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PA27.1-7 | Renal Pathology I: Glomerular Disease & Renal Failure — PBL Case

CLINICAL SETTING

Meenakshi Iyer, a 26-year-old post-graduate student at a university in Coimbatore, presents to a nephrology outpatient clinic with a 6-week history of bilateral ankle swelling and facial puffiness, noticed first on waking each morning. Over the last 10 days she has developed frothy urine that does not clear on standing. She reports joint pains in her hands and wrists for the past 3 months, occasional photosensitivity (develops a facial rash in sunlight), and two episodes of oral ulcers in the past year. She is otherwise healthy, not diabetic, and has no family history of kidney disease. She does not take NSAIDs or any long-term medications. Her periods have been irregular for 6 months. On examination: BP 148/96 mmHg (raised for her age), pulse 84 regular. Periorbital puffiness. Malar erythema in a butterfly distribution across the cheeks, sparing the nasolabial folds. Bilateral mild non-pitting ankle oedema. No lymphadenopathy. No ascites. Urine dipstick: protein 4+ (heavy), blood 2+ (haematuria), leucocytes trace, no nitrites. Serum albumin 2.2 g/dL. Urine protein/creatinine ratio 6.8 (equivalent to ~7 g/day proteinuria). Serum creatinine 1.4 mg/dL (mildly elevated for her body weight).

Trigger 1: Initial Investigation

Blood investigations: Hb 9.8 g/dL (normocytic normochromic), WBC 3,200/µL (leucopenia), platelets 98,000/µL. ESR 88 mm/h. CRP 12 mg/L (mildly elevated). Serum C3 0.42 g/L (markedly low; normal 0.9–1.8), C4 0.04 g/L (markedly low; normal 0.16–0.38). ANA positive 1:640 (homogeneous pattern). Anti-dsDNA titre 1:1280 (strongly positive). Anti-Smith antibody positive. Urine microscopy: 20–30 RBC/HPF, dysmorphic red cells (acanthocytes) on phase-contrast microscopy, red cell casts present, fine granular casts. Serology: Anti-GBM antibody negative. ANCA negative. Anti-phospholipid antibodies: positive (lupus anticoagulant).

DISCUSSION POINTS

  • Meenakshi has nephrotic-range proteinuria (7 g/day) but also haematuria with dysmorphic red cells and red cell casts. She therefore fulfils criteria for both nephrotic and nephritic syndromes simultaneously. Explain the pathophysiological basis for each feature using the glomerular filtration barrier as your framework. How does the simultaneous presence of nephrotic AND nephritic features narrow the differential diagnosis?
  • The complement profile shows both C3 and C4 are markedly low. Contrast this pattern with post-streptococcal GN (C3 low, C4 normal) and with membranous nephropathy (normal complement). Explain the complement activation pathway responsible for C3 AND C4 consumption in this disease, and name the class of immune deposits responsible.
  • Phase-contrast microscopy shows dysmorphic RBCs (acanthocytes). Explain the mechanism by which glomerular haematuria produces dysmorphic rather than isomorphic (normal morphology) RBCs. What is the diagnostic significance of acanthocytes, and how does this finding distinguish glomerular from lower urinary tract bleeding?
  • Meenakshi's urinalysis shows multiple cast types (red cell casts, granular casts). Explain how each cast type forms — what protein constitutes the cast matrix, and what cellular/protein contents indicate glomerular inflammation versus tubular injury. What does the presence of RBC casts specifically localise?
Click to reveal Trigger 2: Renal Biopsy (discuss previous trigger first!)

Trigger 2: Renal Biopsy

Renal biopsy is performed. Light microscopy: 22 glomeruli in the specimen; diffuse endocapillary hypercellularity (increased mesangial and endothelial cells) with inflammatory cell infiltration; thickened capillary loops — some show 'wire-loop' lesions (rigid, thickened capillary walls); segmental fibrous crescents in 3 glomeruli (14%); tubular atrophy and mild interstitial fibrosis (< 25% cortex). Immunofluorescence: granular deposits of IgG3++ , IgA+, IgM+, C3++, C4+, C1q++ in mesangium and capillary walls — a 'full-house' pattern. Electron microscopy: subendothelial and mesangial electron-dense deposits; tubuloreticular inclusions in endothelial cells; podocyte foot process effacement (60% of podocytes). The pathologist's report: 'Lupus nephritis, Class IV (diffuse proliferative), with Class V features (subendothelial + subepithelial deposits).',

DISCUSSION POINTS

  • The biopsy shows 'full-house' immunofluorescence (IgG, IgA, IgM, C3, C4, C1q all present). Explain the immunopathological basis of this pattern. How does nuclear antigen release and autoantibody formation in SLE lead to circulating immune complex deposition in glomeruli? Why are all immunoglobulin classes and complement components deposited together?
  • The pathologist reports Class IV lupus nephritis (diffuse proliferative). Using the ISN/RPS classification, describe Classes I through VI, the morphological criteria distinguishing each class, and the clinical significance of the class in terms of prognosis and treatment intensity. What is the significance of the fibrous crescents (14% of glomeruli)?
  • Electron microscopy shows tubuloreticular inclusions in endothelial cells. These are induced by Type I interferon and are virtually pathognomonic of lupus nephritis among proliferative GNs. Explain why this marker distinguishes lupus nephritis from post-infectious GN, which also produces endocapillary proliferation. What other EM finding (podocyte foot process effacement) explains the massive proteinuria?
  • The lupus anticoagulant is positive. Explain the pathophysiology of lupus anticoagulant-mediated renal vascular disease (thrombotic microangiopathy superimposed on lupus nephritis). How does this complicate the interpretation of renal biopsy findings? What systemic complications of anti-phospholipid syndrome should you screen for in Meenakshi?
Click to reveal Trigger 3: Progression and Systemic Context (discuss previous trigger first!)

Trigger 3: Progression and Systemic Context

Meenakshi is treated with high-dose prednisolone and mycophenolate. After 8 months, her proteinuria has reduced to 0.6 g/day and creatinine is 1.1 mg/dL. However, at month 14, she is brought to casualty with confusion, markedly elevated BP (190/115 mmHg), and oliguria (urine output 250 mL/24 h). Creatinine 6.8 mg/dL (up from baseline 1.1 mg/dL over 6 days). Urine: protein 3+, RBC casts 5–8/HPF. Serum C3 is now normal. BUN 88 mg/dL. Serum K+ 6.4 mEq/L. ECG: peaked T waves. Repeat renal biopsy shows cellular crescents in 60% of glomeruli; linear IgG on immunofluorescence (anti-GBM pattern now positive); silver stain shows breaks in the GBM.

DISCUSSION POINTS

  • Meenakshi has now developed rapidly progressive GN (RPGN) with crescents in 60% of glomeruli. Describe the three immunopathological types of RPGN (Type I anti-GBM, Type II immune-complex, Type III pauci-immune) and classify Meenakshi's current episode. A crescent is a non-specific pathological response — explain its cellular composition and the mechanism by which it compresses and destroys the glomerular tuft.
  • Her serum creatinine rose from 1.1 to 6.8 mg/dL in 6 days. Apply the KDIGO AKI criteria to classify this episode. Distinguish intrinsic AKI (rapidly progressive GN) from prerenal AKI by urinary indices: FENa, urine sodium, urine osmolality, and cast types. Which index is most helpful in this specific clinical context and why?
  • Meenakshi has hyperkalaemia (K+ 6.4 mEq/L) and peaked T waves. Explain the mechanism of hyperkalaemia in AKI — which two processes contribute (reduced renal excretion and transcellular shift from acidosis). What is the threshold for life-threatening cardiac arrhythmia, and what are the immediate treatment priorities in the order of their mechanism of action?
  • Review the progression of Meenakshi's renal disease from initial lupus nephritis (Class IV) to RPGN with crescents at month 14. What factors predict progression of glomerular disease to chronic kidney disease (CKD)? Describe the hyperfiltration–proteinuria–fibrosis cycle that drives CKD progression even after the initial insult is partially controlled, and explain the role of RAAS activation in tubuloglomerular injury.

Group Task Assignments

Group 1: Normal Kidney Histology and Renal Clinical Syndromes

  • Draw and label the glomerular filtration barrier (three layers: fenestrated endothelium, GBM, podocyte foot processes with slit diaphragm). For each layer, indicate its contribution to size selectivity vs charge selectivity, and predict which layer's injury leads to nephrotic vs nephritic syndrome.
  • Construct a comparison table of the eight renal clinical syndromes: nephrotic, nephritic, RPGN, asymptomatic haematuria/proteinuria, AKI, CKD, uraemia, and renovascular hypertension — mapping each to its defining urinary findings, serum changes, and representative pathological diagnosis.

Competencies: PA27.1, PA27.2

Group 2: Nephrotic Syndrome Diseases

  • Compare the four major causes of nephrotic syndrome (minimal change disease, FSGS, membranous nephropathy, MPGN) across: age group, light microscopy, immunofluorescence pattern, electron microscopy findings, complement status, and the most likely autoantibody where applicable.
  • Explain the pathophysiology of the nephrotic syndrome complications — oedema (oncotic vs hydrostatic imbalance), hyperlipidaemia (lipoprotein synthesis vs catabolism), lipiduria (oval fat bodies), and hypercoagulability (loss of antithrombin III). Explain why children with MCD are especially prone to pneumococcal infection.

Competencies: PA27.3, PA27.5

Group 3: Nephritic Syndrome and RPGN

  • Compare post-streptococcal GN and IgA nephropathy: latent period from infection, complement profile, immunofluorescence pattern, electron microscopy deposit location, prognosis, and the one timing feature that distinguishes them (synpharyngitic vs post-infectious latent period).
  • Describe crescentic GN: what is a crescent (cellular composition, mechanism of formation), the three immunopathological types (anti-GBM, immune complex, pauci-immune/ANCA), and the clinical definition of RPGN. Explain why crescents compress and destroy the glomerulus.

Competencies: PA27.2, PA27.5

Group 4: Glomerular Manifestations of Systemic Disease

  • Compare diabetic nephropathy, lupus nephritis (Class IV), and amyloidosis as causes of glomerular disease: pathogenesis, light microscopy (KW nodules / wire loops / amyloid deposits), immunofluorescence, electron microscopy, dominant clinical syndrome, and distinguishing serology.
  • Construct a decision flowchart for evaluating a patient with nephrotic-range proteinuria and positive ANA: steps from serological screening (anti-dsDNA, complement, anti-Sm) through renal biopsy interpretation (IF pattern, crescent %, tubuloreticular inclusions) to ISN/RPS classification and treatment tier.

Competencies: PA27.7

Group 5: Acute and Chronic Renal Failure

  • Construct the urinary index table distinguishing prerenal AKI from intrinsic AKI (ATN): FENa, urine Na, urine osmolality, urine creatinine:serum creatinine ratio, and cast types in each. Describe the four phases of ATN (initiation, oliguria, polyuria, recovery) and explain the mechanism of oliguria in the oliguric phase.
  • Describe the CKD progression pathophysiology: hyperfiltration → proteinuria → RAAS activation → fibrosis cycle. List the five CKD stages by GFR and describe the systemic complications of uraemia affecting each organ system (cardiovascular, haematological, skeletal, neurological, pericardial). Include the secondary hyperparathyroidism pathway in CKD.

Competencies: PA27.3, PA27.4

Learning Issues

Research these questions and bring your findings to the discussion.

  1. [PA27.1] Describe the normal histology of the kidney — the three-layer glomerular filtration barrier, tubular segment anatomy and function, and the juxtaglomerular apparatus. Explain which layer is responsible for size vs charge selectivity, and predict the clinical syndrome resulting from injury to each layer.
  2. [PA27.2] Classify glomerular diseases by clinical syndrome (nephrotic, nephritic, RPGN). Describe the mechanisms of glomerular injury (immune-complex deposition, anti-GBM antibodies, podocyte injury) and the role of complement. Distinguish nephrotic from nephritic syndrome by urinary and serum findings.
  3. [PA27.3] Describe the four major causes of nephrotic syndrome (MCD, FSGS, membranous nephropathy, MPGN) — aetiology, pathogenesis, light microscopy, immunofluorescence, electron microscopy, and prognosis. Explain the complications of nephrotic syndrome (oedema, hyperlipidaemia, hypercoagulability, infection susceptibility).
  4. [PA27.4] Describe the pathogenesis, morphology, laboratory findings, and prognosis of chronic kidney disease. Explain the hyperfiltration-proteinuria-fibrosis cycle and the role of RAAS. Describe the systemic complications of uraemia and the pathophysiology of renal osteodystrophy via secondary hyperparathyroidism.
  5. [PA27.5] Define and classify glomerulonephritis. Describe post-streptococcal GN and IgA nephropathy — their pathogenesis, LM/IF/EM findings, complement profile, and timing relative to infection. Describe crescentic/RPGN: crescent composition, three immunopathological types, and clinical definition of rapid progression.
  6. [PA27.6] Describe IgA nephropathy (Berger disease): the most common primary GN worldwide, its pathogenesis (galactose-deficient IgA1, mesangial deposition), LM/IF/EM findings, complement profile, clinical course, and key distinguishing feature from post-streptococcal GN (synpharyngitic timing, normal C3).
  7. [PA27.7] Describe glomerular manifestations of systemic diseases — diabetic nephropathy (KW nodules, GBM thickening, four pathogenetic mechanisms), lupus nephritis (ISN/RPS classification I–VI, full-house IF, tubuloreticular inclusions), amyloidosis (Congo red, apple-green birefringence), and hypertensive nephrosclerosis (hyaline arteriolosclerosis).