GC057 Glomerular And Tubulo-interstitial Diseases And Acute Kidney Injury
Glomerular and tubulo-interstitial diseases encompass inflammatory, immune-mediated, or toxic disorders affecting the glomeruli or renal interstitium and tubules, which, along with acute kidney injury, result in a rapid or progressive decline in kidney filtration, concentration, and excretory functions.
Glomerular and Tubulo-interstitial Diseases & Acute Kidney Injury
This lecture by Prof. Sydney Tang is a core nephrology session covering three major domains of renal parenchymal disease:
- Glomerular Diseases — classified by histology and clinical presentation (6 clinical syndromes)
- Tubulo-interstitial Diseases (TID) — acute and chronic, with emphasis on drug-induced causes
- Acute Kidney Injury (AKI) — definitions, staging, aetiology (pre-renal/intrinsic/post-renal), and approach
The lecture is the single most testable nephrology deck for the in-house summative. It links directly to GC 043 (Drugs and the Kidney), GC 034 (CKD), the Nephrology Data Interpretation session, and Interactive Tutorials. Examiners love MCQs on distinguishing nephritic vs. nephrotic, identifying RPGN urgency, AKI staging, and drug-induced interstitial nephritis.
How it fits clinically: Any patient presenting with haematuria, proteinuria, oedema, or rising creatinine requires you to think: Is this glomerular, tubulo-interstitial, vascular, pre-renal, or post-renal? This lecture gives you the framework.
1. Renal Parenchyma — Foundations
The renal parenchyma is the functional tissue of the kidney, consisting of the nephrons. [1]
Why this matters: When we say "intrinsic renal disease," we mean disease affecting the parenchyma — glomeruli, tubules, interstitium, or vasculature. Understanding anatomy tells you which compartment is injured, which in turn dictates the clinical syndrome and investigations.
Practice Point 1.1.1 (KDIGO GN Guideline 2021): The kidney biopsy is the "gold standard" for the diagnostic evaluation of glomerular diseases. However, under some circumstances, treatment may proceed without a kidney biopsy confirmation of diagnosis. [1]
Why biopsy? Because glomerular diseases often look similar clinically but differ histologically, and treatment (steroids, immunosuppression, plasmapheresis) depends on the specific histological pattern and aetiology.
When can you skip biopsy? [1]
- Children with nephrotic syndrome (presumed minimal change disease — respond to steroids empirically)
- Diabetic nephropathy with classic clinical features (proteinuria + retinopathy + gradual progression)
- Anti-PLA2R-positive idiopathic membranous nephropathy (serological diagnosis)
- Well-characterised anti-GBM disease or ANCA-associated vasculitis with classic serology (in some guidelines, biopsy is still preferred)
Three modalities are used: Light Microscopy (LM), Immunofluorescence (IF), and Electron Microscopy (EM). [1]
| Modality | Stains/Techniques | What it Shows |
|---|---|---|
| Light Microscopy | H&E, PAS, PASM (silver), Masson Trichrome, Congo Red | Overall architecture, cellularity, fibrosis, amyloid |
| Immunofluorescence | IgA, IgG (& subclasses), IgM, C1q, C3, C4, C4d, Kappa, Lambda, Gd-IgA1 | Immune deposits — pattern/location dictates diagnosis |
| Electron Microscopy | Ultrastructural evaluation | Foot process effacement (podocytes), GBM thickness, electron-dense deposits (EDDs) location |
Key stain details from slides: [1]
- H&E: Nuclei stained dark blue, cytoplasm eosinophilic. Good for overall survey — where is the lesion? Are cells abundant or scarce? But detailed assessment not possible.
- PAS: Stains basement membrane and PAS-positive materials (proteins, glycogen). Essential for assessing GBM changes.
- Masson Trichrome: Collagen stained blue (evaluates fibrosis); deposits stained orange-to-red.
- Silver stain (PASM): Highlights basement membrane architecture — "spikes" in membranous nephropathy, "double contours" in MPGN.
Exam Tip
If asked "What histological stain evaluates kidney fibrosis?" → Masson Trichrome (collagen = blue). If asked about basement membrane detail → Silver stain (PASM) or PAS.
2. Classification of Glomerulonephritis
This is the lecture's core classification framework.
Proliferative GN = increased cellularity in the glomerulus → associated with nephritic syndrome. Nonproliferative GN = no increase in cellularity → associated with nephrotic syndrome. [1]
| Proliferative (Nephritic) | Nonproliferative (Nephrotic) | |
|---|---|---|
| Primary | IgA nephropathy, MPGN, Crescentic GN | Minimal Change Disease, Membranous Nephropathy, FSGS, IgM nephropathy, Thin Membrane Disease |
| Secondary | Lupus nephritis, Post-streptococcal GN, Hepatitis B/C-related MPGN, Systemic vasculitis, Goodpasture syndrome | Diabetic nephropathy, Hypertensive nephrosclerosis, Amyloidosis, Light/heavy chain deposition disease, Alport syndrome, Infection-related membranous GN, HIV nephropathy (FSGS/collapsing), Drug-induced, Malignancy-associated, Reflux nephropathy |
Why this classification isn't perfect (from the slide): [1]
- No single classification is ideal because:
- One histologic pattern can have multiple aetiologies (e.g., membranous pattern → idiopathic OR lupus OR HBV)
- One aetiology can produce multiple histologic patterns (e.g., lupus nephritis → Class I–V)
- One histologic diagnosis can present with different clinical syndromes (e.g., IgAN → asymptomatic haematuria OR synpharyngitic gross haematuria OR RPGN)
High Yield
IgA nephropathy is the most common primary glomerulonephritis worldwide. It is proliferative but can occasionally present with nephrotic-range proteinuria. It can also present as RPGN (crescentic IgAN). This disease crosses boundaries — a favourite exam trap.
3. The Six Clinical Syndromes of Glomerular Disease
Clinical Presentation of Glomerular Disease: 6 clinical syndromes [1]
- Asymptomatic microscopic haematuria / proteinuria
- Macroscopic haematuria
- Acute nephritic syndrome
- Nephrotic syndrome
- Rapidly progressive glomerulonephritis (RPGN)
- Chronic glomerulonephritis / CKD
3.1 Syndrome 1 — Asymptomatic Haematuria
Either macroscopically or microscopically ( > 2 RBC/HPF in spun urine) detected blood in the urine, usually dysmorphic. Detected through health check, pre-employment, pre-school, etc. Usually with normal GFR and no evidence of systemic disease. Variable degrees of proteinuria may be present, usually < 1 g/day. [1]
Key concept — Dysmorphic RBCs: [1]
- When RBCs pass through the damaged glomerular basement membrane, they get "squeezed" and become irregularly shaped
- Acanthocytes have ring-formed cell bodies with one or more blebs of different sizes and shapes — highly specific for glomerular origin
- RBC casts are pathognomonic for glomerular haematuria (RBCs trapped in a Tamm-Horsfall protein cast in the tubule)
Distinguishing glomerular from non-glomerular haematuria:
| Feature | Glomerular | Non-glomerular (Urological) |
|---|---|---|
| Colour | Brown / "smoky" / "coca-cola" | Bright red |
| Clots | Unusual | Common |
| RBC morphology | Dysmorphic, acanthocytes | Isomorphic (normal shape) |
| RBC casts | Present | Absent |
| Proteinuria | Often present | Usually absent or minimal |
| Pain | Usually painless | May be painful (stones, infection) |
Macroscopic haematuria (from slide): [1]
Episodic painless macroscopic haematuria associated with glomerular disease is often brown or "smoky" rather than red, and blood clots are unusual.
Differential Diagnosis of Haematuria: [1]
| Category | Causes |
|---|---|
| Urologic | Stones, Tumour |
| Renal | Glomerulonephritis, Acute interstitial nephritis, Polycystic kidney disease |
| Infection | Cystitis, TB, Schistosomiasis |
Glomerular causes specifically: [1]
- IgA nephropathy
- Alport syndrome (hereditary nephritis) — hearing deficit common
- Thin basement membrane disease (benign familial haematuria)
Mutations in type IV collagen genes. X-linked in 80% (COL4A5). Father-to-son transmission does not occur. Women with X-linked Alport syndrome are heterozygous carriers — almost all have some degree of haematuria, and some develop renal failure [lyonization]. [1]
Why hearing loss? The cochlea depends on the same alpha-3-4-5 type IV collagen network for adhesion of the Organ of Corti to the basilar membrane. The defective collagen causes decreased adhesion → sensorineural hearing loss. [1]
Why no father-to-son transmission? Because the gene is on the X chromosome. Fathers pass their Y chromosome to sons (and their X to daughters). So affected fathers have affected daughters (carriers) but unaffected sons.
GBM thickness: Normal = 300–400 nm; TBMD = 150–225 nm [1]
- Benign condition, usually autosomal dominant
- Gross haematuria unusual ( < 10%)
- No progressive renal failure (unlike Alport)
- Diagnosis is by EM showing uniformly thin GBM without the splitting/lamellation seen in Alport
Evaluation — distinguishing the three causes of glomerular haematuria: [1]
The 3 conditions (IgAN, Alport, TBMD) can often be distinguished by history/urinalysis of family members:
- Gross haematuria: common in IgAN and Alport, unusual in TBMD
- Family history of CKD: Alport (renal failure/deafness primarily in males, X-linked dominant); IgAN runs in families but no particular mode of inheritance
- TBMD: family history of isolated haematuria without CKD progression
First-line:
- Renal function tests
- Urine culture / cytology / AFB
- Urinalysis
- Urine microscopy (for dysmorphic RBCs, casts)
- KUB (plain X-ray)
- USG / Doppler
Other investigations:
- Cystoscopy (essential in older patients or those with risk factors for urothelial malignancy)
- IVP / Retrograde pyelography
- CT urogram (radiation exposure ~2× IVP)
- Pure tone audiometry (if Alport suspected)
Kidney biopsy: Usually NOT required in isolated haematuria. Indicated with concomitant significant proteinuria, e.g. > 1 g/day or UPCR > 1 mg/mg (113 mg/mmol). Such threshold should be lowered in selected patients. Treatment may proceed without a biopsy in some conditions. [1]
Exam Trap
Don't biopsy for isolated haematuria with normal renal function and minimal proteinuria. Biopsy is indicated when there is significant proteinuria, declining renal function, or suspicion of a treatable disease like RPGN.
3.2 Syndrome 2 — Isolated Proteinuria
Normal urinary protein excretion: < 150 mg/day (usually 40–80 mg), of which approximately 10 mg is albumin. [1]
Albumin thresholds: [1]
| Category | Amount | Clinical Significance |
|---|---|---|
| Normal | < 20 mg/day (15 µg/min) | — |
| Microalbuminuria | 30–300 mg/day (20–200 µg/min) | Early marker of diabetic nephropathy; NOT detected by standard dipstick |
| Macroalbuminuria / Overt proteinuria | > 300 mg/day ( > 200 µg/min) | Dipstick becomes positive |
Methods: [1]
- Dipstick — screening tool, measures albumin concentration
- Spot urine (UPCR or UACR) — convenient, correlates well with 24h collection
- Timed urine (24h collection) — gold standard but cumbersome
Dipstick details: [1]
Standard urinary dipstick measures albumin via colorimetric reaction between albumin and tetrabromophenol blue:
- Negative
- Trace: 15–30 mg/dL
- 1+: 30–100 mg/dL
- 2+: 100–300 mg/dL
- 3+: 300–1000 mg/dL
- 4+: > 1000 mg/dL
Dipstick Limitations
The dipstick only detects ALBUMIN. It CANNOT detect:
- Microalbuminuria (need specific albumin assay)
- Bence Jones protein (immunoglobulin light chains in myeloma)
- Tubular proteins (β2-microglobulin, retinol-binding protein)
A patient with myeloma kidney may have a negative dipstick despite heavy proteinuria!
Urine Protein-to-Creatinine Ratio (UPCR): [1]
Normal UPCR < 0.2 mg/mg. Ratios > 3.5 mg/mg are in the nephrotic range.
Recommended approach (from slide): [1]
- First morning specimens preferred (random acceptable)
- Screening with dipstick is acceptable
- Positive dipstick (1+ or greater) → confirm with quantitative measurement
- Two or more positive quantitative tests spaced 1–2 weeks apart → persistent proteinuria → further evaluation
- Monitoring should use quantitative measurements (not dipstick)
The lecture references the NKF-KDIGO heat map classifying CKD prognosis by both eGFR stage and albuminuria category — a key framework examined in the CKD lecture (GC 034).
False positive results:
- Strenuous exercise within 24 hours
- Concomitant systemic infection
- UTI
- Fever
- Pregnancy
- Marked hypertension
- Haematuria
Why these cause false positives: All these conditions transiently increase glomerular permeability or produce proteinuria through non-glomerular mechanisms. Always repeat testing under "ideal" conditions before labelling someone with pathological proteinuria.
Increased protein excretion in the upright position, but not when supine. Benign condition in young subjects. Mechanism unclear (?neurohumoral activation). Proteinuria generally < 1 g/day but may exceed 3 g/day. Requires no further evaluation or specific therapy. In many patients, the condition resolves over time. Split urines are collected to identify this condition. [1]
How to test: Collect a "split" urine — supine overnight collection vs. daytime upright collection. If proteinuria is present only in the upright sample, it's orthostatic.
Acute nephritic syndrome: [1]
- Abrupt onset of macroscopic haematuria
- Oliguria
- Acute renal failure
- Fluid retention → oedema and hypertension
- Urinary protein < 3 g/day
Why these features? Inflammation in the glomerulus (glomerulonephritis) reduces the filtration surface and causes:
- Reduced GFR → oliguria, azotaemia
- Sodium and water retention → oedema, hypertension
- Capillary wall injury → haematuria (RBCs leak through damaged GBM)
- Mild proteinuria (but NOT nephrotic range, because the GBM is inflamed rather than having the diffuse podocyte damage seen in nephrotic syndrome)
Prototype: Post-Streptococcal Glomerulonephritis (PSGN)
Predominantly affects children aged 2–10 years. Pathogenesis: streptococcal antigens "planted" in the glomerulus during early phase of streptococcal infection, followed 10–14 days later by a host immune response. [1]
Clinical picture: [1]
Acute, reversible disease with spontaneous recovery in the vast majority. Gross haematuria, oliguria, HT, and oedema develop 7 days to 12 weeks after streptococcal infection (throat/skin). Diuresis usually ensues within 1–2 weeks, renal function returns to baseline within 4 weeks.
Investigations: [1]
- Total haemolytic complement activity (CH50) and C3 are depressed (because complement is consumed in immune complex formation)
- Antibodies to streptolysin O (ASO titre) may be raised — but not all strains produce streptolysin O
Persistently low C3 > 8 weeks raises the possibility of lupus nephritis or membranoproliferative GN. [1]
This is a critical discriminator: in PSGN, complement normalises within 6–8 weeks. If it stays low, consider alternative diagnoses.
Histology: [1]
- Light microscopy: Diffuse hypercellularity (endocapillary proliferation)
- Electron microscopy: Subepithelial deposits called "humps" — classic and pathognomonic
Treatment: [1]
For acute PSGN, penicillin may be indicated (to eradicate remaining streptococci, not to treat the GN). Otherwise, supportive therapy ± temporary dialysis.
| Feature | Details |
|---|---|
| Age group | 2–10 years |
| Latent period | 7 days – 12 weeks after pharyngitis/skin infection |
| Complement | Low C3 (normalises by 8 weeks) |
| ASO titre | Raised (pharyngitis more than skin) |
| Histology | Diffuse endocapillary proliferation + subepithelial "humps" |
| Prognosis | Excellent in children; adults may have residual CKD |
| Treatment | Supportive + penicillin if active streptococcal infection |
3.4 Syndrome 4 — Nephrotic Syndrome
Nephrotic Syndrome: [1]
- Massive proteinuria ( > 3.5 g/day or > 40 mg/h/m² in children)
- Generalised oedema
- Hypoalbuminaemia ( < 30 g/L)
- Hyperlipidaemia and lipiduria (varying degrees)
Why these features occur:
- Proteinuria: Podocyte injury → loss of charge and size selectivity → albumin leaks through
- Hypoalbuminaemia: Urinary losses exceed hepatic synthesis
- Oedema: Two theories — underfill (low oncotic pressure) and overfill (primary sodium retention). In practice, both mechanisms contribute depending on the specific disease
- Hyperlipidaemia: Liver increases lipoprotein synthesis in response to low oncotic pressure (the liver responds to the "signal" of low albumin by upregulating production of all exportable proteins, including lipoproteins)
- Lipiduria: Lipids cross the damaged glomerular barrier → oval fat bodies and fatty casts in urine
Clinical signs (from slides): [1]
- Periorbital oedema (morning, in children — resolves during day with gravity)
- Dependent ankle oedema (adults)
- Frothy urine
- Muehrcke's bands (white transverse lines on nails during hypoalbuminaemia — grow with the nail)
- Xanthelasma (lipid deposits around eyes from hyperlipidaemia)
- Focal segmental glomerulosclerosis (FSGS)
- Membranous glomerulopathy
- Minimal change disease
- Membranoproliferative glomerulonephritis
- IgA nephropathy (occasionally)
- Diabetes mellitus
- Systemic lupus erythematosus
- Secondary membranous nephropathy:
- Infection: HBV, HCV, HIV, malaria, syphilis
- Malignancy: lymphoma, adenocarcinoma (lung, GI, breast), myeloma
- Drugs: Penicillamine, gold, mercury, NSAIDs, probenecid
- Amyloidosis
- FBC, Renal biochemistry, Urine protein quantification
- Fasting glucose
- Immune markers (ANA, anti-dsDNA, complement)
- Immunoglobulin pattern (serum electrophoresis)
- HBsAg, Anti-HCV, Anti-HIV
- Anti-PLA2R
- Tumour screening: CXR, stool OB, other relevant markers
Discovery of M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy (Beck et al., NEJM 2009). Anti-PLA2R antibody has diagnostic value for iMN — high sensitivity and specificity. [1]
This is clinically important because:
- Positive anti-PLA2R + nephrotic syndrome = likely idiopathic membranous nephropathy → can initiate treatment without biopsy in some cases (KDIGO 2021)
- Also useful for monitoring treatment response (falling titre = remission)
- Negative anti-PLA2R in membranous nephropathy → search for secondary causes (malignancy, lupus, HBV)
Corticosteroid remains the mainstay of treatment. Second-line: calcineurin inhibitor may be useful for steroid-resistant or steroid-dependent cases to achieve steroid-sparing. Other forms of treatment (e.g., cyclophosphamide, rituximab, mycophenolate — disease-specific).
General supportive measures in nephrotic syndrome:
- Sodium restriction + diuretics for oedema
- ACEi/ARB to reduce proteinuria
- Statins for hyperlipidaemia
- Anticoagulation if high thrombosis risk (loss of antithrombin III in urine)
- Vaccination (loss of immunoglobulins → infection risk, especially encapsulated organisms)
High Yield: Complications of Nephrotic Syndrome
- Thromboembolism (loss of antithrombin III, protein C/S, increased fibrinogen synthesis) — renal vein thrombosis especially with membranous nephropathy
- Infection (loss of IgG, complement) — peritonitis, cellulitis
- Hyperlipidaemia → accelerated atherosclerosis
- AKI — hypovolaemia, renal vein thrombosis, NSAIDs
- Protein malnutrition
3.5 Syndrome 5 — Rapidly Progressive Glomerulonephritis (RPGN)
RPGN: [1]
- Signs of GN (haematuria, proteinuria, red-cell casts)
- Rapid decline in renal function → kidney failure within days to weeks
- Pathological hallmark: cellular crescents
- Beware of other organ system involvement: pulmonary haemorrhage (Goodpasture's) or hepatic failure (leptospirosis)
Why crescents? When there is severe GBM damage, fibrin and inflammatory cells leak into Bowman's space. This triggers proliferation of parietal epithelial cells and infiltration of macrophages, forming "crescents" that compress the glomerular tuft and destroy the nephron. This is why RPGN is a medical emergency — each crescent represents a dying glomerulus.
RPGN is a clinical syndrome, not a diagnosis. [2] You must determine the underlying cause.
| Type | Mechanism | IF Pattern | Serology | Key Examples |
|---|---|---|---|---|
| Type I — Anti-GBM | Antibodies against α3 chain of type IV collagen | Linear IgG along GBM | Anti-GBM antibodies | Goodpasture syndrome (if lung + kidney) |
| Type II — Immune complex | Immune complex deposition | Granular deposits | Low complement; specific markers (ANA, ASO, etc.) | Lupus nephritis, PSGN, IgAN, MPGN |
| Type III — Pauci-immune | ANCA-associated vasculitis | Negative/pauci-immune | ANCA (c-ANCA/p-ANCA) | GPA, MPA, EGPA |
- Pauci-immune GN (systemic vasculitis)
- Anti-GBM disease / Goodpasture syndrome
- Crescentic IgAN
- Acute postinfectious GN
- Multisystem diseases: Systemic vasculitides, Cryoglobulinaemia, SLE
- FBC, Biochemistry, Urine protein quantification, Urine sediments
- Autoimmune markers: ANCA, Anti-GBM, ANA, Anti-dsDNA, C3/C4
- CXR (pulmonary haemorrhage?)
- DLCO (raised in pulmonary haemorrhage — carbon monoxide binds to extravasated Hb in alveoli)
Tailored according to aetiology. Usually requires systemic corticosteroid ± immunosuppressants/biologics. Plasmapheresis if anti-GBM antibody present.
Why plasmapheresis for anti-GBM? Anti-GBM antibodies are directly pathogenic IgG molecules. Plasmapheresis physically removes these antibodies from the circulation faster than immunosuppression alone can reduce their production.
RPGN is a MEDICAL EMERGENCY
If you suspect RPGN (rapidly rising creatinine + active urine sediment), do NOT wait for biopsy results before starting treatment. Send ANCA, anti-GBM, and complement urgently. Start empirical high-dose methylprednisolone if clinical suspicion is high. Every day of delay = more crescents = more irreversible nephron loss.
A syndrome manifested by progressive kidney function loss with glomerular inflammation, proteinuria, haematuria, and often hypertension. Important cause of CKD. Kidneys show variable degrees of shrinkage (atrophy). [1]
Evaluation: [1]
Ascertain chronic nature:
- FBC: NcNc anaemia (normochromic normocytic — from EPO deficiency)
- Renal biochemistry: ↑urea, ↑creatinine, ↑PO4, ↓Ca ± ↑K+ and metabolic acidosis
- Urine protein quantification
- USG (small kidneys = chronic; normal-sized kidneys in AKI or certain chronic diseases like diabetic nephropathy/amyloidosis/ADPKD)
- Kidney biopsy usually unnecessary (because chronic changes are often irreversible)
Treatment: [1]
Supportive therapy. Minimize metabolic disturbance and complications. Prepare for renal replacement therapy if approaching stage 5 CKD.
4. Tubulo-interstitial Diseases (TID)
Tubulointerstitium comprises > 95% of the kidney anatomically. Acute TIN may cause important renal dysfunction (~5–15% of acute renal failure cases). Left unchecked, chronic TIN is the major pathway leading to CKD. [1]
Why is TIN the "final common pathway"? Even in primarily glomerular diseases, progressive nephron loss eventually causes tubulointerstitial fibrosis. The degree of interstitial fibrosis on biopsy is actually the best predictor of long-term renal outcome — better than the glomerular lesion itself.
Due to interstitial inflammation & tubular dysfunction:
- Loss of renal function
- Abnormal urine sediment (WBCs, proteinuria — typically tubular pattern, < 2 g/day)
- Electrolyte disturbance (salt-wasting, hypokalaemia or hyperkalaemia depending on segment)
- Acid-base disorders (renal tubular acidosis)
Key point: Tubular proteinuria is typically low-molecular-weight proteins (β2-microglobulin) rather than albumin. Dipstick may be negative even with significant tubular protein loss.
- Acute interstitial nephritis (AIN) — drugs, infections, autoimmune disease
- Chronic interstitial nephritis — various aetiology
- K+-wasting tubular disorders
- Renal tubular acidosis
Classical triad (from senior notes): Fever + Rash + Eosinophilia [4][5]
However, the full triad is present in only ~10–30% of cases. AKI is the most consistent finding.
| Category | Examples |
|---|---|
| Drugs (70–75%) | Antibiotics (penicillin, cephalosporins, ciprofloxacin, rifampicin, sulfonamides), NSAIDs, PPIs, diuretics (furosemide, thiazides), allopurinol, phenytoin, checkpoint inhibitors (PD-1) |
| Infections | Bacterial pyelonephritis, polyomavirus (BK virus) |
| Autoimmune | SLE, Sjögren's, sarcoidosis, IgG4-related disease |
| Neoplasm | NHL infiltration |
Drug-induced TIN: Causes AKI. May lead to permanent damage. Management = STOP the incriminated drug. Immunosuppression usually not necessary, except in drug-induced vasculitis or immune checkpoint inhibitor-associated AKI. [6]
Histology (from RTD notes): [4]
- Acute TIN: Interstitial inflammation (neutrophils + lymphocytes ± eosinophils), interstitial oedema, tubulitis with focal tubular necrosis
- Chronic TIN: Lymphocytes + plasma cells + macrophages, interstitial fibrosis, tubular atrophy
ATN is the most common cause of intrinsic AKI in hospitalised patients. [5]
- Ischaemic ATN: progression of prerenal failure when perfusion isn't restored
- Nephrotoxic ATN: aminoglycosides, contrast, cisplatin, paracetamol overdose
- "Muddy brown casts" on urine microscopy are pathognomonic for ATN [4]
- Management: treat underlying cause, supportive care, avoid further nephrotoxins
5. Acute Kidney Injury (AKI)
AKI is defined by an abrupt decrease in kidney function. Various aetiologies: ATN, AIN, acute glomerular and vasculitic renal diseases, prerenal azotaemia, and acute postrenal obstructive nephropathy. More than one condition may coexist. Even mild, reversible AKI has important clinical consequences (e.g., CKD transition). Akin to acute lung injury or acute coronary syndrome. [1]
The old definitions were inconsistent (from slide): [1]
Various ungraded old criteria existed — rise > 50 µmol/L, 50% increase, doubling, rise of 26.5 µmol/L in 24h, urine output < 0.5 mL/kg/h for > 6h, etc.
Modern KDIGO 2012 criteria (unified): [8]
AKI is diagnosed if ANY ONE of:
- Serum creatinine rise ≥ 26.5 µmol/L within 48 hours
- Serum creatinine rise ≥ 1.5× baseline within 7 days
- Urine output < 0.5 mL/kg/h for ≥ 6 hours
| KDIGO Stage | Serum Creatinine | Urine Output |
|---|---|---|
| Stage 1 | ↑ ≥ 26.5 µmol/L OR 1.5–1.9× baseline | < 0.5 mL/kg/h for 6–12h |
| Stage 2 | 2.0–2.9× baseline | < 0.5 mL/kg/h for ≥ 12h |
| Stage 3 | ≥ 3.0× baseline OR ≥ 353.6 µmol/L OR initiation of RRT | < 0.3 mL/kg/h for ≥ 24h OR anuria for ≥ 12h |
The lecture shows a staged model ranging from normal → increased risk → damage → decreased GFR → kidney failure → death. [1]
This emphasises that AKI is a spectrum, not a binary event. The model mirrors the acute coronary syndrome concept: just as chest pain exists on a spectrum from unstable angina to STEMI, kidney injury ranges from subclinical tubular stress to dialysis-requiring failure.
- Pre-existing CKD
- Diabetic kidney disease
- Heart failure
- Liver disease
- Hypovolaemia
- Age > 50 years
- Sepsis
- Trauma
- Postoperative (e.g., post-CABG)
- Cancer
Pre-renal ( > 1/2), Intrinsic ( < 1/2), Post-renal ( < 10%)
| Category | Proportion | Mechanism | Key Causes |
|---|---|---|---|
| Pre-renal | > 50% | Reduced renal perfusion → GFR drops but parenchyma intact | Hypovolaemia (dehydration, haemorrhage, vomiting/diarrhoea), heart failure, liver cirrhosis (hepatorenal), sepsis, burns, shock |
| Intrinsic | < 50% | Damage to renal parenchyma | Tubular: ATN (ischaemic or toxic), Interstitial: AIN, Glomerular: RPGN, Vascular: vasculitis, TMA, renal artery stenosis |
| Post-renal | < 10% | Obstruction of urinary outflow (must be bilateral or single functioning kidney) | BPH, bladder/prostate cancer, stones, retroperitoneal fibrosis |
Critical point: Prolonged pre-renal disease → ATN (ischaemic). Prolonged post-renal disease → tubulointerstitial fibrosis. Both become intrinsic if not corrected promptly.
| Parameter | Pre-renal | Intrinsic (ATN) |
|---|---|---|
| Urea:Creatinine ratio | > 100 (disproportionate urea rise) | < 40 |
| Urine Na | < 20 mmol/L (avid reabsorption) | > 40 mmol/L |
| FENa | < 1% | > 2% |
| Urine osmolality | > 500 mOsm/kg (concentrated) | < 350 mOsm/kg (dilute) |
| Urine sediment | Bland, hyaline casts | Muddy brown granular casts (ATN); WBC casts (AIN) |
| Response to fluids | Rapid improvement | No improvement |
Why is urea disproportionately high in pre-renal? In states of low perfusion, the proximal tubule reabsorbs more urea (driven by slow tubular flow and increased ADH). Creatinine is not reabsorbed, so the ratio rises.
Drug-induced renal impairment can be:
- Functional (NSAID, ACEi — alter haemodynamics without structural damage)
- Structural → renal parenchymal disease → tubulointerstitial vs. glomerular
| Drug Class | Mechanism of AKI | Clinical Pattern |
|---|---|---|
| NSAIDs | ↓ afferent arteriolar PG → ↓GFR | Pre-renal / AIN / nephrotic syndrome / papillary necrosis |
| ACEi/ARB | ↓ efferent arteriolar tone → ↓GFR | Pre-renal (especially in bilateral RAS) |
| Aminoglycosides | Direct tubular toxicity | Non-oliguric ATN |
| Contrast agents | Tubular toxicity + vasoconstriction | ATN (contrast-induced nephropathy) |
| PPIs | Immune-mediated AIN | AIN → may become chronic TIN |
| Cisplatin | Proximal tubular toxicity | ATN + hypoK + hypoMg |
| Calcineurin inhibitors | Afferent arteriolar vasoconstriction | AKI + chronic nephrotoxicity |
| Checkpoint inhibitors (PD-1) | Immune-mediated AIN | AIN — may need steroids |
Non-oliguric AKI
Aminoglycosides damage tubular cells and impair concentrating ability, so patients may actually have diuresis despite rising creatinine. Don't be falsely reassured by normal urine output — always check creatinine! [3]
| Feature | Nephritic Syndrome | Nephrotic Syndrome |
|---|---|---|
| Proteinuria | < 3 g/day | > 3.5 g/day |
| Haematuria | Prominent (RBC casts) | Minimal or absent |
| Oedema | Mild (periorbital) | Severe, generalised |
| Hypertension | Common | Variable |
| Hypoalbuminaemia | Mild | Severe ( < 30 g/L) |
| Hyperlipidaemia | Absent | Present |
| Renal function | Often impaired acutely | May be preserved initially |
| Complement | Often low (PSGN, lupus, MPGN) | Usually normal |
| Histology | Proliferative | Non-proliferative |
| Common causes | PSGN, IgAN, lupus nephritis | MCD, FSGS, MN, diabetic |
8. Exam Intelligence
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MCQ: A 7-year-old boy presents with periorbital swelling, dark urine, and hypertension 2 weeks after a sore throat. Serum C3 is low. What is the most likely diagnosis? → Post-streptococcal GN
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MCQ: Which finding on urine microscopy is pathognomonic for glomerular haematuria? → Dysmorphic RBCs / acanthocytes / RBC casts
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MCQ/SAQ: A 45-year-old man presents with nephrotic-range proteinuria. Anti-PLA2R is positive. What is the most likely diagnosis? → Idiopathic membranous nephropathy
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SAQ: List the KDIGO criteria for diagnosing AKI. → Three criteria (26.5 µmol/L rise in 48h, 1.5× baseline in 7d, urine output < 0.5 mL/kg/h for 6h)
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SAQ: A patient develops AKI with fever, rash, and eosinophilia after starting a PPI. What is the diagnosis and management? → Drug-induced AIN. Stop PPI. Usually no immunosuppression needed.
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MCQ: Which stain is used to evaluate kidney fibrosis? → Masson Trichrome
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Minicase: An 8-year-old boy with haematuria and sensorineural hearing loss. Family history of male relatives with ESRD. What is the diagnosis? → Alport syndrome (X-linked)
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MCQ: In RPGN, the pathological hallmark is? → Cellular crescents in Bowman's space
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MCQ: Persistently low C3 beyond 8 weeks after suspected PSGN should raise suspicion for? → Lupus nephritis or MPGN
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SAQ: Differentiate pre-renal AKI from intrinsic AKI using urine indices. → Table with FENa, urine Na, urine osmolality, U:Cr ratio
| Trap | Correct Understanding |
|---|---|
| Dipstick negative = no proteinuria | Dipstick misses microalbuminuria, Bence Jones, tubular proteins |
| Normal urine output = no AKI | Aminoglycosides cause non-oliguric ATN |
| RPGN = a diagnosis | RPGN is a clinical syndrome — must identify underlying cause |
| Low C3 = PSGN | Low C3 > 8 weeks → consider lupus or MPGN |
| Biopsy always needed | Can skip in children with nephrotic syndrome, diabetic nephropathy, anti-PLA2R+ MN |
| Orthostatic proteinuria = disease | Benign condition in young people; no treatment needed |
| FSGS = always primary | Can be secondary to obesity, HIV, reflux, drugs |
High Yield Summary
Glomerular Disease: Classified by cellularity (proliferative = nephritic, non-proliferative = nephrotic) and by primary vs. secondary. Six clinical syndromes — asymptomatic haematuria, macroscopic haematuria, nephritic, nephrotic, RPGN, chronic GN. Biopsy is gold standard but can be skipped in specific circumstances (KDIGO 2021). IgAN is most common primary GN worldwide. Anti-PLA2R identifies idiopathic membranous nephropathy.
Tubulo-interstitial Disease: Comprises > 95% kidney mass. AIN (drugs most common cause — classical triad: fever, rash, eosinophilia) and ATN (ischaemic/toxic — muddy brown casts pathognomonic). Chronic TIN is the final common pathway to CKD.
AKI: KDIGO staging (3 stages by creatinine and urine output). Pre-renal > 50%, intrinsic < 50%, post-renal < 10%. Distinguish pre-renal from ATN using urine indices (FENa, urine Na, osmolality). RPGN is a renal emergency — treat before biopsy if needed.
Active Recall - Glomerular & Tubulo-interstitial Diseases and AKI
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (all pages) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (pp. 995–1033) [3] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (p. 3) [4] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (pp. 1, 5, 9, 17) [5] Senior notes: Maksim Medicine Notes.pdf (pp. 205, 234) [6] Lecture slides: GC 043. Drugs and the Kidney.pdf (pp. 8, 16) [7] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (pp. 11–12) [8] Senior notes: learning_points_output.txt (Nephrology - Acute kidney injury section)
GC056 Generalized Muscle Weakness
Generalized muscle weakness is a diffuse reduction in muscle strength affecting multiple muscle groups, resulting from neurological, muscular, metabolic, or systemic disorders that impair the ability to generate normal voluntary force.
GC058 High Blood Pressure
High blood pressure (hypertension) is a chronic cardiovascular condition defined by persistently elevated systemic arterial pressure, typically ≥140/90 mmHg, that increases the risk of end-organ damage to the heart, brain, kidneys, and vasculature.