodies with blebs of different size / shape)
—> may clump together to form **RBC cast (tubular shape) when pass through tubules
- Detected through health check, pre-employment, pre-school etc.
- Usually with **normal GFR + **no evidence of systemic disease
- Variable degrees of **proteinuria may be present, usually ***<1 g/day (low-grade)
Macroscopic haematuria
**Episodic **painless macroscopic haematuria associated with glomerular disease
—> often ***brown / smoky urine rather than red
—> blood clots are unusual (clots usually indicate Lower UT bleeding)
***DDx of Haematuria
Urological conditions:
1. Stones
2. Tumours
Renal conditions:
1. **Glomerulonephritis
- **IgA nephropathy —> usually Gross
- **Alport syndrome (Hereditary nephritis) (hearing deficit common) —> usually Gross
- **Thin membrane disease (TBMD) (Benign familial haematuria)
2. ***Acute interstitial nephritis
3. Polycystic kidney disease
Infection:
1. Cystitis
2. TB
3. Schistosomiasis
Alport syndrome
- Mutations of ***Type 4 collagen genes
- Cochlea
—> ↓ Adhesion of Organ of Corti (auditory sensory cells) to Basilar membrane via defective alpha-3-4-5 type 4 collagen
—> Deafness
Inheritance:
- ***X-linked in 80%
- No male-to-male transmission
- Women with X-linked Alport syndrome are heterozygous carriers of the disease mutation
—> almost all have some degree haematuria + some develop renal failure (∵ lyonisation, a random X-inactivation phenomenon)
***Evaluation of Haematuria
- IgAN
- Alport’s syndrome (Hereditary nephritis) (hearing deficit common)
- Thin membrane disease (Benign familial haematuria)
—> Above conditions can be distinguished by **history + **urinalysis of family members
History taking:
1. **Gross haematuria
- common in **IgAN (haematuria often occur after an episode of mucosal infection e.g. URTI) + ***Alport syndrome
- unusual in TBMD (<10%)
- ***Family history of CKD
- Alport syndrome (renal failure / deafness (primarily in males), X-linked dominant mode of inheritance)
- IgAN (run in families but no particular mode of inheritance ∵ polygenic / multi-hit theory) - ***Electron microscopy of Membrane thickness
- TBMD: 150-225 nm (normal 300-400 nm) —> cannot guard against RBC leakage from blood to urine —> microscopic haematuria
Investigations for Haematuria
- RFT
- ***Urine culture / cytology / AFB
- ***Urinalysis
- ***Urine microscopy (crystal for presence of stone)
- KUB
- ***USG / Doppler
- stones with acoustic shadowing - Cystoscopy (look for bladder space occupying lesion)
- IVP (IV pyelogram) / RP (retrograde pyelogram)
- CT urogram (high radiation exposure: 2x IVP)
- ***Pure tone audiometry (Alport syndrome)
-
**Renal biopsy (to ascertain cause)
- usually not required in isolated haematuria
- indicated with concomitant **significant proteinuria (e.g. >1 g/day)
- Isolated proteinuria
Normal <150 mg (40-80)
- ***10mg is albumin
Urine albumin:
- Normal **<20 mg/day (15 ug/min)
- Persistent microalbuminuria: **30-300 mg/day (20-200 ug/min)
- Macroalbuminuria / Overt proteinuria: ***>=300 mg/day (200 ug/min) —> standard dipstick becomes +ve
(Nephrotic syndrome: >3.5g protein / day)
***Evaluation of Proteinuria
- Dipstix
- screening for detecting proteinuria
- ***>=1+ should undergo confirmation by quantitative measurement
- measures albumin concentration via a colourimetric reaction between albumin and tetrabromophenol blue —> produce different shades of green according to concentration of albumin in sample
—> trace: 15-30 mg/dL
—> 1+: 30-100
—> 2+: 100-300
—> 3+: 300-1000
—> 4+: >1000 - Spot urine (convenient + accurate as Timed urine)
- **Urine protein-to-creatinine ratio
—> Normal: <0.2 mg/mg
—> **>3.5 mg/mg: Nephrotic range for proteinuria
- first morning urine preferred, random sample acceptable - Timed urine (24 hour)
Patients with >=2 positive quantitative tests (spaced by 1-2 weeks)
—> diagnosed as ***Persistent proteinuria
—> Further evaluation needed
Monitoring proteinuria:
- by Quantitative measurements (rather than Dipstix)
Pitfalls in Proteinuria assessment
False positive results:
1. **Strenuous exercise within 24 hours
2. Concomitant systemic infection
3. **UTI
4. Fever
5. **Pregnancy (kidney bloodflow markedly ↑)
6. **Marked HT
7. Haematuria
Orthostatic proteinuria
- ↑ Protein excretion in upright position but not when supine
- Mechanism unclear, ?Neurohumoral activation
- ***Benign condition in young subjects
- Proteinuria <1 g/day, but may >3 g/day
- ***Split urines (Erect + Supine urine) are collected to identify this condition
- Requires no further evaluation / specific therapy —> ***resolves over time
***3. Acute nephritic syndrome
Features:
- **Abrupt onset of **macroscopic haematuria
- **Oliguria
- **Acute renal failure (abrupt ↓ in renal function)
- **Fluid retention (edema + HT)
- Urinary protein **<3 g/day
Disease
1. Post-streptococcal GN
Post-streptococcal GN
Children 2-10 yo predominantly
Pathogenesis:
- Streptococcal Ag “planted” in glomerulus during early phase of streptococcal infection
—> 10-14 days later by host immune response against Streptococcal Ag in glomerulus
—> formation of ***Immune complexes
—> kidney damage
Clinical picture:
- Acute, reversible disease characterised by **spontaneous recovery in vast majority
- **Gross haematuria, Oliguria, HT, Edema: develop ***7 days - 12 weeks after streptococcal infection (throat / skin)
- Spontaneous resolution of clinical manifestations generally rapid
—> diuresis resolves within 1-2 weeks
—> renal function return normal within 4 weeks
Investigation:
1. Total haemolytic complement activity / **C3 concentration ↓
- persistently low C3 >8 weeks —> possibility of **Lupus nephritis / **MPGN
2. **Anti-Streptolysin O ↑ (but not all strains produce Streptolysin O)
3. Diffuse hypercellularity on biopsy (i.e. ***Proliferative)
4. Subepithelial deposits (Immune complex) on electron microscope
Treatment of Acute nephritic syndrome
Depends on etiology
Acute Post-streptococcal GN:
1. **Penicillin (may be indicated)
2. During Oliguric phase
- **Supportive therapy (fluid / salt restriction, Anti-HT)
- +/- ***Temporary dialysis may be needed (grossly edematous, high serum urea, creatinine)
***4. Nephrotic syndrome
Features:
1. Massive proteinuria (>3.5 g/day or 40 mg/hr/m^2 in children)
2. Generalised edema
3. Hypoalbuminaemia (<30 g/L)
4. Hyperlipidaemia + Lipiduria (varying degrees)
Clinical presentations:
1. **Periorbital edema in early morning (resolves during day under gravity)
2. **Dependent ankle edema
3. **Xanthelasma
4. **Muehrcke’s bands (transverse white bands grew on nails during a transient period of hypoalbuminaemia)
Electron microscopy:
- Primary, Secondary, Tertiary, Quaternary processes of podocytes are lost —> ***Effacement of podocytes
Causes:
Primary renal diseases:
1. FSGS
2. Membranous GN
3. Minimal change disease
4. MPGN
5. IgAN (occasionally)
Systemic diseases:
1. DM Type 2
2. SLE
3. Secondary membranous nephropathy
- **Infection: HBV, HCV, HIV, malaria, syphilis
- **Malignancy: lymphoma, adenocarcinoma (lung, GI tract, breast), myeloma
- ***Drugs: penicillamine, gold, mercury, NSAIDs, probenecid
4. Amyloidosis
(5. Cryoglobulinaemia
6. Renal vein thrombosis
7. Kimura’s disease (JC Teaching Clinic))
Investigation of Nephrotic syndrome
- CBC
- Renal biochemistry
- ***Urine protein quantification (spot / 24 hour urine)
- ***FG
- ***Immune markers
- Ig pattern
- HBsAg
- Anti-HCV
- Anti-HIV
- **Anti-PLA2R (Anti-Phospholipase A2 receptor: present in 70% of primary **membranous nephropathy, not present in normal people)
- ***Tumour screening (for >50 yo): CXR, Stool OB, Other tumour markers
***Treatment of Nephrotic syndrome
- Corticosteroid (mainstay)
2nd line:
2. **Calcineurin inhibitor (steroid-resistant / steroid-dependent cases —> **steroid-sparing effects)
- Tacrolimus
- Cyclosporin
- Other forms of treatment
Complications of Nephrotic syndrome (JC Teaching Clinic)
- Hyperlipidaemia and lipiduria
- Infection
- Vascular thrombosis
- ARF
- Protein malnutrition
- Hypovolaemia
***5. Rapidly progressive glomerulonephritis (RPGN)
Features:
- **Signs of GN (Haematuria, Proteinuria, RBC casts)
- **Rapid decline in renal function —> can lead ESRD within days to weeks
Pathological hallmark:
- Presence of ***Cellular crescents in glomerulus (severe inflammation in kidney)
- Beware of other organ system involvement e.g. pulmonary haemorrhage (Goodpasture’s) / hepatic failure (leptospirosis)
Causes:
1. **Pauci-immune GN (systemic vasculitis) (absence of immune staining)
2. **Anti-GBM disease / Goodpasture syndrome (pulmonary capillary BM also destroyed by Ab —> pulmonary haemorrhage)
3. **Crescentic IgAN
4. **Acute post-infectious GN
5. Multisystem diseases
- Systemic vasculitis
- Cryoglobulinaemia (associated with active Hep C infection / haematological diseases e.g. dysproteinaemia)
- SLE
Investigations of RPGN
- CBC
- Renal biochemistry
- Urine protein quantification
- Urine sediments
- ***Autoimmune markers
- ANCA, Anti-GBM, ANA, Anti-dsDNA, C3/C4 - ***CXR
- ***DLCO (pulmonary function for Goodpasture’s)
Treatment of RPGN
According to etiology
1. **Corticosteroids +/- Immunosuppressants
2. **Plasmapheresis (if Anti-GBM Ab present)
***6. Chronic GN
Syndrome manifested by progressive kidney failure in patients with **glomerular inflammation, proteinuria, haematuria, HT (all previously undetected)
- Important cause of CKD
- Kidneys show variable degrees of **atrophy
- Blood tests: ***Very high creatinine
- Urinalysis: Protein + Blood
Investigations of Chronic GN
Ascertain **chronic nature of disease
1. CBC
- **Normochromic normocytic anaemia
- Renal biochemistry
- ↑ Urea, Creatinine, **PO4
- **↓ Ca
- +/- ↑ K
- Metabolic acidosis - Urine protein quantification
- USG (↓ kidney size, ↑ echogenicity)
- Renal biopsy (usually unnecessary, ∵ only show fibrosis, glomerulosclerosis —> cannot identify underlying cause anyway)
Treatment of Chronic GN
- Supportive therapy
- Minimise metabolic disturbance + complications
- Renal replacement therapy (if approaching stage 5 CKD)
***Tubulointerstitial diseases (TIN)
- Anatomically >95% of kidney
- Acute TIN may cause important renal dysfunction (***~5-15% acute renal failure causes)
- If left unchecked, Chronic TIN is major pathway leading to ***CKD
Clinical manifestations (∵ Interstitial inflammation + Tubular dysfunction):
1. Loss of renal function
2. Abnormal urine sediment (e.g. WBC (but without infection), proteinuria)
3. **Electrolyte disturbance
4. **Acid-base disorders
***Entities of TIN
- ***Acute TIN
- Drugs (e.g. Penicillins, NSAID, PPI, Mesalazine (delayed) (Davidson))
- Infections (e.g. pyelonephritis, leptospirosis, TB, Hantavirus (Davidson))
- Autoimmune disease - ***Chronic TIN
- Etiology unknown
Davidson:
- ANY causes of Acute TIN if persistent
- Drugs (e.g. Tenofovir, Lithium, Ciclosporin, Tacrolimus, Analgesic nephropathy)
- Autoimmune disease (e.g. SLE, Sjogren’s)
- Metabolic (e.g. CaPO4 crystallisation, HypoK, Hyperoxaluria) - K-wasting tubular disorders
- ***Renal tubular acidosis (∵ inability of tubules to excrete H / reabsorb HCO3)
***Acute kidney injury
Definition:
- Abrupt decrease in kidney function
- Even mild, reversible AKI can progress to CKD
- AKI viewed as same to Acute lung injury / ACS
Characterised by:
1. Abrupt ↓ in GFR over a period of hours / days
2. 50% ↑ SeCr
(3. ↑ in some damage markers e.g. NGAL, KIM-1, IL18)
Risk factors of AKI:
1. **Pre-existing CKD
2. **Diabetic nephropathy
3. Heart failure
4. Liver disease
5. ***Hypovolaemia
6. Age >50
7. Sepsis
8. Trauma
9. Post-operative (e.g. Post-CABG)
10. Cancer
Causes of AKI
Various etiologies
- May have >=1 of below conditions
- Pre-renal (>50%)
- Prerenal azotaemia (Hypotension, Dehydration, Sepsis, Shock, Heart failure, Hepatorenal syndrome)
- Renal artery (Occlusion, Vasculitis)
- Small vessel disease (Thrombotic microangiopathy, Renal atheroembolism, Vasculitis) - Intrinsic (<50%)
- Acute GN (All causes of RPGN)
- Acute tubular necrosis (Drugs, Toxins, Ischaemia (from dehydration, hypotension, cardiogenic shock, hypovolaemic shock), Rhabdomyolysis, Radiocontrast)
- Acute interstitial nephritis (Drugs, Infection, Autoimmune disease)
- Intratubular obstruction (Cast nephropathy, Drugs, Crystalluria) - Post-renal (<10%)
- Renal vein thrombosis
- Obstructive causes (e.g. Ureteric stone, BPH, Neurogenic bladder)
Management of AKI
General principles:
1. Rapid + Accurate diagnosis
2. Identify + Reverse underlying cause (e.g. nephrotoxins, sepsis, hypovolaemia, obstruction, cardiogenic)
Treatment:
1. Diuretics (for fluid overload, acute pulmonary edema)
2. Electrolyte disturbance (HyperK, **acidosis): **Polysulphonate (for binding K in gut), **D/I drip (drive K into cells, dextrose is buffer for insulin to prevent hypoglycaemia), **HCO3
3. HCO3 (for acidosis)
4. **Acute dialysis support
- usually **HD
- vascular access
- ICU admission if indicated
Indications for dialysis (Blue book + SpC Medicine):
1. Severe HyperK
2. Severe Metabolic acidosis
3. Fluid overload (e.g. APO)
4. Uraemia complications (Uraemic encephalopathy / pericarditis)
Natural history and progression of Diabetic nephropathy (From GIS + MSS + HNS + HIS + ERS PBL)
First changes
- **Microalbuminuria
- **Glomerular BM thickening —> Microangiopathy
- Accumulation of matrix material in mesangium
Subsequent changes
- **Heavy proteinuria
- Nodular deposits
- **Glomerulosclerosis
Pathogenesis:
1. Chronic hyperglycaemia
—> ***↑ Mesangial Cell matrix production + apoptosis —> Mesangial cell expansion + injury
- Glomerular hypertrophy (↑ Renal size)
—> ↑ shear stress on glomerular capillary wall - Glomerular hyperfiltration (↑ GFR)
—> dilatation of afferent arteriole by ***AGEs, Sorbitol, IGF-1
—> ↑ Renal blood flow
—> ↑ Intra-glomerular pressure (Intra-glomerular hypertension) - Glomerulosclerosis
—> ∵ Intra-glomerular hypertension
—> ∵ Hyaline narrowing of vessels supplying the glomeruli (Hyaline deposition induced by ischaemic injury)
Histology:
1. Diabetic **Glomerulosclerosis —> ECM deposition in glomeruli
2. **Mesangial expansion
3. **GBM thickening
4. **Arteriolar Hyalinosis / Arteriolosclerosis
Consequence:
Microalbuminuria
Management:
1. Protein restriction
2. Antihypertensive
3. Glycaemic control
Contraindications to Renal biopsy (JC Teaching Clinic + SpC Teaching Clinic)
- ***Uncorrectable bleeding diathesis
- check Plt, Clotting profile
- stop Antiplatelet, Anticoagulants - ***Small kidneys which are generally indicative of chronic irreversible disease
- futile + risky due to puncturing a hard fibrotic structure —> bleeding - ***Severe hypertension, which cannot be controlled with antihypertensive
- one dose of amlodipine —> wait several hours for BP to decrease - Multiple, bilateral cysts / renal ***tumour
- Hydronephrosis
- Active renal / perirenal ***infection
- Uncooperative patient
- Solitary kidney
- ∵ in case of several bleeding may need embolisation / nephrectomy
Minimal change nephrotic syndrome (MCNS)
“Nephrotic syndrome, normal-looking glomeruli + absence of hypertension, haematuria or azotaemia”
Epidemiology:
- ***Children: >90% of nephrotic syndrome
- Adult: 10-15% of nephrotic syndrome
- Elderly: suspect possible underlying malignancy, esp. lymphoid origin (e.g. Hodgkin’s disease)
Clinical features:
1. Heavy proteinuria
2. Onset of edema may be insidious / acute, initially affecting periorbital area upon awakening and shifting to the ankles towards the end of day
3. Ascites / Pleural effusion in severe cases
Pathology:
- Light microscopy demonstrates essentially **normal glomerular morphology
- Immunofluorescence is usually **negative for immunoglobulins
- Only detectable abnormality is **total effacement of foot processes (podocytes) of visceral epithelial cells shown on ultrastructural examination by **EM
- These morphological alterations are typical of nephrotic syndrome but not specific to MCNS
- Some patients with clinical features of MCNS have **positive mesangial IgM staining, along with mesangial **proliferative changes
- These patients, more likely to also have **microscopic haematuria and less likely to respond to steroid, are said to have **IgM nephropathy
- Relationship between MCNS, IgM nephropathy, and FSGS is **poorly defined, but responsiveness to steroid therapy is a shared feature —> **Continuum of pathology
Treatment:
1. Corticosteroid
- Adult: Prednisolone started at 1 mg/kg/day (up to max 80 mg/day)
—> slowly tailed off over a period of around 4 months
- Children: Prednisone at 60 mg/m2/day (up to max 80 mg/day) for 4 to 6 weeks
—> 40 mg/m2 every other day for 4 to 6 weeks
2nd line agents
2. Alkylating agents
3. Cyclosporine, Tacrolimus
4. Levamisole
- antihelminthic agent with immunomodulatory effects, used alone / in combination with steroid
in MCNS in children
- well tolerated
- SE: neutropenia, rash, liver toxicity
Membranous nephropathy
- Most common cause of nephrotic syndrome in adults
- Defined by the presence of **subepithelial immune deposits leading to a spectrum of glomerular capillary wall alterations, most typically the formation of intervening **“GBM spikes”
- Primary vs Secondary
- Primary MN is regarded as **prototypic glomerular disease mediated by **in situ immune complex formation
- Can also occur secondary to autoimmune disease, neoplasia, infection, exposure to certain therapeutic agents
Epidemiology:
- Most common in Caucasian individuals + Adults
- Rare in infants and young children
- M:F = 2:1
- Secondary MN most commonly encountered in young children and in individuals >60 yo
Clinical features:
1. ***Proteinuria (defining clinical feature of MN)
- majority of patients have full nephrotic syndrome
2. Normal RFT (most patients at time of presentation)
3. Microhaematuria (~50%)
Secondary MN:
- 25% of cases
- 4 categories:
1. Autoimmune / Collagen vascular diseases,
- SLE (most notably, i.e. membranous lupus nephritis)
- RA
- Sjogren’s syndrome
- mCTD
- Sarcoidosis
- Grave’s disease
- Hashimoto’s thyroiditis
- Malignancy
- Carcinomas of the lung, prostate, breast, GI tract - Drugs
- Gold
- Penicillamine
- NSAIDs, COX-2 inhibitors
- Captopril - Infections
- Hepatitis B / C
- Syphilis
- Malaria
- Parasites
HBV associated nephropathy
- Membranous GN
- Mesangiocapillary glomerulonephritis (MCGN)
- IgA nephropathy
Clinical features:
1. Proteinuria, usually in the nephrotic range
2. Mild to moderate renal impairment (may be present at presentation)
Children:
- Male preponderance
- Nephrotic syndrome most frequent
- Transaminase levels are usually normal
Adults:
- Proteinuria / Nephrotic syndrome
- More likely than children to have HT, renal dysfunction, and clinical evidence of liver disease
Prognosis:
- Children: Favourable; high rates of spontaneous remission
- Adults: Worse in patients with nephrotic range proteinuria and overt hepatitis at presentation
Treatment:
1. General measures for CKD
- Optimise BP control
- Reduce proteinuria with ACEI / ARB
- Control lipid levels
- Sodium restriction
- Quit smoking
- Optimise body weight
- Regular exercise
- Specific measures
- Eradication of the underlying HBV by nucleoside analog e.g. Lamivudine
