# Lecture 10: Glomerular Diseases ## Unit 2.1: Renal System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the clinical syndromes of glomerular disease 2. Differentiate nephrotic from nephritic syndrome 3. Explain the pathophysiology of major primary glomerulonephritides 4. Describe secondary causes of glomerular disease 5. Interpret kidney biopsy findings in glomerular diseases 6. Explain the management of glomerular diseases --- ## Clinical Syndromes Glomerular diseases produce recognizable clinical patterns that guide differential diagnosis and management. Understanding these syndromes provides a framework for approaching the diverse conditions that affect the glomerulus. While individual diseases may present variably, most can be categorized into nephrotic syndrome, nephritic syndrome, or overlapping presentations. Nephrotic syndrome results from severe disruption of the glomerular filtration barrier, allowing massive protein loss into urine. The defining features include proteinuria exceeding 3.5 grams per day (or urine protein-to-creatinine ratio above 3.5 g/g), hypoalbuminemia below 3 g/dL, peripheral and periorbital edema, hyperlipidemia with elevated LDL and total cholesterol, and lipiduria with oval fat bodies and fatty casts visible on urine microscopy. These features represent downstream consequences of protein loss rather than separate disease manifestations. Nephritic syndrome reflects inflammatory glomerular injury with disruption of capillary integrity. Hematuria constitutes the hallmark finding, with dysmorphic red blood cells and red blood cell casts indicating glomerular origin. Proteinuria occurs but typically remains below nephrotic range at less than 3.5 grams per day. Hypertension develops from sodium retention and volume expansion. Azotemia with rising creatinine and reduced GFR reflects compromised filtration, while oliguria may accompany severe inflammation. Additional presentations include asymptomatic hematuria or proteinuria discovered incidentally on routine testing, rapidly progressive glomerulonephritis (RPGN) characterized by GFR decline over days to weeks with crescents on biopsy, and chronic glomerulonephritis presenting as slowly progressive CKD. Many diseases present with overlapping features of both nephrotic and nephritic syndromes, and the clinical picture may evolve over time. Panel A: Nephrotic syndrome glomerular cross-section showing damaged filtration barrier with protein molecules escaping, and key features including heavy proteinuria (greater than 3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, and lipiduria with oval fat bodies. Panel B: Nephritic syndrome glomerular cross-section showing inflamed capillaries with red cell extravasation, and key features including hematuria with RBC casts, subnephrotic proteinuria, hypertension, azotemia, and oliguria. Panel C: Overlap zone showing diseases with mixed nephrotic-nephritic features including membranoproliferative GN and lupus nephritis. Panel D: Additional presentations including asymptomatic hematuria or proteinuria, rapidly progressive glomerulonephritis with crescents, and chronic glomerulonephritis as slowly progressive CKD. --- ## Pathophysiology of Glomerular Injury Multiple mechanisms can injure the glomerulus, each producing characteristic patterns of damage. Understanding these mechanisms guides diagnosis and treatment. Immune complex deposition accounts for many glomerulonephritides, with circulating antigen-antibody complexes lodging in glomerular structures or complexes forming in situ when antibodies bind planted antigens. Post-streptococcal glomerulonephritis and lupus nephritis exemplify this mechanism. Anti-glomerular basement membrane antibodies target the alpha-3 chain of type IV collagen, producing linear immunofluorescence along the GBM. Goodpasture syndrome results when these antibodies attack both kidney and lung. Antineutrophil cytoplasmic antibodies (ANCA) cause pauci-immune glomerulonephritis by activating neutrophils that injure glomerular capillaries without significant immune complex deposition. Podocyte injury underlies minimal change disease and focal segmental glomerulosclerosis, disrupting the filtration barrier and causing nephrotic-range proteinuria. Complement dysregulation drives C3 glomerulopathy and atypical hemolytic uremic syndrome through uncontrolled alternative pathway activation. The location of immune deposits correlates with clinical presentation and specific diseases. Subepithelial deposits between podocytes and GBM characterize membranous nephropathy and the subepithelial "humps" of post-streptococcal GN. Subendothelial deposits beneath endothelial cells occur in lupus nephritis and membranoproliferative GN. Mesangial deposits define IgA nephropathy. Linear GBM staining indicates anti-GBM disease. Complement profiles help narrow the differential diagnosis. Low C3 with low C4 indicates classical pathway activation, typical of lupus nephritis and cryoglobulinemia. Low C3 with normal C4 suggests alternative pathway involvement, as seen in C3 glomerulopathy and post-streptococcal GN. Normal complement levels occur in IgA nephropathy, ANCA-associated disease, and anti-GBM disease. Panel A: Glomerular capillary wall cross-section showing layers (endothelium, GBM, podocyte foot processes) with immune deposit locations marked at subepithelial (membranous nephropathy), intramembranous, subendothelial (lupus nephritis, MPGN), and mesangial (IgA nephropathy) positions. Panel B: Linear GBM staining pattern indicating anti-GBM disease, distinct from granular patterns of immune complex deposition. Panel C: Complement pathway diagram showing classical pathway activation (low C3 and C4, seen in lupus and cryoglobulinemia), alternative pathway (low C3, normal C4, seen in C3 glomerulopathy and post-infectious GN), and normal complement (IgA nephropathy, ANCA, anti-GBM). Panel D: Podocyte injury mechanisms underlying minimal change disease and FSGS, and complement dysregulation driving C3 glomerulopathy and atypical HUS. --- ## Minimal Change Disease Minimal change disease represents the most common cause of nephrotic syndrome in children and accounts for 10-15% of adult nephrotic syndrome. The condition derives its name from the normal appearance of glomeruli on light microscopy. The pathology lies at the ultrastructural level, where electron microscopy reveals diffuse podocyte foot process effacement—the flattening and fusion of normally interdigitating foot processes that maintain the filtration barrier. The clinical presentation typically involves sudden onset of severe edema, with massive proteinuria and full nephrotic syndrome. Immunofluorescence is characteristically negative, distinguishing MCD from immune complex-mediated diseases. The pathogenesis likely involves circulating factors or cytokines that alter podocyte function, though specific causative agents remain elusive. T cell dysfunction may play a role, as MCD can accompany Hodgkin lymphoma and responds to immunosuppression. Treatment with corticosteroids produces complete remission in approximately 90% of patients, often within weeks. This dramatic steroid responsiveness is itself a diagnostic feature, as persistent proteinuria prompts biopsy to exclude other diagnoses. Relapses occur frequently, affecting up to 50% of patients, but generally respond to repeat steroid courses. Steroid-dependent or frequently relapsing disease may require second-line agents including cyclophosphamide, calcineurin inhibitors, or rituximab. Despite frequent relapses, the long-term prognosis remains excellent with preserved kidney function. Panel A: Light microscopy showing completely normal-appearing glomerulus with patent capillary loops and thin GBM, labeled Normal LM. Panel B: Immunofluorescence showing negative staining with dark background, distinguishing MCD from immune complex-mediated diseases. Panel C: Electron microscopy showing diffuse flattened and fused podocyte foot processes along the GBM with loss of normal interdigitation, with normal EM inset for comparison showing regular foot process architecture. Panel D: Treatment response graph showing rapid proteinuria decline with corticosteroid therapy, approximately 90% complete remission rate, and notation of 50% relapse rate with steroid-dependent options including cyclophosphamide, calcineurin inhibitors, and rituximab. --- ## Focal Segmental Glomerulosclerosis Focal segmental glomerulosclerosis has become the most common primary glomerular disease causing nephrotic syndrome in adults in the United States. The name describes the histologic pattern: sclerosis that affects some glomeruli (focal) and involves only portions of affected glomeruli (segmental). FSGS encompasses several distinct entities unified by this morphologic appearance but differing in pathogenesis and treatment response. Primary FSGS results from an intrinsic podocytopathy, likely involving circulating permeability factors that damage podocytes. Secondary FSGS develops as an adaptive response to hyperfiltration from conditions including obesity, unilateral kidney agenesis, or any cause of reduced nephron mass. Genetic forms result from mutations in podocyte structural proteins including nephrin, podocin, and alpha-actinin-4. These distinctions matter because primary FSGS may respond to immunosuppression, while secondary and genetic forms generally do not. Clinical presentation includes nephrotic syndrome in most cases, often with concurrent hypertension and renal insufficiency at diagnosis. The presence of hypertension and reduced GFR distinguishes FSGS from minimal change disease, though both cause foot process effacement on electron microscopy. Light microscopy shows segmental sclerosis with hyalinosis and adhesions to Bowman's capsule in affected segments. Immunofluorescence typically shows IgM and C3 trapped in sclerotic areas, representing nonspecific trapping rather than pathogenic deposits. Treatment of primary FSGS begins with prolonged corticosteroid courses, though response rates of 30-50% are lower than in MCD. Non-responders may benefit from calcineurin inhibitors, mycophenolate, or rituximab. RAAS blockade and SGLT2 inhibitors provide renoprotection regardless of immunosuppression response. Without treatment, FSGS progresses to end-stage kidney disease, and the condition can recur rapidly in transplanted kidneys due to the circulating permeability factor. Panel A: Glomerular schematic showing segmental area of sclerosis with consolidated scarred tissue affecting part of one glomerular lobule while adjacent lobules appear normal, with light microscopy showing segmental sclerosis and hyalinosis. Panel B: Classification flowchart distinguishing primary FSGS (podocytopathy with circulating permeability factor), secondary FSGS (adaptive hyperfiltration from obesity or reduced nephron mass), and genetic forms (mutations in nephrin, podocin, alpha-actinin-4). Panel C: Treatment algorithm showing prolonged corticosteroid courses with approximately 30-50% response rate, second-line options (calcineurin inhibitors, mycophenolate, rituximab), and universal RAAS blockade plus SGLT2 inhibitors. Panel D: Transplant recurrence warning showing rapid recurrence possible due to circulating permeability factor, and prognosis of progression to ESRD without treatment. --- ## Membranous Nephropathy Membranous nephropathy constitutes the most common cause of nephrotic syndrome in adults worldwide, though FSGS has surpassed it in some populations. The characteristic histologic finding is diffuse thickening of the glomerular basement membrane caused by subepithelial immune deposits. As deposits accumulate and the GBM reacts by producing new basement membrane material, a distinctive "spike and dome" pattern develops on silver stain, with basement membrane spikes projecting between immune deposits. Primary membranous nephropathy results from autoantibodies targeting podocyte membrane proteins. Anti-phospholipase A2 receptor (PLA2R) antibodies account for approximately 70% of primary cases, while anti-thrombospondin type-1 domain-containing 7A (THSD7A) antibodies explain another 3-5%. These antibodies form immune complexes in situ at the podocyte surface. Secondary membranous nephropathy occurs with infections (hepatitis B and C, syphilis), systemic lupus erythematosus (class V), medications (NSAIDs, gold, penicillamine), and malignancies (solid tumors, particularly lung, colon, and stomach). A unique complication of membranous nephropathy is markedly elevated thromboembolism risk, especially renal vein thrombosis. Urinary loss of anticoagulant proteins (antithrombin III, protein C, protein S) combined with increased hepatic synthesis of procoagulant factors creates a hypercoagulable state. Patients presenting with sudden flank pain or unexplained pulmonary embolism should be evaluated for renal vein thrombosis. Natural history is variable: roughly one-third of patients experience spontaneous remission, one-third remain stable with persistent proteinuria, and one-third progress. Anti-PLA2R antibody levels correlate with disease activity and help guide treatment decisions. High-risk patients benefit from immunosuppression with rituximab, calcineurin inhibitors, or cyclophosphamide-based regimens. All patients receive RAAS blockade and anticoagulation consideration based on thrombosis risk. Panel A: Electron microscopy schematic showing subepithelial electron-dense deposits (dome-shaped masses) between podocyte foot processes and GBM, with GBM spikes projecting upward between deposits and silver stain demonstrating the classic spike and dome pattern. Panel B: Immunofluorescence showing granular IgG staining along capillary loops in a beaded pattern indicative of subepithelial immune complex deposition. Panel C: Primary versus secondary causes with anti-PLA2R antibodies (70% of primary cases) targeting podocyte membrane, and secondary causes including hepatitis B and C, lupus (class V), NSAIDs, and malignancies (lung, colon, stomach). Panel D: Thromboembolism complication showing renal vein thrombosis from urinary loss of anticoagulant proteins (antithrombin III, protein C, protein S) with increased hepatic procoagulant synthesis, and anticoagulation indication. --- ## Nephrotic Syndrome Complications and Secondary Causes Nephrotic syndrome carries significant morbidity from its systemic complications. Thromboembolism represents the most dangerous acute complication, resulting from urinary losses of anticoagulant proteins including antithrombin III, protein C, and protein S, while hepatic synthesis of fibrinogen and other procoagulants increases. Renal vein thrombosis occurs most frequently in membranous nephropathy but can complicate any severe nephrotic syndrome. Deep venous thrombosis and pulmonary embolism also occur with increased frequency. Infection risk increases due to urinary immunoglobulin losses that impair humoral immunity. Encapsulated organisms including Streptococcus pneumoniae pose particular risk. Hyperlipidemia results from increased hepatic lipoprotein synthesis stimulated by decreased plasma oncotic pressure. Protein malnutrition can develop from ongoing urinary losses despite adequate intake. Acute kidney injury may occur from severe volume depletion, NSAID use, or bilateral renal vein thrombosis. Diabetic nephropathy has become the most common secondary cause of nephrotic syndrome. The progression from hyperfiltration through microalbuminuria to overt proteinuria and declining GFR follows a predictable pattern. Histologically, diffuse mesangial expansion progresses to nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) in advanced disease. Management emphasizes RAAS blockade, SGLT2 inhibitors, and optimal glycemic control. Other secondary causes include amyloidosis (both AL from plasma cell dyscrasias and AA from chronic inflammation), lupus nephritis class V (membranous pattern), infections (HIV-associated FSGS, hepatitis B-associated membranous or MPGN, hepatitis C-associated cryoglobulinemic MPGN), and malignancy (solid tumors associated with membranous nephropathy). Drug-induced causes include NSAIDs (minimal change pattern) and various medications causing membranous nephropathy. Panel A: Thromboembolism complication showing clot in vein with urinary loss of anticoagulant proteins (antithrombin III, protein C, protein S) and infection risk from urinary immunoglobulin losses with encapsulated organism susceptibility. Panel B: Metabolic complications showing hyperlipidemia from increased hepatic lipoprotein synthesis, protein malnutrition from ongoing urinary losses, and AKI risk from volume depletion, NSAIDs, or bilateral renal vein thrombosis. Panel C: Diabetic nephropathy as the most common secondary cause showing progression from hyperfiltration through microalbuminuria to Kimmelstiel-Wilson nodular glomerulosclerosis. Panel D: Other secondary causes including amyloidosis (AL and AA with Congo red staining), lupus nephritis class V, infections (HIV-associated FSGS, HBV membranous, HCV cryoglobulinemic MPGN), and malignancy-associated membranous nephropathy. --- ## IgA Nephropathy IgA nephropathy, also known as Berger disease, stands as the most common glomerulonephritis worldwide. The pathogenesis involves galactose-deficient IgA1, an abnormal IgA molecule lacking normal galactose residues on its hinge region. This structural abnormality allows autoantibodies to recognize and bind the aberrant IgA1, forming immune complexes that deposit in the glomerular mesangium. The classic clinical presentation involves episodic gross hematuria occurring within 24-48 hours of upper respiratory infection—so-called "synpharyngitic" hematuria that contrasts with the longer latency of post-streptococcal glomerulonephritis. Between episodes, microscopic hematuria typically persists. Some patients present with asymptomatic microscopic hematuria discovered incidentally. Proteinuria varies from minimal to nephrotic range. Histologic findings include mesangial hypercellularity and matrix expansion on light microscopy. The diagnostic feature is dominant or codominant mesangial IgA staining on immunofluorescence, often accompanied by C3 and sometimes IgG. Electron microscopy confirms mesangial electron-dense deposits. Prognosis varies widely, with 20-40% of patients progressing to end-stage kidney disease over 20-30 years. Risk factors for progression include proteinuria exceeding 1 gram per day, hypertension at presentation, reduced GFR at diagnosis, and histologic features including interstitial fibrosis, tubular atrophy, and crescents. The MEST-C scoring system (Mesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents) standardizes pathologic assessment. Treatment centers on RAAS blockade for all patients, reducing proteinuria and slowing progression. Immunosuppression with corticosteroids benefits patients with progressive disease despite optimal supportive care. Newer targeted therapies including sparsentan (dual endothelin and angiotensin receptor antagonist) and SGLT2 inhibitors show promise for reducing proteinuria and progression. Panel A: Pathogenesis flowchart showing galactose-deficient IgA1 molecule with missing galactose residues, anti-glycan antibodies recognizing abnormal IgA, immune complex formation, and mesangial deposition. Panel B: Clinical presentation with URI trigger, synpharyngitic gross hematuria within 24-48 hours (contrasted with post-streptococcal latency), and return to microscopic hematuria baseline, alongside immunofluorescence showing dominant mesangial IgA staining. Panel C: MEST-C histologic scoring components (Mesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents) with prognostic implications. Panel D: Risk stratification showing progression factors (proteinuria greater than 1 g/day, hypertension, low GFR, fibrosis, crescents) and treatment algorithm with RAAS blockade for all patients and corticosteroids or sparsentan for progressive disease. --- ## Post-Infectious Glomerulonephritis Post-streptococcal glomerulonephritis represents the prototype of post-infectious glomerulonephritis, developing after infection with nephritogenic strains of group A beta-hemolytic streptococci. The latent period between infection and nephritis depends on the infection site: 1-2 weeks following pharyngitis but 3-6 weeks after skin infection (impetigo). This timing reflects the interval required for immune complex formation rather than direct bacterial invasion. Clinical presentation features acute nephritic syndrome with hematuria, often producing tea or cola-colored urine. Periorbital edema is particularly common, distinguishing PSGN from other causes of nephritic syndrome. Hypertension and oliguria reflect volume expansion from impaired sodium excretion. Children predominate, though adults can be affected and often have worse outcomes. Laboratory findings include elevated anti-streptolysin O (ASO) titers following pharyngitis and anti-DNase B following skin infection. Complement studies show depressed C3 with C4 often low-normal or mildly decreased, reflecting alternative pathway activation with some classical pathway involvement. Histologically, glomeruli show endocapillary hypercellularity with neutrophil infiltration. Immunofluorescence reveals granular deposits of IgG and C3 along capillary walls and in the mesangium, producing a "starry sky" pattern. Electron microscopy demonstrates characteristic large subepithelial electron-dense deposits called "humps" that produce the distinctive appearance. Treatment is supportive, focusing on volume management, blood pressure control, and diuretics for edema. Prognosis in children is excellent, with over 95% achieving complete recovery. Adults more frequently develop chronic kidney disease or persistent urinary abnormalities. Prevention involves appropriate antibiotic treatment of streptococcal infections. Other infections can cause similar glomerulonephritis patterns. Staphylococcal infection-associated GN develops with ongoing infection (abscess, infected device) rather than following infection resolution. Hepatitis B causes membranous nephropathy or MPGN patterns. Hepatitis C classically produces cryoglobulinemic MPGN. HIV associates with collapsing FSGS. Infective endocarditis can trigger immune complex glomerulonephritis. Panel A: Timeline showing streptococcal pharyngitis or impetigo followed by latent period (1-2 weeks for pharyngitis, 3-6 weeks for skin infection) and nephritic syndrome onset with tea-colored urine, periorbital edema, and hypertension. Panel B: Light microscopy showing hypercellular glomerulus packed with inflammatory cells including neutrophils, and immunofluorescence showing starry sky granular IgG/C3 pattern along capillary walls and mesangium. Panel C: Electron microscopy showing characteristic large subepithelial humps as dome-shaped electron-dense deposits on the epithelial side of the GBM. Panel D: Laboratory findings (elevated ASO titers for pharyngitis, anti-DNase B for skin, depressed C3) and prognosis comparison showing greater than 95% recovery in children versus higher CKD risk in adults. --- ## Rapidly Progressive Glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) constitutes a nephrology emergency characterized by rapid GFR decline over days to weeks. The histologic hallmark is crescent formation—crescents are cellular proliferations in Bowman's space composed of parietal epithelial cells, macrophages, and fibrin that compress and destroy the glomerular tuft. When crescents affect more than 50% of glomeruli, the term crescentic glomerulonephritis applies. Classification divides RPGN into three types based on immunofluorescence pattern. Type I (anti-GBM disease) shows linear IgG staining along the glomerular basement membrane and accounts for 10-15% of cases. Type II (immune complex-mediated) demonstrates granular deposits and encompasses lupus nephritis, IgA nephropathy with crescents, and post-infectious GN; this represents 40-50% of cases. Type III (pauci-immune, ANCA-associated) shows absent or minimal immunoglobulin staining and accounts for 40-50% of cases. Anti-GBM disease results from antibodies against the alpha-3 chain of type IV collagen, a component of both glomerular and alveolar basement membranes. When both organs are affected, the syndrome is called Goodpasture syndrome, presenting with RPGN and pulmonary hemorrhage (hemoptysis). Linear IgG staining on renal biopsy immunofluorescence is pathognomonic. Treatment requires plasmapheresis to remove circulating antibodies combined with cyclophosphamide and corticosteroids to suppress antibody production. Prognosis is poor once creatinine exceeds 6 mg/dL or dialysis dependence develops. ANCA-associated vasculitides include granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). GPA typically causes upper and lower respiratory tract disease along with glomerulonephritis, with cytoplasmic ANCA pattern directed against proteinase-3 (PR3). MPA primarily affects kidneys and lungs, with perinuclear ANCA pattern against myeloperoxidase (MPO). EGPA features asthma, eosinophilia, and vasculitis, usually MPO-ANCA positive. Treatment of ANCA-associated vasculitis involves induction with corticosteroids plus either rituximab or cyclophosphamide, followed by maintenance therapy with rituximab or azathioprine. Plasmapheresis may benefit severe disease with diffuse alveolar hemorrhage. Panel A: Crescent formation illustration showing normal glomerulus progressing to crescent with cellular proliferation of parietal epithelial cells, macrophages, and fibrin in Bowman's space compressing the glomerular tuft. Panel B: Three-type classification with Type I (linear IF pattern, anti-GBM mechanism, Goodpasture syndrome with lung and kidney involvement), Type II (granular IF, immune complex mechanism including lupus, IgA, and post-infectious GN), and Type III (pauci-immune/negative IF, ANCA mechanism with GPA, MPA, and EGPA). Panel C: ANCA patterns showing c-ANCA (cytoplasmic fluorescence targeting PR3, associated with GPA) versus p-ANCA (perinuclear fluorescence targeting MPO, associated with MPA and EGPA). Panel D: Treatment showing plasmapheresis plus cyclophosphamide and steroids for anti-GBM disease, and rituximab or cyclophosphamide plus steroids for ANCA vasculitis with maintenance therapy. --- ## Lupus Nephritis Systemic lupus erythematosus affects the kidneys in approximately 50% of patients, and renal involvement significantly impacts prognosis. Lupus nephritis results from immune complex deposition, with anti-double-stranded DNA antibodies playing a central pathogenic role. Antibody levels correlate with disease activity, and rising titers often herald renal flares. Complement consumption through the classical pathway produces low C3 and C4 during active nephritis. The ISN/RPS (International Society of Nephrology/Renal Pathology Society) classification guides prognosis and treatment through six histologic classes. Class I (minimal mesangial) shows normal light microscopy with mesangial deposits on IF or EM only. Class II (mesangial proliferative) demonstrates mesangial hypercellularity. Class III (focal) involves less than 50% of glomeruli with active or chronic lesions. Class IV (diffuse) affects more than 50% of glomeruli and represents both the most common and most severe form. Class V (membranous) shows membranous nephropathy pattern and may occur alone or combined with Class III or IV. Class VI (advanced sclerosis) indicates more than 90% globally sclerosed glomeruli. Immunofluorescence in lupus nephritis classically demonstrates a "full house" pattern with IgG, IgA, IgM, C3, and C1q staining—a finding nearly pathognomonic for lupus. Treatment intensity matches histologic class. Classes I and II require only observation or low-dose steroids. Classes III and IV demand aggressive induction therapy with mycophenolate mofetil or cyclophosphamide combined with corticosteroids, followed by maintenance immunosuppression with mycophenolate or azathioprine. Class V management depends on proteinuria severity. Refractory disease may respond to rituximab, calcineurin inhibitors, or the newer agent voclosporin. Hydroxychloroquine provides benefit for all lupus patients, reducing flares and improving survival. Panel A: ISN/RPS Classes I through III showing Class I (normal LM with mesangial deposits on EM only), Class II (mesangial proliferation), and Class III (focal involvement affecting less than 50% of glomeruli with possible crescents). Panel B: ISN/RPS Classes IV through VI showing Class IV (diffuse involvement affecting more than 50% of glomeruli with severe proliferation, most common and severe), Class V (membranous pattern with thickened GBM), and Class VI (more than 90% globally sclerosed glomeruli). Panel C: Full house immunofluorescence showing five panels with IgG, IgA, IgM, C3, and C1q all positive, nearly pathognomonic for lupus. Panel D: Treatment algorithm by class showing observation for Classes I/II, aggressive induction with mycophenolate or cyclophosphamide plus steroids for III/IV, proteinuria-based management for V, supportive care for VI, with hydroxychloroquine for all lupus patients. --- ## Other Glomerular Diseases Membranoproliferative glomerulonephritis (MPGN) represents a pattern of injury rather than a single disease, characterized by mesangial proliferation with GBM thickening and duplication. On light microscopy, the duplicated GBM creates a "tram-tracking" appearance on silver stain, where new basement membrane material forms on either side of interposed cells. Modern classification distinguishes immune complex-mediated MPGN from complement-mediated MPGN (C3 glomerulopathy). Immune complex-mediated MPGN results from chronic immune complex deposition, most commonly from hepatitis C infection with or without cryoglobulinemia. Autoimmune diseases, monoclonal gammopathies, and chronic infections can also produce this pattern. C3 glomerulopathy results from uncontrolled alternative complement pathway activation due to genetic mutations or acquired factors (C3 nephritic factor autoantibody); immunofluorescence shows C3 staining without significant immunoglobulin. Alport syndrome results from mutations in genes encoding type IV collagen, which forms essential components of the GBM, lens capsule, and cochlea. X-linked inheritance (COL4A5 mutations) predominates, though autosomal recessive (COL4A3 or COL4A4) and autosomal dominant forms exist. The classic triad includes progressive nephritis, sensorineural hearing loss, and ocular abnormalities (anterior lenticonus). Renal biopsy shows progressive GBM changes, with early thinning followed by thickening, splitting, and a characteristic "basket-weave" lamellation pattern on electron microscopy. Males with X-linked disease typically reach ESRD by their 20s to 40s, while carrier females have variable expression. Thin basement membrane disease, sometimes called benign familial hematuria, presents with persistent microscopic hematuria and diffusely thin GBM (less than 250 nm) on electron microscopy. Often caused by heterozygous COL4A3 or COL4A4 mutations, the condition follows a benign course without progression to kidney failure and requires no treatment beyond reassurance. Panel A: MPGN showing light microscopy with tram-tracking pattern (duplicated GBM with interposed cells on silver stain), classified as immune complex-mediated (hepatitis C, cryoglobulinemia, monoclonal gammopathy) versus complement-mediated C3 glomerulopathy (alternative pathway dysregulation, C3 nephritic factor). Panel B: Alport syndrome showing X-linked inheritance (COL4A5 mutations), classic triad of progressive nephritis, sensorineural hearing loss, and anterior lenticonus, with males reaching ESRD by their 20s-40s. Panel C: Alport electron microscopy showing basket-weave GBM lamellation with thickening, splitting, and characteristic layered appearance. Panel D: Thin basement membrane disease showing diffusely thinned GBM (less than 250 nm versus normal 300-400 nm), persistent microscopic hematuria, benign course without progression to kidney failure, and heterozygous COL4A3 or COL4A4 mutations. --- ## Approach to Diagnosis Systematic evaluation of suspected glomerular disease begins with quantifying proteinuria and characterizing hematuria. Spot urine protein-to-creatinine ratio provides convenient estimation of 24-hour protein excretion, while 24-hour collection allows precise measurement. Urine microscopy seeking dysmorphic red blood cells (irregularly shaped from passage through damaged glomeruli) and red blood cell casts (formed in tubules from erythrocytes and Tamm-Horsfall protein) confirms glomerular origin of hematuria. Serologic evaluation guides differential diagnosis. Antinuclear antibody (ANA) and anti-double-stranded DNA screen for lupus. ANCA testing identifies vasculitis, with PR3 and MPO specificity determining subtype. Anti-GBM antibodies diagnose Goodpasture syndrome. Anti-PLA2R antibodies indicate primary membranous nephropathy. Complement levels distinguish hypocomplementemic conditions (lupus, cryoglobulinemia, post-infectious, MPGN) from normocomplementemic diseases (IgA, ANCA, anti-GBM). Hepatitis B and C serologies, HIV testing, and serum and urine protein electrophoresis complete the evaluation. Kidney biopsy provides definitive diagnosis in most glomerular diseases. Indications include unexplained nephrotic syndrome in adults (children with presumed minimal change disease may receive empiric steroids first), nephritic syndrome in most cases, RPGN urgently, and staging of systemic diseases such as lupus. The biopsy undergoes three examinations: light microscopy reveals glomerular architecture and cellularity; immunofluorescence identifies immunoglobulin, complement, and other protein deposits with their patterns (linear, granular, mesangial); and electron microscopy localizes deposits precisely and assesses podocyte ultrastructure. Complement level patterns aid diagnosis. Both C3 and C4 low suggests classical pathway activation (lupus, cryoglobulinemia). Low C3 with normal C4 indicates alternative pathway involvement (post-infectious GN, C3 glomerulopathy, atypical HUS). Normal C3 and C4 occurs in IgA nephropathy, ANCA-associated disease, anti-GBM disease, and FSGS. Panel A: Initial evaluation showing proteinuria quantification (spot UPCR or 24-hour collection) and urine microscopy identifying dysmorphic red blood cells and RBC casts to confirm glomerular origin. Panel B: Serologic workup panel organized in columns with autoantibodies (ANA, anti-dsDNA, ANCA, anti-GBM, anti-PLA2R), complement levels (C3, C4), infection serologies (HBV, HCV, HIV), and paraprotein testing (SPEP/UPEP). Panel C: Kidney biopsy with three specimen processing methods showing light microscopy for architecture, immunofluorescence for deposit patterns (linear, granular, mesangial), and electron microscopy for deposit localization and podocyte ultrastructure. Panel D: Complement interpretation table showing low C3 and C4 (classical pathway: lupus, cryoglobulinemia), low C3 with normal C4 (alternative pathway: post-infectious GN, C3 glomerulopathy), and normal C3 and C4 (IgA nephropathy, ANCA, anti-GBM, FSGS). --- ## Summary Glomerular diseases present as distinct clinical syndromes. Nephrotic syndrome features proteinuria exceeding 3.5 grams per day with hypoalbuminemia, edema, and hyperlipidemia. Nephritic syndrome manifests with hematuria (RBC casts), hypertension, azotemia, and oliguria. Many diseases show overlapping features. The primary nephrotic diseases include minimal change disease, most common in children, characterized by normal light microscopy, foot process effacement on electron microscopy, and excellent steroid responsiveness. FSGS represents the most common primary glomerular disease in US adults, showing segmental sclerosis and variable treatment response. Membranous nephropathy demonstrates the characteristic "spike and dome" GBM pattern with anti-PLA2R antibodies in primary cases and carries significant thrombosis risk. IgA nephropathy stands as the most common glomerulonephritis worldwide, presenting with episodic hematuria concurrent with upper respiratory infection and showing mesangial IgA deposits. Post-streptococcal GN follows streptococcal infection by 1-6 weeks, produces low C3 and characteristic subepithelial "humps," and carries excellent prognosis in children. RPGN represents a medical emergency with rapid GFR decline and crescents on biopsy. Type I involves anti-GBM antibodies with linear GBM staining. Type II includes immune complex diseases with granular deposits. Type III encompasses pauci-immune ANCA-associated vasculitis. Lupus nephritis is classified into six ISN/RPS classes, with Class IV the most common and severe. Kidney biopsy with light microscopy, immunofluorescence, and electron microscopy is essential for definitive diagnosis of most glomerular diseases. --- ## Key Terms | Term | Definition | |------|------------| | Nephrotic syndrome | Heavy proteinuria (>3.5g/day) with hypoalbuminemia, edema, and hyperlipidemia | | Nephritic syndrome | Hematuria with RBC casts, hypertension, azotemia, and reduced GFR | | Crescents | Cellular proliferations in Bowman's space indicating rapidly progressive disease | | Foot process effacement | Flattening and fusion of podocyte foot processes seen on electron microscopy | | Anti-GBM disease | Autoimmune disease with antibodies against glomerular basement membrane collagen | | ANCA | Antineutrophil cytoplasmic antibodies associated with pauci-immune vasculitis | | Full house pattern | Immunofluorescence showing IgG, IgA, IgM, C3, and C1q, characteristic of lupus nephritis | | Subepithelial deposits | Immune deposits located between podocytes and GBM, as in membranous nephropathy | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*