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 may a biopsy be deferred? (lecture decision tree, interpreted in current context) ^{[1][15][17][20]}

Patients classically treated without kidney biopsy diagnosis:

• Children with steroid-sensitive nephrotic syndrome (< 12 years old) — presumed minimal change disease
• Children with post-streptococcal GN and classic presentation

Other selected contexts where the diagnosis or urgent initial treatment may not require waiting for biopsy: ^[1]

• PLA2R-antibody-positive membranous nephropathy (especially with normal eGFR)
• MPO- or PR3-positive ANCA vasculitis
• Anti-GBM disease with classic serology
• Alport disease
• Fabry disease
• Familial FSGS in families with well-characterised mutations
• Biopsy contraindicated as judged by synthesis of history, physical exam, and laboratory testing

This list is not permission to omit biopsy whenever one of these labels is suspected. Biopsy still provides activity, chronicity, prognosis, and competing-diagnosis information. In particular, kidney biopsy is generally central to classifying suspected lupus nephritis, and current KDIGO guidance advises considering biopsy in adults with possible IgA nephropathy and proteinuria ≥0.5 g/day (or equivalent) when not contraindicated. In rapidly deteriorating, serology-supported ANCA vasculitis or suspected anti-GBM disease, urgent therapy may start before the biopsy is performed or reported. ^{[15][16][17][20]}

Three modalities are used: Light Microscopy (LM), Immunofluorescence (IF), and Electron Microscopy (EM). ^[1]

How to read the biopsy-processing diagram: cortex contains glomeruli plus proximal and distal tubules, whereas medulla contains loops of Henle and collecting ducts. A diagnostic core is therefore triaged across LM, IF, and EM so the same lesion can be assessed as architecture, immune pattern, and ultrastructure; an all-medulla sample cannot diagnose most glomerular lesions. ^[1]

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.

On the lecture micrographs, a normal glomerular tuft has open capillary loops and delicate mesangium; the hyalinised/sclerotic example replaces that architecture with acellular eosinophilic/PAS-positive material. This visual distinction is different from hypercellularity, in which nuclei crowd the tuft. ^[1]

Silver stain — glomerular cell identification (from slide): ^[1]

• Silver-stained glomerular sections allow identification of the three key cell types: podocytes, mesangial cells, and endothelial cells

This is the lecture's core classification framework.

Lecture heuristic: proliferative GN has increased glomerular cellularity and often presents nephritically; nonproliferative patterns lack hypercellularity and often present nephrotically. These are associations, not interchangeable definitions. ^[1]

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)

The visual takeaway is therefore pattern first, cause second. For example, “MPGN” describes capillary-wall remodelling and mesangial/endocapillary proliferation rather than one disease, while crescents signal severe capillary-wall injury but do not identify whether the cause is immune-complex, anti-GBM, or pauci-immune. ^[1]

These terms describe the extent of involvement on biopsy: ^[2][3]

Acute nephritic syndrome: ^[1]

• Abrupt onset of macroscopic haematuria
• Oliguria
• Acute kidney injury
• Fluid retention → oedema and hypertension
• Usually sub-nephrotic proteinuria

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)
• Usually sub-nephrotic proteinuria; nephrotic-range proteinuria can nevertheless occur in severe proliferative or mixed glomerular disease

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]

Lecture-era range: gross haematuria, oliguria, hypertension, and oedema were described 7 days to 12 weeks after throat/skin infection, with diuresis usually within 1–2 weeks. ^[1]

Current CDC guidance gives a typical latent period of about 10 days after pharyngitis and up to 3 weeks after impetigo. Prognosis is excellent in most children, but adults more often have severe AKI or residual kidney dysfunction; “reversible” is therefore not universal. ^[22]

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

Anti-DNase B is particularly useful after skin infection, where ASO may be less sensitive.

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 endocapillary hypercellularity, often with neutrophils narrowing/occluding capillary lumina
• Immunofluorescence: Coarse granular C3 with or without IgG along capillary walls/mesangium (“starry sky” pattern)
• Electron microscopy: Classic dome-shaped subepithelial deposits (“humps”)

The paired lecture images make the compartment clear: the LM panel shows a crowded cellular tuft, whereas EM places the dome-shaped humps on the epithelial side of the GBM. Humps are classic for infection-related GN but should be interpreted with clinical and IF findings rather than treated as exclusive to one organism. ^[1]

Treatment: ^[1][22]

For acute PSGN, an appropriate antibiotic eradicates any remaining group A streptococcus and limits transmission; it does not reverse immune-complex GN once established. Supportive care includes salt/fluid management, control of oedema and hypertension, and dialysis when standard AKI indications arise.

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 may be low yield when kidneys are markedly shrunken and disease is clearly advanced, but is still appropriate when diagnosis is uncertain and the result could alter treatment or prognosis

Treatment: ^[1]

Supportive therapy. Minimize metabolic disturbance and complications. Prepare for renal replacement therapy if approaching stage 5 CKD.

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.

Compartment-to-clue map from the nephron diagram: tubular injury impairs reabsorption and secretion, so disproportionate low-molecular-weight proteinuria, glycosuria without marked hyperglycaemia, phosphate/urate wasting, potassium disturbance, or a normal-anion-gap acidosis can localise dysfunction. Interstitial inflammation commonly produces sterile pyuria/WBC casts, while medullary disease first impairs concentrating ability, causing polyuria/nocturia. ^[1]

• 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.

Causes: ^[5][7]

Drug-induced TIN: stop the suspected culprit promptly, review every prescription/over-the-counter/herbal exposure, and provide AKI supportive care. Persistent or severe disease may cause permanent loss of function. Corticosteroids are sometimes considered after specialist assessment—particularly when kidney function fails to improve after withdrawal or in immune-checkpoint-inhibitor AIN—but evidence and timing are not uniform; “usually unnecessary” is too absolute. ^[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

Acute tubular injury is a common cause of intrinsic AKI in hospitalised patients; the older term acute tubular necrosis (ATN) persists clinically even though frank necrosis may be absent or patchy. ^[5]

• Ischaemic ATI: may follow prolonged or severe hypoperfusion
• Nephrotoxic ATI: aminoglycosides, cisplatin, pigment injury, and selected toxic exposures; use contrast-associated AKI unless causality from iodinated contrast is established
• Muddy-brown granular casts and renal tubular epithelial-cell casts strongly support ATI but are not perfectly sensitive or exclusive ^[4]
• Management: treat underlying cause, supportive care, avoid further nephrotoxins

Causes include: ^[5]

• Analgesic nephropathy (NSAIDs, paracetamol)
• Cisplatin
• Reflux nephropathy
• Radiation nephropathy
• TB, GPA, sarcoidosis
• Aristolochic acid nephropathy — aristolochic acid is nephrotoxic and carcinogenic, causing progressive tubulointerstitial fibrosis and upper-tract urothelial cancer risk ^[19]
• PPI-associated chronic TIN ^[7]

Historical visual on slide 68: the newspaper clipping records Hong Kong's 2004 recall/prohibition of 21 proprietary Chinese medicines containing aristolochic acid. This is not a current product list. The enduring clinical lesson is to ask specifically about herbal/proprietary remedies in unexplained TIN or urothelial malignancy; Hong Kong has prohibited import and sale of aristolochic-acid-containing herbs/products since 2004. ^[1][19]

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.

KDIGO 2012 diagnostic and staging criteria (also used in current NICE guidance): ^[18][21]

AKI is diagnosed if ANY ONE of:

1. Serum creatinine rise ≥ 26.5 µmol/L within 48 hours
2. Serum creatinine rise ≥ 1.5× baseline within 7 days
3. Urine output < 0.5 mL/kg/h for ≥ 6 hours

Serum creatinine is delayed and affected by muscle mass, dilution, and non-steady-state kinetics; urine output is affected by obstruction, diuretics, and measurement quality. Diagnose and stage using the worst criterion, then interpret the whole clinical trajectory. ^[18]

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.

Key elements of the conceptual model (from slide): ^[1]

• Stages progress: Normal → Increased risk → Damage → ↓ GFR → Kidney failure → Death
• Early stages are bidirectional (recovery possible); the final transition to death is unidirectional
• Complications can arise at any stage along the continuum and independently contribute to death
• Creatinine and urine output are surrogates for GFR decline
• Biomarkers of tubular damage — NGAL, KIM-1, and IL-18 — are surrogates for the damage phase and may detect injury before creatinine rises

Reading the arrows: recovery can occur from several intermediate states, while complications can arise before “kidney failure.” Creatinine/urine output reflect functional change; damage biomarkers represent a different axis and are not universal replacements for KDIGO criteria in routine practice. ^[1][18]

• Pre-existing CKD
• Diabetic kidney disease
• Heart failure
• Liver disease
• Hypovolaemia
• Older age (the slide used > 50 years; NICE uses age ≥65 years as a pragmatic adult risk flag)
• Sepsis
• Trauma
• Postoperative (e.g., post-CABG)
• Cancer

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.

The numeric urea:creatinine threshold is unit-dependent. More broadly, every entry in this table is a supporting clue, not a diagnostic rule. FENa is altered by diuretics, CKD, sepsis, pigment injury, and early GN; urine sodium/osmolality vary with timing and treatment. A fluid challenge is appropriate only when hypovolaemia is plausible and must be reassessed promptly to avoid pulmonary oedema. Urine sediment, haemodynamics, medication/exposure history, ultrasound when obstruction is possible, and serial response are more important than any one cut-off. ^[18]

Drug-induced renal impairment can be:

• Functional (NSAID, ACEi — alter haemodynamics without structural damage)
• Structural → renal parenchymal disease → tubulointerstitial vs. glomerular

1. Confirm trajectory and severity: compare creatinine with baseline, measure urine output, repeat electrolytes/acid-base status, and assess for life-threatening hyperkalaemia, pulmonary oedema, severe acidosis, or uraemic complications.
2. Find reversible causes: review volume status and haemodynamics, sepsis, recent procedures, every drug/contrast/herbal exposure, urinalysis and sediment, and bladder retention. AKI is commonly multifactorial.
3. Image selectively but urgently: ultrasound within 24 hours when the cause is unclear or obstruction risk exists; suspected infected obstruction (pyonephrosis) needs immediate ultrasound and urgent drainage/urology.
4. Prevent further injury: stop avoidable nephrotoxins, adjust renally cleared medicines, treat the cause, and use carefully reassessed crystalloid only when hypovolaemia is plausible. Loop diuretics do not treat AKI itself but may be used for fluid overload; low-dose dopamine should not be used.
5. Escalate by physiology, not a creatinine number: refractory hyperkalaemia, metabolic acidosis, uraemic complications, fluid overload, or pulmonary oedema require immediate nephrology/critical-care discussion for kidney replacement therapy.

1. 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

2. MCQ: Which urine-microscopy findings strongly support glomerular/renal parenchymal bleeding? → Acanthocytes and RBC casts

3. MCQ/SAQ: A 45-year-old man presents with nephrotic-range proteinuria. Anti-PLA2R is positive. What is the most likely diagnosis? → Primary membranous nephropathy, while still evaluating secondary associations

4. 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)

5. SAQ: A patient develops AKI with fever, rash, and eosinophilia after starting a PPI. What is the diagnosis and initial management? → Drug-induced AIN. Stop the PPI, provide AKI care, and seek specialist input if severe or non-resolving.

6. MCQ: Which stain is used to evaluate kidney fibrosis? → Masson Trichrome

7. 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)

8. MCQ: In RPGN, the pathological hallmark is? → Cellular crescents in Bowman's space

9. MCQ: Persistently low C3 beyond 8 weeks after suspected PSGN should raise suspicion for? → Lupus nephritis or MPGN

10. SAQ: Differentiate pre-renal AKI from intrinsic AKI using urine indices. → Table with FENa, urine Na, urine osmolality, U:Cr ratio