The Urinary System

KIDNEY

1. Gross Anatomy

  • Kidneys are bean-shaped paired organs.
  • Weight: ~150 gm in adult males, ~135 gm in adult females.
  • Located on either side of the vertebral column.
  • Hilum (on medial side): Entry/exit for renal artery, vein, lymphatics, and ureter.
  • Surrounded by a thin fibrous capsule (especially adherent at the hilum).

2. Gross Internal Structure

Cut surface reveals three main parts:

  1. Cortex (outer):

    • ~1 cm thick.

    • Contains all glomeruli and ~85% of nephron tubules.

    • Columns of cortex between pyramids: Renal columns of Bertin (contain interlobar arteries).

    • Medullary rays: Striated structures in cortex made of straight tubules headed to the medulla.

  2. Medulla (inner):

    • Contains 8–18 renal pyramids (cone-shaped).

    • Base of pyramid: Cortico-medullary junction.

    • Apex (renal papilla): Opens into minor calyces for urine drainage.

  3. Renal Pelvis (innermost):

    • Funnel-shaped collecting area.

    • Minor calyces (8–18): Collect urine from papillae.

    • Join into 2–3 major calyces, which drain into the renal pelvis → ureter.

๐Ÿ”น Histology of the Kidney

Each kidney contains ~1 million nephrons, which are the functional units of urine formation.

Parts of a nephron:

  1. Glomerulus + Bowman’s capsule
  2. Proximal convoluted tubule (PCT)
  3. Loop of Henle
  4. Distal convoluted tubule (DCT)
  5. Collecting duct

๐Ÿ”น Important Functional Components

1. Renal Vasculature

  • Renal artery (from aorta) → divides into anterior & posterior divisions.

  • Branches:

    • Segmental arteries → Interlobar arteries → Arcuate arteries → Interlobular arteries

    • Afferent arterioles from interlobular arteries supply individual glomeruli.

    • Efferent arterioles leave glomeruli:

      • Form peritubular capillaries (around cortical nephrons)

      • Form vasa recta (in juxtamedullary nephrons) → supply medulla.

๐Ÿง  Clinical Concepts:

  • Cortex gets ~90% of blood; thus, more prone to hypertension-related damage.
  • Medulla has low perfusion, making it vulnerable to ischemia/necrosis.
  • Arteries are end-arteries (no collateral circulation): Occlusion = infarction.

2. Glomerulus

  • Formed by capillary tuft inside Bowman’s capsule.
  • Blood supply: Afferent arteriole in → Efferent arteriole out
  • Covered by podocytes (visceral epithelial cells).
  • Bowman’s space: Where filtrate collects before entering PCT.

Glomerular Filtration Barrier:

  1. Fenestrated endothelium

  2. Glomerular basement membrane (GBM): 3 layers – lamina rara interna, lamina densa, lamina rara externa

  3. Slit pores between podocyte foot processes

✅ GFR (Glomerular Filtration Rate) ≈ 125 ml/min
✅ No proteins or cells in filtrate under normal conditions

3. Juxtaglomerular Apparatus (JGA)

Located at the vascular pole of glomerulus. Has 3 main parts:

  1. Juxtaglomerular (JG) cells – Modified smooth muscle cells in afferent arteriole that secrete renin

  2. Macula densa – Specialized DCT cells (monitor sodium levels)

  3. Lacis cells – Non-granular cells between JG cells and macula densa

⚠️ JGA regulates blood pressure and sodium balance through renin-angiotensin system

4. Tubules

i) Proximal Convoluted Tubule (PCT):

  • First part of nephron after Bowman’s capsule.
  • Lined by cuboidal cells with brush border (microvilli).
  • Function: Reabsorbs ~80% of water and electrolytes like Na⁺, K⁺, glucose, amino acids, etc.

ii) Loop of Henle:

  • Parts: Descending limb → Thin ascending → Thick ascending

  • Descending: Simple epithelium

  • Ascending: Columnar epithelium

  • Function: Concentrates urine via:

    • Active transport of ions

    • Passive reabsorption of water

iii) Distal Convoluted Tubule (DCT):

  • Continuation from thick ascending limb.

  • Lined by cuboidal cells.

  • Macula densa part near glomerulus (part of JGA).

  • Functions:

    • Sodium balance

    • Acid-base regulation

    • Urinary concentration

iv) Collecting Ducts:

  • Final part where filtrate becomes urine.

  • Lined by cuboidal cells (no brush border).

  • Reabsorbs water under ADH influence, and secretes H⁺ & K⁺ ions.

5. Interstitium

  • Cortical interstitium: Sparse, few fibroblast-like cells

  • Medullary interstitium:

    • Contains stellate cells

    • Produce anti-hypertensive substances

    • Involved in prostaglandin metabolism

✅ Summary Table

Component Structure Function
Cortex Outer layer, contains glomeruli Filtration
Medulla Inner pyramids Concentration of urine
Renal Pelvis Funnel-like chamber Collects urine
Nephron Glomerulus + tubules Urine formation
Juxtaglomerular App. JG cells + Macula densa + Lacis cells Renin secretion, BP regulation
PCT Cuboidal, brush border Bulk reabsorption
Loop of Henle Descending/Ascending limbs Urine concentration
DCT Cuboidal, macula densa Acid-base balance
Collecting Duct Cuboidal ADH-dependent water absorption
Interstitium Sparse (cortex), rich (medulla) Support, prostaglandins

RENAL FUNCTION TESTS

Functions of the Kidneys

The kidneys perform the following vital roles:

  1. Excretion of waste products from protein metabolism (e.g., urea, creatinine).

  2. Acid-base balance by excreting H⁺ and bicarbonate ions.

  3. Water and salt regulation through hormones.

  4. Hormone production:

    • Renin → regulates blood pressure.

    • Erythropoietin → stimulates RBC production.

Parameters Evaluated in Renal Function Tests

Renal function is assessed via:

  • Renal blood flow

  • Glomerular filtration rate (GFR)

  • Tubular function

  • Urinary outflow (to detect obstruction)

Main Groups of Renal Function Tests

  1. Urine Analysis
  2. Concentration and Dilution Tests
  3. Blood Chemistry
  4. Renal Clearance Tests

1. Urine Analysis

i. Physical Examination

  • 24-hour output: Normal = 700–2500 mL/day (average = 1200 mL)
  • Colour: Clear, pale or straw-colored (due to urochrome pigment)
  • Specific Gravity: Measures concentration (Normal = 1.003–1.030)
  • pH and Osmolality also assessed

ii. Chemical Tests

  • Detect protein, glucose, blood (RBCs/hemoglobin)
  • Dipstick tests: Paper strips with reagents give instant results

iii. Bacteriological Examination

  • Requires a midstream urine sample, collected aseptically

iv. Microscopy

  • Fresh, unstained sample examined for:

    • RBCs, WBCs, epithelial cells, crystals, and casts

  • Casts: Protein-based cylindrical structures formed in tubules

    • Tamm-Horsfall protein: Secreted normally; increases in disease

    • Types of casts:

      • Hyaline (non-inflammatory)
      • Leukocyte (inflammatory)
      • Red cell (haematuria)

2. Concentration and Dilution Tests

Evaluate the tubular function of nephrons:

i. Concentration Test (Water Deprivation Test)

  • Patient is deprived of fluids (>20 hours)
  • Normal: High solute urine (Specific gravity ≥ 1.025)
  • Abnormal: Fixed specific gravity (~1.010)

ii. Dilution Test (Excess Water Intake)

  • Normal: Diluted urine (Specific gravity ≤ 1.003)
  • Diseased tubules: Fixed specific gravity, fails to dilute urine

3. Blood Chemistry Tests

Assesses retention of waste products:

  • Urea: Normal = 20–40 mg/dL
  • Blood Urea Nitrogen (BUN): 10–20 mg/dL
  • Creatinine: 0.6–1.2 mg/dL
  • ฮฒ2-Microglobulin: Increases in glomerular/tubular diseases

Azotaemia: ↑ BUN and creatinine
Uraemia: Azotaemia + clinical symptoms

4. Renal Clearance Tests

Measure glomerular filtration rate (GFR) and renal blood flow

Formula:

C = (U × V) / P
Where:

  • C = Clearance (ml/min)
  • U = Urine concentration
  • V = Urine volume/min
  • P = Plasma concentration

i. Inulin/Mannitol Clearance

  • Most accurate for GFR
  • Requires IV infusion and timed urine samples

ii. Creatinine Clearance

  • Easy and widely used
  • Uses 24-hour urine + blood sample
  • Small error due to tubular secretion

iii. Urea Clearance

  • Less sensitive
  • Affected by diet, hydration, infection, etc.

iv. PAH (Para-Aminohippuric Acid) Clearance

  • Measures renal blood flow
  • PAH is both filtered and secreted

Renal Biopsy

Used for diagnosing kidney disease:

  • Fixed in alcoholic Bouin’s solution

  • Examined with:

    • PAS stain (for basement membrane)
    • Silver stain (for glomerular/tubular outlines)
    • Immunofluorescence (for antigens, Ig, complement)
    • Electron microscopy (ultrastructural changes)

RENAL FAILURE

Types of Renal Diseases

  1. Glomerular diseases – Usually immunologic
  2. Tubular diseases – Often toxic/infectious, acute
  3. Interstitial diseases – Involve tubules + interstitium
  4. Vascular diseases – Due to hypertension or ischemia

Other conditions: Congenital anomalies, obstructions, tumors

Major Renal Syndromes

  1. Acute Renal Failure (ARF)
  2. Chronic Renal Failure (CRF)

ACUTE RENAL FAILURE (ARF)

Definition

  • Sudden onset of kidney dysfunction
  • ↓ Urine output (oliguria or anuria)
  • ↑ Waste products in blood (urea, creatinine) → uraemia

Causes of ARF

  1. Pre-renal (↓ Blood supply):

    • Hypovolemia, low cardiac output, vascular disease

  2. Intra-renal (Damage inside kidney):

    • Glomerular diseases

    • Acute tubular necrosis (from toxins or ischemia)

    • Tubulointerstitial nephritis

    • Pyelonephritis

  3. Post-renal (Urine flow blocked):

    • Obstruction in ureter, bladder, or urethra

Note: Pre- and post-renal causes may lead to intra-renal disease if untreated.

Clinical Patterns of ARF

  1. Acute Nephritic Syndrome

    • Often from post-streptococcal glomerulonephritis

    • Features:

      • Mild proteinuria

      • Haematuria

      • Oedema

      • Mild hypertension

  2. Tubular Pathology (Acute Tubular Necrosis)

    • Three stages:

      • Oliguric Phase (7–10 days): ↓ Urine (<400 ml/day), azotaemia, acidosis, hyperkalaemia, pulmonary oedema

      • Diuretic Phase: ↑ Urine output (dilute), tubules healing

      • Recovery Phase: Full recovery in some; others may die or progress to chronic failure

  3. Pre-renal Syndrome

    • No damage to nephron structures

    • From ischemia or heart failure

    • ↓ GFR → oliguria, fluid retention, but tubular concentration ability remains intact

Chronic Renal Failure (CRF)

Definition

Chronic Renal Failure is a progressive, irreversible decline in kidney function due to slow destruction of the renal parenchyma, ultimately resulting in death when most nephrons are damaged.

  • Major complication: Metabolic acidosis
  • Biochemical hallmark: Azotaemia (high nitrogenous waste in blood)
  • Clinical syndrome: Uraemia

Etiopathogenesis

CRF can result from all types of chronic kidney diseases, primarily categorized into:

1. Glomerular Pathology

Glomerular diseases often have an immune basis, leading to nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema).

i. Primary Glomerular Causes:

  • Chronic glomerulonephritis from:

    • Membranous glomerulonephritis

    • Membranoproliferative glomerulonephritis

    • Minimal change disease (lipoid nephrosis)

    • Anti-GBM nephritis

ii. Systemic Glomerular Causes:

  • Systemic lupus erythematosus (SLE)

  • Diabetic nephropathy

  • Serum sickness nephritis

2. Tubulointerstitial Pathology

Affects tubular reabsorption and secretion → leads to polyuria and loss of concentration ability.

Categories:

  • Vascular: Nephrosclerosis from long-standing hypertension
  • Infectious: Chronic pyelonephritis
  • Toxic: Chronic analgesic nephritis (phenacetin, aspirin), heavy metals (lead, cadmium)
  • Obstructive: Urinary obstruction due to stones, tumors, strictures, enlarged prostate

Stages of CRF

  1. Decreased Renal Reserve:

    • ~50% nephron function remains

    • Normal BUN/Creatinine

    • Asymptomatic except during stress

  2. Renal Insufficiency:

    • ~75% nephron loss

    • GFR ~25%

    • Elevated BUN/Creatinine

    • Symptoms: Polyuria, nocturia

  3. Renal Failure:

    • ~90% nephron loss

    • GFR ~10%

    • Loss of sodium and water regulation → Oedema, acidosis, hypocalcaemia, uraemia

  4. End-Stage Kidney:

    • GFR <5%

    • Full-blown uraemic syndrome with multi-organ involvement

Clinical Features of CRF

A. Primary (Renal) Uraemic Manifestations

  1. Metabolic Acidosis:

    • ↓ Bicarbonate, ↑ H⁺

    • Kussmaul breathing, hyperkalaemia

  2. Hyperkalaemia:

    • Cardiac arrhythmias

    • Nausea, muscle weakness, flaccid paralysis

  3. Sodium & Water Imbalance:

    • Hypervolaemia, hypertension, CHF

  4. Hyperuricaemia:

    • Can cause gout (uric acid crystals in joints)

  5. Azotaemia:

    • Accumulation of urea, creatinine → toxicity

B. Secondary (Systemic) Uraemic Manifestations

  1. Anaemia:

    • ↓ Erythropoietin

    • GI bleeding may worsen anaemia

  2. Skin:

    • Sallow-yellow skin due to urochrome

    • Uraemic frost (white powdery deposits on skin)

  3. Cardiovascular:

    • Hypertension, CHF

  4. Respiratory:

    • Pulmonary oedema, uraemic pneumonitis (butterfly pattern on X-ray)

  5. Digestive System:

    • Mucosal ulceration → GI bleeding

    • Nausea, vomiting, diarrhoea

  6. Skeletal System (Renal Osteodystrophy):

    • Osteomalacia (due to ↓ active Vitamin D)

    • Osteitis fibrosa (due to ↑ PTH → bone resorption)

Congenital Malformations of the Kidney

Prevalence

  • ~10% of individuals
  • May be isolated or associated with other organ malformations

Types

I. Amount of Renal Tissue

  • Hypoplasia: One or both kidneys underdeveloped

  • Supernumerary kidney: Extra kidney present

II. Position/Form/Orientation

  • Ectopic kidney (e.g., pelvic kidney)

  • Horseshoe kidney (fusion of kidneys)

  • Persistent fetal lobulation

III. Differentiation Abnormalities

  • Cystic diseases of the kidney

Cystic Diseases of the Kidney

Classification

A. Non-Neoplastic Cystic Lesions

  1. Multicystic Renal Dysplasia (Potter Type II)

  2. Polycystic Kidney Disease (PKD)

    • ADPKD (Adult, autosomal dominant)

    • ARPKD (Infantile, autosomal recessive)

  3. Medullary Cystic Disease

    • Medullary sponge kidney

    • Nephronophthisis

  4. Simple renal cysts

  5. Acquired cysts

  6. Para-renal cysts

B. Neoplastic Cystic Lesions

  1. Cystic nephroma

  2. Cystic partially differentiated nephroblastoma

  3. Cystic Wilms’ tumor

Multicystic Renal Dysplasia (Potter Type II)

Definition:

  • Abnormal kidney development with disorganized structure and non-functional cysts

  • Most common congenital cystic renal disease in infants

Associated Anomalies:

  • PUJ obstruction

  • Urethral atresia

  • Congenital syndromes (e.g., Down syndrome)

Morphology:

  • Unilateral or bilateral

  • Gross: Enlarged, cystic kidney (grape-like)

  • Histology: Immature ducts, mesenchyme, cartilage, few or absent glomeruli

Clinical Features:

  • Flank mass in infants

  • Unilateral cases: Good prognosis after nephrectomy

  • Bilateral cases: Fatal unless transplanted early

๐Ÿ”ท PART 1: CYSTIC RENAL DISEASES

1. Multicystic Renal Dysplasia (Potter Type II)

  • Definition: Developmental disorder with disorganized kidney structure and abnormal nephrogenesis.

  • Common In: Newborns and infants.

  • Etiology:

    • Sporadic or familial.

    • Often associated with urinary tract obstructions (e.g., PUJ obstruction, ureteral atresia).

  • Morphology:

    • May be unilateral or bilateral.

    • Gross: Affected kidney replaced by multiple cysts—grape-like appearance. Normal renal tissue absent.

    • Microscopy: Presence of undifferentiated mesenchyme (includes cartilage, smooth muscle, immature ducts), dilated tubules with flattened epithelium.

  • Clinical Features:

    • Unilateral: Detected as a flank mass in infants; good prognosis after nephrectomy.

    • Bilateral: Fatal without transplant.

    • Often associated with congenital syndromes (e.g., Down’s syndrome, VSD, meningomyelocele).

2. Polycystic Kidney Disease (PKD)

Divided into:

  • A. Autosomal Dominant (Adult Type) – ADPKD

  • B. Autosomal Recessive (Infantile Type) – ARPKD

A. ADPKD

  • Inheritance: Autosomal dominant.

  • Genetics:

    • PKD1 (chromosome 16) – 85%

    • PKD2 (chromosome 4) – 15%

  • Onset: Adulthood (30–50 years).

  • Morphology:

    • Bilateral kidney enlargement (up to 4 kg).

    • Gross: Numerous large cysts (up to 5 cm), clear or brownish fluid; pelvis distorted but cysts do not communicate with it.

    • Microscopy: Cysts from all parts of nephron (Bowman’s capsule, tubules, collecting ducts), interstitial fibrosis, inflammation.

  • Clinical Features:

    • Lumbar pain, haematuria, hypertension, polyuria, UTI, progressive CRF.

    • Associated Conditions:

      • Liver cysts (~30%)

      • Intracranial berry aneurysms (15%)

      • Cysts in pancreas, spleen, lungs

B. ARPKD

  • Inheritance: Autosomal recessive.

  • Genetics: PKHD1 gene on chromosome 6 (6p21).

  • Onset: Neonatal or infantile period.

  • Morphology:

    • Gross: Bilateral smooth kidneys; medullary cysts radiate to cortex—sponge-like appearance.

    • Microscopy: Cysts from dilated collecting ducts, cuboidal/columnar epithelium.

  • Clinical Features:

    • Severe forms cause neonatal death.

    • May lead to congenital hepatic fibrosis and portal hypertension.

๐Ÿ” Comparison of ADPKD vs ARPKD

Feature ADPKD ARPKD
Inheritance Autosomal dominant Autosomal recessive
Mutation PKD1 (chr 16), PKD2 (chr 4) PKHD1 (chr 6)
Onset Adult (30–50 yrs) Neonatal/Infantile
Cyst Origin All parts of nephron Collecting ducts only
External Appearance Lobulated, bilateral enlarged Smooth, sponge-like
Other Organs Affected Liver, brain (aneurysms) Liver fibrosis

3. Medullary Cystic Diseases

A. Medullary Sponge Kidney

  • Inheritance: Autosomal dominant.

  • Features:

    • Cystic dilatation of papillary ducts in medulla.

    • Usually asymptomatic or mild symptoms: flank pain, haematuria, dysuria.

  • Morphology:

    • Multiple small medullary cysts (<0.5 cm), may contain calculi.

    • Cysts lined by various epithelium (columnar to squamous).

    • Renal cortex: usually unaffected or shows pyelonephritis.

B. Nephronophthisis-Medullary Cystic Disease Complex

  • Inheritance: Autosomal recessive.

  • Types: Infantile, juvenile (most common), adolescent.

  • Clinical Features:

    • Polyuria, polydipsia, enuresis

    • Growth retardation, anaemia

    • Progressive renal failure → uraemia

  • Morphology:

    • Gross: Small kidneys with granular surface, cortico-medullary cysts.

    • Microscopy: Tubular atrophy, interstitial fibrosis, cysts lined by flattened epithelium.

4. Simple Renal Cysts

  • Common: Seen in >50% people >50 yrs.

  • Usually asymptomatic.

  • May cause symptoms if rupture, bleeding, or infection occurs.

  • Gross: Solitary or multiple cortical cysts, yellow-white wall, clear or rust-coloured fluid.

  • Microscopy: Flattened epithelium, fibrous cyst wall ± haemosiderin/calcium.

5. Acquired Renal Cysts

  • Causes:

    1. Dialysis-associated cystic disease
    2. Hydatid cyst (echinococcus)
    3. Tuberculosis
    4. Carcinoma-related cystic degeneration
    5. Traumatic haematoma
    6. Drug-induced (experimental)

6. Pararenal Cysts

  • Location: Outside the kidney but adjacent.

  • Types:

    • Pyelocalyceal cysts

    • Hilar lymphangiectatic cysts

    • Retroperitoneal cysts

    • Perinephric pseudocysts (trauma)

GLOMERULAR DISEASES

Definition:

  • Group of diseases primarily affecting renal glomeruli.

Classification:

I. Primary Glomerulonephritis

  • Glomeruli are the main site of disease.

  • Types include:

    • Acute GN (post-streptococcal/non-strep)

    • Rapidly Progressive GN (RPGN)

    • Minimal Change Disease (MCD)

    • Membranous GN

    • Membranoproliferative GN

    • Focal Segmental Glomerulosclerosis (FSGS)

    • IgA Nephropathy

    • Chronic GN

II. Secondary Glomerular Diseases

  • Systemic diseases secondarily affect glomeruli:

    • SLE (lupus nephritis)

    • Diabetes mellitus

    • Amyloidosis

    • Vasculitis (e.g., PAN, Wegener’s)

    • Infections: HBV, HCV, HIV, malaria

    • Others: Cryoglobulinaemia, Goodpasture’s

III. Hereditary Nephritis

  • Alport’s Syndrome

  • Fabry’s Disease

  • Nail-patella Syndrome

Clinical Manifestations of Glomerular Disease

  • Four major signs (varying degrees):

    1. Proteinuria

    2. Haematuria

    3. Hypertension

    4. Impaired excretory function

  • Confirmed by renal biopsy (light, EM, IF microscopy)

๐Ÿ”ท MAJOR GLOMERULAR SYNDROMES

1. Acute Nephritic Syndrome

  • Features: Haematuria, mild proteinuria, oedema, hypertension, oliguria.

  • Typically post-infectious.

  • Urine: Smoky, RBC casts.

  • Causes: Post-strep GN, RPGN, IgA nephropathy.

2. Nephrotic Syndrome

  • Features:

    • Heavy proteinuria (>3 g/day)

    • Hypoalbuminaemia

    • Oedema (peripheral/facial in children)

    • Hyperlipidaemia, lipiduria

    • Hypercoagulability

  • Causes:

    • Children: Minimal change disease (65%)

    • Adults: Membranous GN (40%)

    • Others: Diabetes, SLE, amyloidosis

3. Acute Renal Failure (ARF)

  • Rapid decline in renal function.

  • Causes: RPGN, acute diffuse proliferative GN.

4. Chronic Renal Failure (CRF)

  • Progressive renal damage over years.

  • Features: Small kidneys, proteinuria, hypertension.

5. Asymptomatic Proteinuria

  • Mild, discovered incidentally.

  • May be benign or early glomerular disease.

6. Asymptomatic Haematuria

  • Seen in children/adolescents.

  • Causes: Glomerular diseases, bleeding disorders.

๐Ÿ”ท Pathogenesis of Glomerular Injury

Immunologic reactions — especially involving antigen-antibody (Ag-Ab) complexes — play a key role in most glomerular diseases.

๐Ÿ”น A. Antibody-Mediated Glomerular Injury

1. Immune Complex Disease

๐Ÿ‘‰ Most common mechanism of glomerular injury.

  • Involves deposits of immune complexes (Ag-Ab) in glomeruli.

  • Immune complexes contain immunoglobulins (IgG, IgA, IgM) and complement (mainly C3).

Patterns of Immune Complex Deposition

  • Mesangial deposits → Mild disease

  • Subendothelial deposits (inside GBM) → Severe lesions with hypercellularity and sclerosis

  • Subepithelial deposits (outside GBM) → Between GBM & podocytes

๐Ÿ” Deposits may occur in one or multiple sites in a single case.

Mechanisms of Immune Complex Formation

i. In Situ Formation (Local Formation)

  • Immune complexes form directly in the glomerulus.

  • Antibodies bind to:

    • Intrinsic antigens (from glomerulus itself)

    • Planted antigens (e.g., DNA, streptococcal proteins, drugs)

๐Ÿงช Example: Heymann nephritis (rat model) mimics membranous GN in humans.

ii. Circulating Immune Complexes

  • Form outside the kidney → get trapped in glomeruli.

  • Cause injury only when:

    • In high amounts

    • Have glomerulus-binding properties

    • Body fails to clear them

๐Ÿงฌ Sources of antigens:

  • Endogenous: e.g., SLE

  • Exogenous: e.g., Hepatitis B, syphilis, malaria, tumors

Examples of Immune Complex GN

  • Primary: Acute diffuse proliferative GN, membranous GN, membranoproliferative GN, IgA nephropathy

  • Secondary: SLE, malaria, syphilis, hepatitis, Henoch-Schรถnlein purpura, cryoglobulinaemia

2. Anti-Glomerular Basement Membrane (Anti-GBM) Disease

  • <5% of GN cases

  • Autoantibodies target type IV collagen in GBM

  • Causes linear deposits of IgG (sometimes IgA, IgM) and C3

๐Ÿงช Model: Masugi nephritis (nephrotoxic serum nephritis in rats)

๐Ÿงซ Seen in:

  • Goodpasture’s syndrome: GN + lung hemorrhage (due to antibodies also attacking alveolar basement membrane)

  • Some rapidly progressive GN

3. Alternate Pathway Disease (Complement-Mediated Injury)

  • Complement system (especially C3) causes injury

  • No immunoglobulin involvement

⚙️ Features:

  • ↓ Serum C3, factor B, properdin

  • Normal C1, C2, C4

  • C3 & properdin deposits in glomeruli

๐Ÿฆ  C3NeF: Autoantibody (IgG) that stabilizes C3 convertase → continuous complement activation

๐Ÿ”ฌ Findings:

  • Electron-dense deposits → “dense deposit disease”

๐Ÿงซ Seen in:

  • Type II membranoproliferative GN

  • Some RPGN, acute GN, IgA nephropathy, and SLE

4. Other Antibody-Mediated Mechanisms

i. ANCA (Anti-Neutrophil Cytoplasmic Antibodies)

  • Seen in ~40% cases of pauci-immune GN (little/no immune deposits)

  • ANCA causes damage via ROS production from neutrophils

๐Ÿงซ Seen in:

  • Wegener’s granulomatosis (GPA)

  • Churg-Strauss syndrome (EGPA)

ii. AECA (Anti-Endothelial Cell Antibodies)

  • Target endothelial antigens

  • Promote leukocyte adhesion → inflammation

  • Seen in vasculitis and some GN types

๐Ÿ“Œ Summary

Mechanism Key Feature Examples
Immune Complex GN Granular deposits of Ig + C3 SLE, membranous GN, MPGN, IgA nephropathy
Anti-GBM GN Linear IgG deposits along GBM Goodpasture’s syndrome
Alternate Complement Activation C3 deposits, no immunoglobulin MPGN type II, dense deposit disease
ANCA-Associated Injury No immune deposits, positive ANCA Pauci-immune GN, Wegener's, Churg-Strauss
AECA-Mediated Injury Endothelial autoantibodies Vasculitis-related GN

B. Cell-Mediated Glomerular Injury (Delayed-Type Hypersensitivity)

Cell-mediated immunity plays a role in some types of glomerular injury, especially when antibody involvement is minimal.

๐Ÿงฌ Key Mechanisms:

  • T cells (CD4+ and CD8+) get activated and release cytokines, which:

    • Recruit more immune cells (especially macrophages).

    • Stimulate fibrosis (scarring).

    • Cause cytotoxic injury to glomerular cells.

  • Natural Killer (NK) cells and CD8+ T cells cause direct injury to glomerular cells via antibody-dependent cell-mediated cytotoxicity.

  • In Minimal Change Disease and Focal Segmental Glomerulosclerosis (FSGS), T cell-derived soluble factors are implicated in proteinuria.

➡️ This mechanism is less well understood than antibody-mediated injury.

๐Ÿ“Œ C. Secondary Pathogenetic Mechanisms (Mediators of Immunologic Injury)

These mediators contribute to glomerular injury once immune responses are activated.

๐Ÿ”ฌ 1. Neutrophils:

  • Present in acute proliferative GN and lupus nephritis.

  • Cause injury via:

    • Complement activation.

    • Release of proteases, arachidonic acid metabolites, and reactive oxygen species (ROS).

๐Ÿงซ 2. Mononuclear Phagocytes (Monocytes/Macrophages):

  • Present in many GN forms.

  • Cause hypercellularity by releasing inflammatory substances.

๐Ÿงช 3. Complement System:

  • Classical and alternative pathways contribute to injury.

  • Membrane Attack Complex (MAC: C5b–C9) damages the glomerular basement membrane (GBM) directly.

๐Ÿงฌ 4. Platelets:

  • Aggregate and release mediators.

  • Increased intrarenal platelet consumption observed in some GN types.

๐Ÿงฉ 5. Mesangial Cells:

  • Can produce inflammatory mediators and contribute to glomerular damage.

๐Ÿฉธ 6. Coagulation System:

  • Fibrin in Bowman’s space stimulates crescent formation and scarring.

  • Fibronectin promotes transformation into scar tissue.

๐Ÿ“Œ II. Non-Immunologic Mechanisms of Glomerular Injury

Although immune mechanisms dominate, other causes include:

๐Ÿง  A. Metabolic Disorders:

  • Diabetic nephropathy (due to high glucose).

  • Fabry’s disease (lipid storage disorder).

❤️ B. Hemodynamic Injury:

  • Systemic or intraglomerular hypertension (e.g. in FSGS).

⚠️ C. Deposition Disorders:

  • Amyloidosis leads to abnormal protein deposition.

๐Ÿฆ  D. Infectious Causes:

  • HBV, HCV, HIV, and bacterial toxins.

๐Ÿ’Š E. Drugs:

  • NSAIDs may cause Minimal Change Disease.

๐Ÿงฌ F. Inherited Disorders:

  • Alport’s syndrome, nail-patella syndrome.

๐Ÿ“‰ Progression to ESRD: Due to compensatory glomerular hypertrophy, leading to:

  • ↑ Blood flow and pressure → intraglomerular hypertension.

  • Results in mesangial matrix expansion, glomerulosclerosis, and ultimately renal failure.

๐Ÿ“Œ SPECIFIC TYPES OF GLOMERULAR DISEASES

๐Ÿงช I. Primary Glomerulonephritis (GN)

⚡ Acute Glomerulonephritis (GN)

(Acute Diffuse Proliferative GN / Endocapillary GN)

๐Ÿ“ Common Cause:

  • Post-infectious, mainly post-streptococcal.

๐Ÿ”ฌ Acute Post-Streptococcal GN (APSGN)

  • Common in children (2–14 years), more rare in adults.

  • Follows streptococcal throat or skin infection (e.g. impetigo).

  • Appears 1–2 weeks after infection.

๐Ÿ”ฌ Etiopathogenesis:

  • Caused by immune complex deposition in glomeruli.

  • Streptococcal antigens trigger immune response.

  • Common serotypes: Type 12, 4, 1 of group A ฮฒ-haemolytic streptococci.

  • Serologic evidence: ↑ ASO, anti-DNase B, ASKase, anti-NADase, AHase.

  • ↓ Complement levels (C3) due to consumption.

๐Ÿ”ฌ Morphology:

  • Kidney: Enlarged, flea-bitten appearance.

  • LM:

    • Diffuse glomerular hypercellularity.

    • Neutrophil & monocyte infiltration.

    • Fibrin in capillaries.

  • EM: Electron-dense “humps” (immune complexes).

  • IF microscopy: IgG and C3 in granular pattern.

๐Ÿ” Clinical Features:

  • Abrupt onset in children.

  • Hematuria, red cell casts, mild proteinuria, hypertension, periorbital edema, oliguria.

  • In adults: Atypical, worse prognosis.

  • Prognosis: Excellent in children; complications more in adults.

⚡ Acute Non-Streptococcal GN

  • Caused by:

    • Bacteria: Staphylococci, pneumococci, Salmonella, etc.

    • Viruses: Hepatitis B, mumps, varicella.

    • Parasites: Malaria, toxoplasmosis.

    • Syphilis

  • Similar morphology to APSGN.

  • Prognosis poorer than APSGN.

⚡ Rapidly Progressive GN (RPGN / Crescentic GN / Extracapillary GN)

  • Characterized by rapid decline in renal function (weeks–months).

  • Formation of crescents in Bowman’s space.

  • Most common in adults; slight male predominance.

๐Ÿงช Types of RPGN

Feature Type I (Anti-GBM) Type II (Immune Complex) Type III (Pauci-immune)
Immunofluorescence Linear IgG + C3 Granular IgG + C3 Minimal/absent deposits
Serologic Markers +Anti-GBM ↓C3 (may be) +ANCA
Examples Goodpasture’s syndrome Post-infectious, SLE Wegener’s, Microscopic polyangiitis

๐Ÿ”ฌ Goodpasture’s Syndrome (Type I RPGN)

  • Affects kidney + lungs (causes hemoptysis).

  • Anti-GBM antibodies target type IV collagen in GBM & alveoli.

  • IF shows linear deposits of IgG and C3.

๐Ÿ”ฌ Type II RPGN (Immune Complex)

  • Seen in post-streptococcal, non-streptococcal GN, and SLE.

  • Shows granular deposits and low complement.

๐Ÿ”ฌ Type III RPGN (Pauci-immune)

  • Seen in ANCA-positive vasculitis (e.g. Wegener’s).

  • No immune complexes; normal complement.

๐Ÿ”ฌ Morphology of RPGN:

  • Gross: Enlarged pale kidneys (white kidney).

  • LM:

    • Crescents compress glomerular tuft.

    • ↑ Mesangial and endothelial cells.

    • Fibrin in glomeruli and Bowman’s space.

  • Tubules: Casts, RBCs, fibrin.

  • Interstitium: Edema, fibrosis, lymphocytes.

  • Vessels: May show hypertensive damage.

  • EM Findings:

    • Type I: Linear IgG on GBM.

    • Type II: Granular immune complex deposits.

    • Type III: Few or no deposits.

๐Ÿ” Clinical Features:

  • Rapid renal failure in all types.

  • Goodpasture’s: May present with hemoptysis.

  • Prognosis: Poor overall, but better in post-infectious type.

๐ŸŒŸ 1. Minimal Change Disease (MCD)

Synonyms: Lipoid Nephrosis, Foot Process Disease, Nil Deposit Disease

๐Ÿ“Œ Key Points:

  • Most common cause of nephrotic syndrome in children (<16 years; Boys > Girls, 2:1).

  • No visible change in glomeruli under light microscope.

  • Called foot process disease due to podocyte (epithelial cell) flattening.

๐Ÿ”ฌ Etiopathogenesis:

  • Mostly idiopathic.

  • Associated with:

    • Hodgkin’s disease

    • HIV infection

    • NSAIDs, Rifampicin, Interferon-ฮฑ

  • Probable immunologic basis:

    • ↑ Suppressor T-cell activity → cytokines (IL-8, TNF) damage podocytes

    • Loss of heparan sulfate → ↓ GBM charge

    • Nephrin gene mutation in congenital cases

๐Ÿ”ฌ Morphology:

  • Gross: Kidneys normal in size and appearance.

  • Light Microscopy:

    • Glomeruli: Normal (minimal change)

    • Tubules: Lipid droplets, hyaline (fatty changes = "lipoid nephrosis")

    • Interstitium: May show edema

    • Vessels: No changes

  • Electron Microscopy:

    • Flattened/fused podocyte foot processes

    • Normal GBM

  • Immunofluorescence: No immune deposits (Nil deposit disease)

⚕️ Clinical Features:

  • Nephrotic syndrome (massive selective proteinuria → albumin loss)

  • Usually in children (6–8 years), often following URTI, allergy, or immunization

  • Responds well to steroids

  • Excellent prognosis; most recover after years

๐ŸŒŸ 2. Membranous Glomerulonephritis (GN)

Synonym: Epimembranous Nephropathy

๐Ÿ“Œ Key Points:

  • Common cause of nephrotic syndrome in adults

  • Characterised by thickened capillary walls in glomeruli

๐Ÿ”ฌ Etiopathogenesis:

  • Idiopathic (85%) or secondary to:

    • SLE, Hepatitis B/C, Syphilis, Malaria

    • Drugs: Penicillamine

  • Immune complex deposition → complement-mediated podocyte damage (via MAC complex C5b-C9)

๐Ÿ”ฌ Morphology:

  • Gross: Kidneys enlarged, pale, smooth

  • Light Microscopy:

    • Glomeruli: Diffuse GBM thickening, "spike & dome" pattern (silver stain)

    • Tubules: Early lipid vacuolation

    • Interstitium: Mild fibrosis, chronic inflammation

    • Vessels: Late arteriolar thickening (if hypertensive)

  • Electron Microscopy: Subepithelial electron-dense deposits, spikes between them

  • Immunofluorescence: Granular deposits of IgG + C3

⚕️ Clinical Features:

  • Insidious nephrotic syndrome in adults

  • Non-selective proteinuria, microscopic haematuria

  • 50% progress to chronic kidney disease (CKD) within 2–20 years

  • Risk of renal vein thrombosis

  • Steroid therapy response is variable

๐ŸŒŸ 3. Membranoproliferative GN (MPGN)

Synonym: Mesangiocapillary GN

๐Ÿ“Œ Key Points:

  • Affects children and young adults

  • Features:

    • Mesangial proliferation

    • GBM thickening with double-contour ("tram-track") appearance

๐Ÿ”ฌ Types:

  1. Type I (Classic):

    • Subendothelial immune complex deposits

    • Seen with SLE, Hepatitis B/C, chronic infections, malignancies

  2. Type II (Dense Deposit Disease):

    • Intramembranous dense deposits

    • IgG autoantibody = C3 nephritic factor

    • Associated with partial lipodystrophy

  3. Type III:

    • Rare; features of both type I and membranous GN

๐Ÿ”ฌ Morphology:

  • Gross: Pale, firm kidneys

  • Light Microscopy:

    • Glomeruli: Lobulated tufts, mesangial hypercellularity, thickened GBM

    • Tubules: Vacuolated, hyaline droplets

    • Interstitium: Chronic inflammation, foam cells

    • Vessels: May show hypertensive changes

  • Electron Microscopy:

    • Type I: Subendothelial deposits (IgG, C3)

    • Type II: Intramembranous deposits (C3, properdin)

    • Type III: Subendo + subepithelial + intramembranous

  • Immunofluorescence: C3 in all types, ± IgG/IgM

⚕️ Clinical Features:

  • Age: 15–20 years

  • 50%: Nephrotic syndrome

  • 30%: Asymptomatic proteinuria

  • 20%: Nephritic syndrome

  • Non-selective proteinuria, haematuria, hypocomplementaemia

  • Type I has better prognosis than type II

๐ŸŒŸ 4. Focal Proliferative GN

Synonym: Mesangial Proliferative GN

๐Ÿ“Œ Key Points:

  • Focal (only some glomeruli) + Segmental (only some lobules)

  • Seen as a manifestation of systemic diseases or as isolated GN

๐Ÿ”ฌ Etiopathogenesis:

Occurs in:

  • SLE, Henoch-Schรถnlein purpura, Wegener’s, polyarteritis nodosa, IgA nephropathy

  • Idiopathic

May involve immune complex deposition in mesangium (IgA ± IgG ± C3)

๐Ÿ”ฌ Morphology:

  • Light Microscopy:

    • Some glomeruli show mesangial ± endothelial proliferation

    • Others remain normal

  • Immunofluorescence: IgA, C3, and fibrin in mesangium

⚕️ Clinical Features:

  • Haematuria (most common)

  • Mild to moderate proteinuria

  • Hypertension is uncommon

๐ŸŒŸ 5. Focal Segmental Glomerulosclerosis (FSGS)

Synonyms: Focal Sclerosis, Focal Hyalinosis

๐Ÿ“Œ Key Points:

  • Sclerosis and hyalinosis in <50% glomeruli; focal and segmental

  • Common in adults; ~1/3 of adult nephrotic syndrome cases

๐Ÿ”ฌ Types:

  1. Idiopathic (most cases)

    • Non-selective proteinuria

    • Steroid-resistant

    • May lead to renal failure

  2. Superimposed on other GN (e.g. MCD, IgA GN)

  3. Secondary (HIV, diabetes, heroin use, reflux, analgesics)

๐Ÿ”ฌ Morphology:

  • Light Microscopy:

    • Segmental sclerosis in some glomeruli

    • Hyalinosis = PAS-positive material in capillary loops

    • Mesangial hypercellularity

    • Tubular atrophy, interstitial fibrosis, mononuclear infiltrates

  • Variant: Collapsing glomerulopathy (seen in HIV)

  • Electron Microscopy:

    • Podocyte foot process effacement

    • Electron-dense deposits at sclerotic sites

  • Immunofluorescence: IgM + C3 deposits

⚕️ Clinical Features:

  • All ages; more in males

  • Presents with nephrotic syndrome, haematuria, hypertension

  • May have renal failure at presentation

๐ŸŒŸ 6. IgA Nephropathy

Synonyms: Berger’s Disease, IgA GN

๐Ÿ“Œ Key Points:

  • Most common glomerulopathy worldwide

  • IgA deposits in mesangium

  • Often seen in young males

๐Ÿ”ฌ Etiopathogenesis:

  • Idiopathic (most cases)

  • Seen with Henoch-Schรถnlein purpura

  • Associated with mucosal infections (e.g., respiratory, GI, urinary tract)

  • Increased IgA synthesis + defective clearance

๐Ÿ”ฌ Morphology:

  • Light Microscopy:

    • Varies → focal proliferative GN, FSGS, MPGN, or RPGN

  • Electron Microscopy: Granular mesangial deposits

  • Immunofluorescence: IgA (± IgG, C3, properdin) in mesangium

⚕️ Clinical Features:

  • Common in children/young adults

  • Recurrent haematuria, often after infections

  • Mild proteinuria; rarely nephrotic syndrome

๐ŸŒŸ Chronic Glomerulonephritis (Chronic GN)

Synonym: End-Stage Kidney Disease

๐Ÿ”น Definition:

Chronic GN is the final stage of various glomerular diseases leading to irreversible renal damage and chronic renal failure.

๐Ÿ”น Common Causes (in descending order of frequency):

Cause Approximate % Cases
Rapidly progressive GN 90%
Membranous GN 50%
Membranoproliferative GN 50%
Focal Segmental Glomerulosclerosis (FSGS) 50%
IgA Nephropathy 40%
Acute Post-streptococcal GN 1%
Idiopathic cases (unknown cause) ~20%

๐Ÿ”ฌ Morphologic Features:

๐Ÿ“Œ Gross Appearance:

  • Kidneys are small, shrunken and contracted (as low as 50g each).

  • Capsule is firmly adherent to cortex.

  • Cortical surface is granular.

  • Cortex is atrophic; medulla usually unaffected.

๐Ÿ“Œ Microscopic Features:

  1. Glomeruli:

    • Reduced in number.

    • Many are completely hyalinised—appear as acellular eosinophilic PAS-positive masses.

  2. Tubules:

    • Many are atrophic or completely disappear.

    • Tubular degeneration and hyaline casts often seen.

  3. Interstitial Tissue:

    • Shows fibrosis.

    • Infiltrated by chronic inflammatory cells.

  4. Blood Vessels:

    • Show arteriolar and arterial sclerosis, especially in patients with hypertension.

๐Ÿงช Dialysis-related Changes:

  • Acquired renal cystic disease.

  • Adenomas and adenocarcinomas of the kidney.

  • Calcification of glomerular tufts.

  • Calcium oxalate crystal deposition in tubules.

๐Ÿฉบ Clinical Features:

  • Seen in adults.

  • Presents with:

    • Hypertension

    • Uraemia

    • Progressive renal failure

  • Death inevitable without renal transplant.

  • Multiple systemic complications of uraemia may develop.

๐Ÿงฌ Secondary Glomerular Diseases

๐Ÿ”น 1. Lupus Nephritis (from Systemic Lupus Erythematosus - SLE)

๐Ÿ“Œ Key Facts:

  • Renal involvement in 40–75% of SLE cases.

  • Clinical signs:

    • Proteinuria

    • Haematuria

    • Hypertension

    • Urinary casts (RBC, WBC, fatty casts)

๐Ÿงช Pathogenesis:

  • Related to MHC genes, B-cell signaling (e.g., TNF pathways).

  • Immune complex deposition causes damage.

๐Ÿ”ฌ WHO Classification (6 Classes):

Class Microscopy Description
I Light microscopy normal Mesangial deposits (IgG, C3) on EM/IF
II Mesangial hypercellularity Mesangial matrix ↑, IgG, C3 deposits
III Focal segmental Mesangial + endothelial proliferation; immune deposits
IV Diffuse proliferative Most severe; all glomeruli involved; heavy immune deposits
V Membranous Capillary wall thickening; subepithelial immune deposits
VI Sclerosing End-stage disease; glomeruli hyalinised/sclerosed

๐Ÿ”น 2. Diabetic Nephropathy

๐Ÿ“Œ Key Facts:

  • Major complication of Type 1 diabetes (30–40%).

  • Also affects Type 2 diabetes (20%).

  • Clinical presentation:

    • Proteinuria

    • Nephrotic syndrome

    • Renal failure

    • Hypertension

๐Ÿงฌ Pathogenesis:

  • Hyperglycaemia → Glomerular hypertension → Mesangial protein deposition → Glomerulosclerosis → Renal failure

  • Involvement of TGF-ฮฒ (transforming growth factor-beta) in fibrosis.

๐Ÿ”ฌ Morphologic Types of Lesions:

1. Diabetic Glomerulosclerosis:

a. Diffuse Type:

  • GBM thickening.

  • Diffuse mesangial expansion.

  • Fibrin caps and capsular drops seen.

b. Nodular Type (Kimmelstiel-Wilson lesions):

  • PAS-positive, spherical hyaline nodules.

  • Surrounded by thickened glomerular capillaries.

  • Lead to ischemia and glomerular tuft destruction.

2. Vascular Lesions:

  • Atherosclerosis of renal arteries.

  • Hyaline arteriolosclerosis (afferent & efferent arterioles).

  • Cause renal ischemia, tubule atrophy, and interstitial fibrosis.

3. Diabetic Pyelonephritis:

  • Common in poorly controlled diabetics.

  • Can cause papillary necrosis and chronic pyelonephritis.

4. Tubular Lesions (Armanni-Ebstein):

  • Glycogen accumulation in proximal tubule cells.

  • Seen in severe hyperglycaemia, reversible with glucose control.

๐Ÿ“ Summary Table: Primary Glomerular Diseases (Table 22.11 Highlights)

Type Clinical Pathogenesis LM EM IF
Acute GN Nephritic Immune complex Diffuse prolif. Subepithelial deposits IgG, C3
RPGN Renal failure Type I: anti-GBMType II: ICType III: pauci-immune Crescents Subepithelial or none Linear/granular/negative
Minimal Change Nephrotic T-cell mediated Normal Foot process effacement Negative
Membranous GN Nephrotic IC Capillary wall thickening Subepithelial Granular IgG, C3
MPGN Nephrotic Type I: ICType II: dense deposits Lobular prolif. Subendothelial or dense C3 ± IgG
Focal GN Variable IC Segmental prolif. Mesangial IgA ± IgG, C3
FSGS Nephrotic Idiopathic/secondary Segmental sclerosis Foot process loss IgM, C3
IgA Nephropathy Recurrent hematuria Unknown Mesangial prolif. Electron-dense deposits IgA ± C3
Chronic GN Renal failure End-stage of any GN Hyalinised glomeruli Variable Variable

Hereditary Nephritis (Alport Syndrome)

Definition:

Hereditary nephritis, commonly known as Alport Syndrome, is a group of inherited disorders primarily affecting the glomerular basement membrane (GBM), leading to progressive renal failure, hearing loss, and sometimes eye abnormalities.

Genetics and Inheritance:

  • Most common form: X-linked (85% of cases)

    • Mutation in COL4A5 gene on X chromosome, encoding type IV collagen ฮฑ5 chain.

  • Less common: Autosomal recessive or autosomal dominant inheritance

    • Mutations in COL4A3 or COL4A4 genes (ฮฑ3 and ฮฑ4 chains of type IV collagen).

Pathogenesis:

  • Type IV collagen is a critical component of the GBM.

  • Mutations in collagen genes cause:

    • Abnormal GBM structure

    • Progressive thinning, splitting, and lamellation (layering) of GBM.

  • Over time, this leads to:

    • Proteinuria

    • Hematuria

    • Chronic renal failure

Clinical Features:

Renal Involvement:

  • Microscopic hematuria (earliest sign; often asymptomatic)

  • Progressive proteinuria

  • Chronic renal failure (usually manifests in adolescence or early adulthood)

  • Hypertension may develop in advanced stages.

Extrarenal Manifestations:

  1. Sensorineural Hearing Loss

    • Typically bilateral

    • Involves high-frequency hearing

    • Begins in late childhood or adolescence

  2. Eye Abnormalities

    • Anterior lenticonus (pathognomonic)

    • Retinopathy

    • Corneal dystrophy in some cases

Morphologic Changes:

Light Microscopy (LM):

  • Initially: Non-specific changes

  • Later: Segmental sclerosis, interstitial fibrosis, and tubular atrophy

Electron Microscopy (EM):

  • Key diagnostic tool

  • Shows characteristic GBM changes:

    • Irregular thickening

    • Splitting and lamellation of lamina densa (known as “basket-weave” appearance)

Diagnosis:

  • Urinalysis: Persistent microscopic hematuria, proteinuria

  • Family history: X-linked inheritance pattern

  • Audiometry: For early detection of hearing loss

  • Renal biopsy: Electron microscopy to detect GBM abnormalities

  • Genetic testing: Identification of mutations in COL4A3, COL4A4, or COL4A5 genes

Differential Diagnosis:

  • Thin basement membrane disease (Benign familial hematuria)

  • IgA nephropathy

  • Other inherited glomerular diseases

Prognosis:

  • Progressive renal failure in males with X-linked form

  • Females (carriers) may have milder disease or remain asymptomatic

  • Early diagnosis and supportive therapy can slow progression

Treatment:

  • No specific cure; management is supportive:

    • ACE inhibitors or ARBs to reduce proteinuria and slow renal damage

    • Hearing aids for auditory defects

    • Renal transplantation in end-stage renal disease

      • Rare cases may develop anti-GBM nephritis post-transplant (due to immune response against normal GBM)

๐Ÿ”ด 1. Hypercalcaemia and Nephrocalcinosis

  • Causes of Severe Hypercalcaemia:

    • Endocrine Disorders: Hyperparathyroidism, hyperthyroidism

    • Vitamin Overload: Hypervitaminosis D

    • Bone Destruction: Metastatic cancer

    • Dietary: Excessive calcium intake (e.g. milk-alkali syndrome)

    • Granulomatous Diseases: Sarcoidosis

  • Clinical Features:

    • Renal colic

    • Band keratopathy (calcium deposits in cornea)

    • Metastatic calcification in organs

    • Polyuria

    • Renal failure

  • Morphology:

    • Calcium deposits in:

      • Tubular epithelial cells

      • Basement membrane

      • Mitochondria

    • Leads to:

      • Tubular atrophy

      • Interstitial fibrosis

      • Chronic inflammation

    • Radiological signs appear late (calcification begins in renal papillae)

๐ŸŸก 2. Renal Vascular Diseases

Affected due to:

  • High blood pressure

  • Hemodynamic or hormonal disturbances

Major Types:

  1. Hypertensive vascular diseases

  2. Thrombotic microangiopathy

  3. Renal cortical necrosis

  4. Renal infarcts

๐Ÿ”ต 3. Hypertension and Kidney

➤ Definition:

  • Stage 1 Hypertension: 140–159/90–99 mmHg

  • Stage 2 Hypertension: ≥160/≥100 mmHg

  • Prehypertension: 120–139/80–89 mmHg

➤ Types:

  1. Essential (Primary) Hypertension (90–95%)

    • Cause unknown

  2. Secondary Hypertension (5–10%)

    • Due to renal, endocrine, vascular, or nervous system disease

➤ Based on Course:

  • Benign Hypertension: Gradual progression

  • Malignant Hypertension: Sudden onset; BP ≥200/140 mmHg

๐ŸŸข 4. Essential Hypertension: Causes & Mechanisms

➤ Etiologic Factors:

  • Genetic: Family history, angiotensinogen gene

  • Racial/Environmental: More common in African Americans; high salt intake, stress

  • Other risk modifiers: Age, sex, smoking, diabetes, cholesterol

➤ Pathogenesis:

  • High catecholamines

  • Increased blood volume or cardiac output

  • Renin abnormalities (low or high renin)

๐ŸŸฃ 5. Secondary Hypertension

➤ 1. Renal Hypertension:

  • Renovascular: e.g. renal artery stenosis, polyarteritis nodosa

  • Renal parenchymal: e.g. GN, pyelonephritis, diabetic nephropathy

▶ Mechanisms:

  • Activation of renin-angiotensin-aldosterone system (RAAS)

  • Sodium and water retention

  • Release of vasodepressor substances (prostaglandins, kallikrein)

➤ 2. Endocrine Hypertension:

  • Adrenal: Cushing’s, Conn’s syndrome, pheochromocytoma

  • Parathyroid: Hyperparathyroidism

  • Oral contraceptives: Estrogen increases renin substrate

➤ 3. Coarctation of Aorta:

  • Causes systolic hypertension in upper body

➤ 4. Neurogenic Causes:

  • Rare: e.g. psychogenic, polyneuritis

๐Ÿ”ถ 6. Effects of Hypertension on Kidney

➤ Early Marker:

  • Albuminuria or microalbuminuria indicates renal damage

๐Ÿ”ต 7. Benign Nephrosclerosis

➤ Gross Appearance:

  • Small, shrunken kidneys

  • V-shaped scars

  • Firm and granular cortex

➤ Microscopy:

  • Vascular changes:

    • Hyaline arteriolosclerosis

    • Intimal thickening

  • Parenchymal changes:

    • Glomerular and tubular atrophy

    • Interstitial fibrosis

➤ Clinical Features:

  • Mild to moderate hypertension

  • Headache, dizziness

  • Mild proteinuria

  • Renal failure is rare in early stages

๐Ÿ”ด 8. Malignant Nephrosclerosis

➤ Seen in:

  • 5% of hypertensive patients

  • Young males

➤ Gross Appearance:

  • "Flea-bitten kidney" (petechial hemorrhages)

  • Enlarged and edematous kidney

➤ Microscopy:

  • Necrotizing arteriolitis

  • Onion-skin thickening (hyperplastic arteriosclerosis)

  • Parenchymal infarction, tubular loss, interstitial fibrosis

➤ Clinical Features:

  • BP ≥200/140 mmHg

  • Papilloedema, vision issues

  • Hematuria, proteinuria

  • Rapid renal failure, high mortality if untreated

๐ŸŸก 9. Thrombotic Microangiopathy (TMA)

➤ Pathogenesis:

  • Endothelial injury → Subendothelial fibrin deposition → Thrombosis

➤ Causes (Table 22.16):

  • Infections (E. coli, Shigella)

  • Drugs (mitomycin, cisplatin)

  • Autoimmune (SLE, scleroderma)

  • TTP, HUS, pre-eclampsia, malignant HTN

➤ Morphology:

  • Fibrinoid necrosis of arterioles

  • Thrombi in glomeruli and vessels

  • Glomerular necrosis and congestion

๐Ÿ”ต 10. Renal Cortical Necrosis

➤ Definition:

  • Infarction of renal cortex

  • Medulla usually spared

➤ Causes:

  • Obstetric: Eclampsia, placenta abruption

  • Others: Sepsis, trauma, poisoning

➤ Clinical Features:

  • Sudden anuria/oliguria, hematuria

  • Rapid progression to acute renal failure

  • Poor prognosis if diffuse necrosis

๐Ÿ”ด 11. Obstructive Uropathy

➤ Consequences:

  • Increased infection risk

  • Stone formation

  • Leads to: Hydronephrosis, hydroureter, bladder hypertrophy

➤ Classification of Causes (Table 22.17):

A. Intraluminal:

  • Stones, tumors, clots, foreign body

B. Intramural:

  • PUJ obstruction, urethral valves, strictures, inflammation

C. Extramural:

  • Pregnancy, tumors (cervix, colon), prostate issues, trauma

๐ŸŸข 12. Nephrolithiasis (Urinary Stones)

➤ Definition:

  • Formation of calculi anywhere in urinary tract

➤ Epidemiology:

  • Common in US, India, South Asia

  • Peak: 2nd–3rd decade

  • M:F ratio = 2:1

➤ Clinical Features:

  • Renal colic

  • Hematuria

  • May cause obstruction and infection

๐ŸงŠ URINARY CALCULI (Kidney Stones)

Definition:

Solid masses formed from crystals in the urine that may obstruct urinary flow and cause renal colic and hematuria.

Types of Urinary Calculi:

  1. Calcium Stones (75%)

    • Composition:

      • Pure calcium oxalate (50%)

      • Calcium phosphate (5%)

      • Mixed (45%)

    • Causes:

      • Idiopathic hypercalciuria (no high serum calcium)

      • Hypercalcemia due to:

        • Hyperparathyroidism

        • Vitamin D excess

        • Renal/bowel defects

      • Hyperuricosuria

      • Unknown (idiopathic stone disease)

    • Pathogenesis:

      • Crystals form due to urine supersaturation

      • Alkaline pH, low urine volume, high oxalate/uric acid are risk factors

    • Morphology:

      • Small, hard, ovoid

      • Rough surface

      • Dark brown due to old blood pigments

  2. Struvite (Mixed) Stones (15%)

    • Composition: Magnesium-ammonium-calcium phosphate

    • Also called: Infection or triple phosphate stones

    • Causes: Infection with urea-splitting bacteria (e.g. Proteus, Klebsiella)

      • E. coli does not cause these

    • Morphology:

      • Yellow-white, soft, friable

      • Irregular shape

      • May form large staghorn calculi

  3. Uric Acid Stones (6%)

    • Causes:

      • Hyperuricemia and hyperuricosuria (e.g. gout, leukemia)

      • Acidic urine (pH < 6)

      • Low urine volume

    • Radiolucent on X-ray

    • Pathogenesis:

      • Acidic pH reduces uric acid solubility → stone formation

    • Morphology:

      • Smooth, yellow-brown, hard

      • Often multiple

      • Lamellated on section

  4. Cystine Stones (<2%)

    • Cause: Genetic defect → cystinuria (defective cystine transport)

    • Pathogenesis:

      • Excess cystine (least soluble AA) → crystal/stones

    • Morphology:

      • Small, smooth, round

      • Yellow, waxy

      • Often multiple

  5. Other Rare Types (<2%)

    • E.g., Xanthine stones from hereditary xanthinuria

๐Ÿ’ง HYDRONEPHROSIS

Definition:

Dilatation of the renal pelvis and calyces due to partial or complete obstruction of urine outflow.

Types:

  1. Unilateral Hydronephrosis

    • Causes:

      • Intraluminal: Stones

      • Intramural: PUJ obstruction, inflammation, neoplasm

      • Extramural: Tumor compression (prostate, cervix), fibrosis

  2. Bilateral Hydronephrosis

    • Causes:

      • Congenital: Posterior urethral valve, urethral atresia

      • Acquired: Prostatic enlargement, bladder tumors, strictures

Pathology:

  • Early stage: Extrarenal sac-like dilatation of pelvis

  • Advanced:

    • Intrarenal hydronephrosis

    • Thin renal cortex covering dilated calyces

  • Microscopy:

    • Tubular and glomerular atrophy

    • Fibrosis

    • Chronic inflammation

    • Risk of pyonephrosis (pus in the kidney)

๐Ÿ”ฌ RENAL TUMORS

A. Benign Tumors

  1. Cortical Adenoma

    • Tiny, multiple, white or yellow nodules

    • Composed of uniform cuboidal tubular cells

    • Tumors >3 cm may behave malignantly

  2. Oncocytoma

    • From collecting ducts

    • Brown mahogany color, granular cytoplasm (rich in mitochondria)

  3. Angiomyolipoma

    • Hamartoma (muscle, fat, vessels)

    • Often bilateral in tuberous sclerosis

  4. Mesoblastic Nephroma

    • Congenital tumor in infants

    • Resembles leiomyoma (whorled appearance)

  5. Multicystic Nephroma

    • Unilateral, multilocular

    • Lined by tubular epithelium

    • Completely benign

  6. Medullary Interstitial Cell Tumor

    • Tiny nodules in medulla, fibroblast-like

  7. Juxtaglomerular Tumor (Reninoma)

    • Produces renin → hypertension

    • Epithelioid cells with rich vasculature

B. Malignant Tumors

1. Renal Cell Carcinoma (RCC)

  • Also known as: Adenocarcinoma, Hypernephroma

  • Age: 50–70 years, M > F

  • Most common primary renal cancer (70–80%)

Risk Factors:

  • Smoking (main risk)

  • Genetic syndromes (e.g., VHL disease)

  • Polycystic kidney, dialysis cysts

  • Obesity, estrogen, asbestos, analgesics

Types of RCC:
Type Incidence Features
Clear cell 70% Clear cytoplasm, VHL mutation
Papillary 15% Papillary architecture, MET gene mutation
Granular cell 8% Acidophilic cytoplasm, high atypia
Chromophobe 5% Clear cells with perinuclear halo
Sarcomatoid 1.5% Spindle, poorly differentiated
Collecting duct 0.5% Tubular & papillary, medulla origin
Gross Features:

  • Yellow, solid, upper pole mass

  • Necrosis, hemorrhage

  • May invade renal vein → vena cava

Microscopic:

  • Clear cell: Delicate vessels, lipid-rich cytoplasm

  • Papillary: Fibrovascular cores, psammoma bodies

  • Sarcomatoid: Spindle cells (anaplastic)

Clinical Features:

  • Classic triad: Hematuria, flank pain, abdominal mass

  • Paraneoplastic syndromes:

    • Polycythemia (↑EPO)

    • Hypercalcemia (PTH-like peptide)

    • Hypertension (renin)

    • Cushing’s, feminization

  • Common metastases: Lungs, brain, bones

Prognosis:

  • 5-year survival: ~70%

  • Poor prognosis: High grade, metastasis, vein invasion

2. Wilms’ Tumor (Nephroblastoma)

  • Most common renal tumor in children (1–6 yrs)

  • Often unilateral, may be bilateral (5–10%)

Etiology:

  • Chromosome 11p13 mutation (WT1 gene)

  • Associated syndromes: WAGR, Denys-Drash

  • Congenital GU tract anomalies

Gross:

  • Large, gray-white, fleshy mass

  • Necrosis, hemorrhage, cartilage

Microscopy:

  • Triphasic pattern:

    • Blastemal (small blue cells)

    • Epithelial (abortive tubules/glomeruli)

    • Mesenchymal (muscle, cartilage)

Clinical:

  • Palpable abdominal mass

  • Hematuria, fever, hypertension

  • Spreads to lungs

Prognosis:

  • Excellent with nephrectomy + chemo/radiation

  • 5-year survival: 80–90%

C. Secondary (Metastatic) Tumors

  • Kidney is a common site for:

    • Leukemia infiltration

    • Metastasis from lung, breast, stomach

Lower Urinary Tract: Normal Structure

1. Components

  • Ureters

  • Urinary bladder

  • Urethra

2. Ureters

  • Structure: Tubular, ~30 cm long, 0.5 cm wide.

  • Pathway: From renal pelvis (pelvi-ureteric junction) to bladder (vesico-ureteric junction).

  • Entry into Bladder: Oblique, preventing vesicoureteric reflux during urination.

  • Location: Lies retroperitoneally.

Histology

  • Inner lining: Transitional epithelium (urothelium)

  • Muscular layer: Thick smooth muscle

  • Outer layer: Fibrous connective tissue

3. Urinary Bladder

  • Position: Lies extraperitoneally; only dome is covered by peritoneum.

  • Surfaces: Dome (superior), base (posterior), and two lateral surfaces.

  • Trigone: Smooth triangular area at the base, leads into the neck.

  • Capacity: 400–500 ml (normal without over-distension).

  • Micturition: Controlled reflexively and voluntarily via sympathetic & parasympathetic nerves.

Histology

  • Muscular Layer: Detrusor muscle (3 layers: inner, middle, outer)

  • Trigone Muscle: From longitudinal muscle of ureters.

  • Inner Lining: Transitional epithelium (6–7 layers)

    • Umbrella cells: Superficial large eosinophilic cells.

4. Urethra

Male Urethra

  • Parts: Prostatic, membranous, penile

  • Lining:

    • Prostatic: Transitional epithelium

    • Others: Stratified columnar → squamous at orifice

  • Layers: Submucosa (vascular), striated muscle

  • Glands: Mucous glands in mucosa

Female Urethra

  • Shorter; runs parallel to vaginal anterior wall

  • Epithelium:

    • Columnar epithelium throughout

    • Transitional near bladder

  • Other Layers: Similar to male urethra

Congenital Anomalies

1. Vesicoureteric Reflux

  • Most common; backward flow of urine from bladder into ureters.

2. Double Ureter

  • Entire or partial duplication.

  • Often associated with double renal pelvis.

  • Two ureteric orifices or joined before entering bladder.

3. Ureterocele

  • Cystic dilatation of terminal ureter.

  • Located beneath bladder mucosa.

  • Visualized by cystoscopy.

4. Ectopia Vesicae (Exstrophy)

  • Anterior bladder wall defect + abdominal wall defect.

  • Posterior bladder mucosa exposed.

  • Associated with epispadias in males.

  • Risks: Infection, squamous metaplasia, carcinoma.

5. Urachal Abnormalities

  • Persistent urachus: Urine discharge from umbilicus.

  • Urachal cyst (central portion persists): Risk of adenocarcinoma.

Inflammations

1. Ureteritis

  • Usually secondary to pyelitis (above) or cystitis (below).

  • May become chronic if infection persists.

2. Cystitis (Urinary Bladder Inflammation)

Causes

  • Infection: E. coli (most common), Klebsiella, Pseudomonas, Proteus, Candida, Schistosoma.

  • Others: Radiation, chemicals, trauma, catheters.

Risk Factors

  • Females: Short urethra, sexual activity

  • Males: Prostatic obstruction

Symptoms (Triad)

  • Frequency (frequent urination)

  • Dysuria (burning pain)

  • Lower abdominal pain

Types

  • Acute Cystitis

    • Red, swollen bladder mucosa with ulcers/exudate

    • Neutrophilic infiltrate, oedema, congestion

  • Chronic Cystitis

    • Red, thickened mucosa, polypoid masses

    • Fibrosis, lymphocyte infiltration

    • May form cystitis follicularis

Special Forms

  • Interstitial Cystitis (Hunner’s Ulcer): Severe pain, middle-aged women

  • Cystitis Cystica: Brunn’s nests form cysts, may show metaplasia

  • Malakoplakia: Yellow plaques; macrophages with Michaelis-Gutmann bodies

  • Polypoid Cystitis: Papillary projections due to catheters/infection

3. Urethritis

Types

  • Gonococcal: Neisseria gonorrhoeae → suppurative, strictures

  • Non-gonococcal: E. coli (common), accompanies cystitis/prostatitis

  • Reiter’s Syndrome: Arthritis + Conjunctivitis + Urethritis

Tumours

A. Bladder Tumours

Epithelial Tumours (90%)

  • Arise from urothelium

  • Types:

    1. Transitional Cell Papilloma: Benign, branching papillae

    2. Carcinoma in situ (CIS): Pre-cancerous, confined to mucosa

    3. Transitional Cell Carcinoma (TCC):

      • Grade I: Mild atypia, non-invasive

      • Grade II: Nuclear hyperchromatism, mitosis, +/- invasion

      • Grade III: Anaplastic, invasive, pleomorphic

  • Other Variants:

    • Squamous Cell Carcinoma: 5%; often ulcerated, schistosomiasis-related

    • Adenocarcinoma: Rare; from urachal remnants or glandular metaplasia

    • Mixed carcinoma: 5%

Etiological Factors

  • Industrial exposure (aniline dyes)

  • Schistosomiasis (S. haematobium)

  • Smoking

  • Drugs (cyclophosphamide, analgesics)

  • Chronic inflammation/metaplasia

  • Genetic mutations: p53, RB, p21

Staging of Bladder Cancer

  • Stage 0: Confined to mucosa

  • Stage A: Invades lamina propria

  • Stage B1: Invades superficial muscle

  • Stage B2: Invades deep muscle

  • Stage C: Invades perivesical tissue

  • Stage D1: Regional lymph node metastasis

  • Stage D2: Distant metastasis

B. Non-Epithelial Bladder Tumours

  • Benign: Leiomyoma, haemangioma, neurofibroma

  • Malignant:

    • Rhabdomyosarcoma

      • Adult form: Like skeletal muscle tumour

      • Childhood form: "Sarcoma botryoides" – grape-like, polypoid mass

C. Tumours of Renal Pelvis and Ureters

  • Same types as in bladder (transitional/squamous/adeno).

  • Rare in ureters.

D. Tumours of the Urethra

  • Urethral Caruncle: Inflammatory mass at female external meatus

    • Red, friable, 1–2 cm; resembles pyogenic granuloma

  • Urethral Carcinoma: Rare; usually squamous cell, near meatus


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