Glomerular Diseases — Comprehensive Study Notes (McGraw Hill – Chapter 326)

Glomerular Diseases — Comprehensive Study Notes

Glomerular architecture and filtration (intro to Chapter 326)

• Human kidneys contain ~1.8 million glomerular capillary tufts, each in Bowman’s space; Bowman’s capsule is lined by parietal epithelium that can transition to tubular epithelium or replenish podocytes.
• Glomerular capillary tuft derives from an afferent arteriole → glomerular capillary bed (tuft) → efferent arteriole; drained by cortical peritubular capillaries or medullary vasa recta.
• Glomerular capillaries are an arteriolar portal system; fenestrated endothelium sits on glomerular basement membrane (GBM).
• Podocyte foot processes cover capillaries; slit-pore membranes between podocyte processes form the selective filtration barrier.
• Filtration: ~$120{-}180 ext{ L/day}$ of plasma water and solutes filtered; large proteins and cells are largely excluded by size and charge.
• Albumin as example of imperfect barrier: Albumin radius ~$3.6 ext{ nm}$; GBM/slit-pore pore radius ~$4 ext{ nm}$, so some albumin crosses barrier and is reclaimed in proximal tubule via megalin and cubilin.
• Normal urinary albumin excretion averages $8{-}10 ext{ mg/day}$, representing ~20–60% of total excreted protein; after glomerular injury, albumin (and other proteins) can rise to gram quantities.
• Glomerular diseases are diverse; clinicians group them into clinical syndromes to bring order to the subject.

Pathogenesis of glomerular disease

• Multiple etiologies: genetic mutations, infection, toxins, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, diabetes mellitus.
• Sometimes etiology remains unknown (idiopathic).
• Genetic/founder mutations contribute to specific diseases:
  • Congenital nephrotic syndrome: NPHS1 (nephrin) and NPHS2 (podocin) — slit-pore membrane defects at birth.
  • TRPC6 mutations: adult focal segmental glomerulosclerosis (FSGS).
  • APOL1 variants: major risk for African Americans with non-diabetic ESKD, esp. FSGS (~70% attributed risk in this group).
  • Complement pathway mutations: MPGN variants and C3 glomerulopathies (dense deposit disease, aHUS).
  • Type IV collagen gene mutations (COL4A3, COL4A4, COL4A5) in Alport’s and related basement membrane disorders.
  • Other monogenetic causes linked to basement membrane control, collagen, podocyte structure, and glomerular injury.
• Systemic diseases can injure glomeruli via pressure, ischemia, lipid oxidants, or immune injury; diseases may present with nephritic, nephrotic, or other patterns.
• Inflammatory and autoimmune processes: glomerular epithelial or mesangial cells can express or shed epitopes that trigger immune responses; infectious agents contribute antigens; autoimmunity can be kidney-limited (primary) or part of systemic disease (secondary).
• Key immunopathogenic themes:
  • Immune deposits (circulating immune complexes) can precipitate along GBM or form in situ; complement activation (C3, C5–9) amplifies injury.
  • Local oxidants and proteases expand inflammation; TLR activation on glomerular cells can recruit mononuclear cells.
  • Adaptive immunity (CD4+/CD8+ T cells) often drives glomerulonephritis; often humoral responses accompany cellular injury.
  • Injury location determines histologic patterns: endocapillary proliferation, extracapillary (crescents), subepithelial or subendothelial immune deposits, mesangial deposits.
• Proteinuric injury exacerbates tubulointerstitial damage and fibrosis; several hypotheses link glomerular injury to downstream tubulointerstitial nephritis (e.g., inflammatory mediators in proximal tubule, filtered proteins carrying cytokines and lipoproteins).
• Fibrogenesis: chronic nephritis leads to interstitial fibroblast activation and scar (fibrosis) via mediators such as $TGF{-}\beta, ext{F}GF{-}2, ext{HIF}{-}1 ext{α}, ext{PDGF}$; fibroblasts arise from epithelial/endothelial transitions, bone-marrow-derived cells, and resident fibroblasts; scar becomes acellular if survival factors are exhausted. Reversibility is possible early (e.g., BMP7 and HGF can reverse early fibrogenesis in experiments).

Clinical manifestations: hematuria, proteinuria, pyuria

• Glomerular disease commonly presents with hematuria and variable proteinuria; hematuria is often microscopic and may be silent; gross hematuria more common in IgA nephropathy and certain other conditions.
• Suspicious microscopic hematuria: first-void urine with red blood cells in sediment; if red blood cell casts or dysmorphic RBCs are present, glomerulonephritis is likely.
• Albuminuria baseline: $8{-}10 ext{ mg/day}$ in normal individuals; early nephropathy (e.g., diabetic nephropathy) shows microalbuminuria $30{-}300 ext{ mg/day}$ or $30{-}300 ext{ mg/g}$ albumin/creatinine ratio (UACR).
• Sustained proteinuria: typically >$1{-}2 ext{ g/day}$; transient/probable benign proteinuria can occur with fever, exercise, obesity, sleep apnea, emotional stress, or orthostatic proteinuria.
• Nephrotic-range proteinuria: >$3.0 ext{ g/day}$; often with edema, hypoalbuminemia, hyperlipidemia, and sometimes hypertension.
• Proteinuric pattern differences by age: children with minimal change disease (MCD) have selective proteinuria (mostly albumin); adults with glomerular disease typically have nonselective proteinuria (albumin plus multiple serum proteins).
• Disease patterns by syndrome (Table 326-2 patterns of glomerular syndromes): various combinations of proteinuria, hematuria, vascular injury; these are bedside diagnoses guiding workup and management.
• Lab and imaging workup boundary: bedside history/physical, serum studies (HIV, HBV, HCV antigens/antibodies; ASO, anti-DNase, anti-DNase B; antiphospholipid antibodies; ANCA; anti-GBM antibodies; PLA2R/THSD7A/DNAJB9 etc.), complement levels (C3, C4), nephritic/nephrotic panels, and kidney ultrasound.

Diagnosis approach to glomerular disease (clinical workflow)

• Six bedside categories guide initial thinking: infectious, systemic autoimmune, nephritic syndromes, nephrotic syndromes, basement membrane syndromes, and glomerular vascular syndromes.
• Initial testing helps determine primary (isolated kidney) vs secondary (systemic disease) glomerulonephritis; confirm with serologies and complement studies; consider kidney biopsy in selected stable patients to guide treatment.
• Acute vs chronic presentation considerations depend on history, ultrasound kidney size (often smaller in chronic disease), and symptom burden.
• Kidney biopsy is used when diagnosis will alter management; it involves:
  • Light microscopy with stains: H&E, PAS, Jones–silver, Congo red, Masson’s trichrome.
  • Immunofluorescence for IgG, IgM, IgA, C3, C4 and antigens (e.g., PLA2R, THSD7A, DNAJB9).
  • Electron microscopy to localize immune deposits and assess GBM status.
• Biopsy yield: ideally ~20 glomeruli; classification by focal (
• Other biopsy findings: background sclerosis with aging; vascular lesions; tubulointerstitial changes; interstitial fibrosis portends irreversible damage.
• Lupus nephritis and ANCA-associated vasculitides require integration of histology with serology to guide therapy; repeat biopsy may be needed to reassess activity and chronicity.

Acute nephritic syndromes and classic patterns

• Acute nephritic syndrome: 1–2 g/day proteinuria, hematuria with red blood cell casts, pyuria, hypertension, edema, rising creatinine (GFR fall).
• RPGN (crescentic GN): rapid decline in kidney function with crescents on biopsy; may accompany Goodpasture syndrome, ANCA-associated vasculitis, lupus nephritis, cryoglobulinemia.
• Pulmonary–renal syndromes: Goodpasture (anti-GBM) with lung hemorrhage; ANCA-associated vasculitis or lupus can cause pulmonary hemorrhage with RPGN.

Poststreptococcal glomerulonephritis (PSGN)

• Prototypical acute endocapillary proliferative GN; classically follows pharyngitis or skin infection by nephritogenic streptococci (M types).
• Pathogenesis: immune-mediated with circulating immune complexes; alternate complement pathway activation; nephritogenic antigens SPEB (streptococcal pyrogenic exotoxin B) and NAPlr (nephritis-associated plasmin receptor).
• Biopsy: hypercellular mesangial and endothelial cells; leukocyte infiltration; granular subendothelial IgG/IgM/C3/C4/C5–9; subepithelial “humps.”
• Clinical: abrupt nephritic presentation; headache, malaise, flank pain; 5% children and 20% adults have nephrotic-range proteinuria; depressed CH50 and low C3 with normal C4 in first week.
• Diagnosis is often clinical; biopsy rarely needed unless uncertain or atypical course.
• Treatment: supportive care (hypertension, edema); dialysis as needed; treat active streptococcal infection in contacts; no role for immunosuppression; prognosis favorable in children; elderly have worse prognosis; most children recover within 3–6 weeks; some have persistent microscopic hematuria or hypertension; progression to ESKD is uncommon but higher in elderly.

Subacute bacterial endocarditis (SBE)–associated GN

• GN occurs in a subset of endocarditis due to circulating immune complexes and complement activation.
• Presentation: proteinuria, microscopic hematuria, mild proteinuria; RPGN with crescents can occur; often subcapsular hemorrhages or “flea-bitten” kidneys described grossly.
• Biopsy: MPGN, DP GN, mesangioproliferative GN; immune deposits with C3 largely and IgG/IgA; may see crescents.
• Treatment: urgent infection control with antibiotics; sometimes treat as endocarditis with prolonged antibiotics; ANCA-associated vasculitis may coexist and must be ruled out; prognosis guarded depending on infection control and renal recovery.

Lupus nephritis (systemic lupus erythematosus, SLE)

• Lupus nephritis is a common, serious complication; kidney disease present in ~30% at diagnosis; most develop abnormalities during disease course.
• Pathogenesis: immune complexes (DNA/anti-DNA) activate complement; in-situ immune complex formation; various patterns of immune deposition in mesangium, subendothelial, and/or subepithelial spaces.
• Clinical features: proteinuria is most common; hematuria, hypertension, active urinary sediment, and varying degrees of kidney injury; low complements common during flares (C3, C4).
• WHO/ISN classification (Tables 326-3): six classes with different patterns and prognoses.
  • Class I: Minimal mesangial nephritis — essentially normal light microscopy; minimal mesangial deposits on IF/EM; good prognosis; minimal therapy.
  • Class II: Mesangial proliferative nephritis — mesangial hypercellularity; generally good prognosis without heavy treatment.
  • Class III: Focal nephritis — <50% glomeruli involved; endocapillary proliferation; mild mesangial expansion; variable prognosis.
  • Class IV: Diffuse nephritis — >50% glomeruli involved; diffuse endocapillary and/or extracapillary proliferation; crescents may be present; often associated with high anti-DNA, low complements; nephrotic-range proteinuria in ~50%; crescents correlate with RAPID progression if untreated.
  • Class V: Membranous nephritis — thickened GBM with diffuse subepithelial immune deposits; may occur with Class III/IV (mixed proliferative and membranous); nephrotic syndrome common; risk of renal vein thrombosis and other thrombotic events; prognosis variable; management may combine steroids with immunosuppressants; RAAS blockade and possibly SGLT2 inhibitors to reduce proteinuria.
  • Class VI: Sclerotic nephritis — >90% global sclerosis; poor prognosis; high risk of ESRD.
• Treatment strategies depend on class; remission induction for Class III/IV typically with high-dose steroids plus cytotoxic agents (cyclophosphamide) or mycophenolate mofetil; maintenance therapy with steroids and mycophenolate or azathioprine; tacrolimus, cyclosporine, or rituximab may be used in selected cases; belimumab addition in maintenance has some utility; rituximab or other agents considered in refractory cases; ACE inhibitors/ARBs to reduce proteinuria; cautious RAAS inhibition in nephrotic proteinuria; antiphospholipid antibodies may complicate disease with microthromboses.
• For Class V: nephrotic-range proteinuria management similar to membranous nephropathy; treatment tailored to nephrotic syndrome severity and renal function; many patients progress to nephrotic syndrome requiring aggressive management.
• Prognosis: variable by class; progression to ESRD more likely with Class III/IV if untreated; maintenance strategies aim for remission with fewer flares; some patients transform between classes on follow-up kidney biopsies.

Antiglomerular basement membrane disease (Goodpasture's syndrome)

• Autoantibodies directed against α3 NC1 domain of type IV collagen in GBM; can also involve lungs (pulmonary hemorrhage).
• Pathogenesis: autoantibodies target conformational epitopes exposed by infection, smoking, oxidants; disease is a quiescent conformeropathy.
• Presentation: lung hemorrhage with hemoptysis and RPGN; older patients may present with isolated glomerulonephritis; younger patients with Goodpasture's syndrome present with both kidney disease and lung hemorrhage.
• Biopsy: focal or segmental necrosis progressing to crescents; interstitial nephritis and fibrosis with time.
• Immunofluorescence: linear IgG (often with C3) deposition along GBM; ELISA-based anti-GBM testing targets α3 NC1 specifically.
• Prognosis: worse with >50% crescents, high creatinine (>5–6 mg/dL), oliguria, or need for dialysis.
• Therapy: plasmapheresis to remove circulating antibodies; steroids and cyclophosphamide to suppress production; maintenance immunosuppression until antibodies negative; kidney transplantation after seronegativity for ~6 months; rituximab or mycophenolate mofetil as alternatives in some cases.

IgA nephropathy (Berger disease)

• Classic pattern: episodic hematuria with IgA deposition in mesangium; most common glomerulonephritis worldwide; male predominance; peak in 2nd–3rd decades; geographic variation in prevalence.
• Pathogenesis: dominant or codominant mesangial IgA deposits (IgA1 with J-chain); deposition often IgA-dominant with or without IgG/IgM or C3; abnormal hinge-region O-glycosylation of IgA1 leads to galactose-deficient IgA1, promoting immune complex formation via anti-IgA antibodies; exposure to viral/antigen triggers or genetic complement abnormalities influence phenotype.
• Biopsy findings: mesangial IgA-dominant deposits; light microscopy can show various patterns including DP GN; Oxford MEST-C scoring (M: mesangial hypercellularity; E: endocapillary hypercellularity; S: segmental sclerosis; T: tubular-interstitial fibrosis; C: crescents).
• Clinical presentation: persistent asymptomatic microscopic hematuria or recurrent macroscopic hematuria after URIs; proteinuria may be present; nephrotic syndrome is uncommon; progression to CKD occurs in a minority; ~25–30% progress to ESRD over 20–25 years depending on population and risk factors.
• Risk factors for worse outcomes: persistent proteinuria, hypertension, older age at onset, male sex, lack of macroscopic hematuria.
• Prognosis and scoring: MEST-C score helps predict outcomes; IgA nephropathy shows heterogeneity; some patients remit, others progress to CKD.
• Treatment (no universal consensus): ACE inhibitors/ARBs for proteinuric or declining GFR; steroids/immunosuppressives show mixed results; targeted-release budesonide shows promise in reducing proteinuria and preserving kidney function in high-risk patients; SGLT2 inhibitors and endothelin receptor antagonists (sparsentan) show potential in reducing kidney outcomes; tonsillectomy and certain supplements have been explored in small studies.

ANCA-associated vasculitis and small-vessel vasculitides

• Group of diseases with circulating ANCA (PR3-ANCA and MPO-ANCA) causing pauci-immune GN (little or no immune deposits).
• Classic diseases: Granulomatosis with polyangiitis (GPA, Wegener’s), Microscopic polyangiitis (MPA), Eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss), and renal-limited vasculitis.
• Serologies help guide management; targeted ANCA testing is useful for monitoring and relapse prediction.
• Induction therapy typically: glucocorticoids + cyclophosphamide or rituximab; plasmapheresis may be used in rapidly progressive disease or with pulmonary hemorrhage or anti-GBM overlap.
• Remission achieved in ~75–90%; relapse common (25–50%); consider reduced-dose steroid regimens to minimize adverse effects.
• Maintenance therapy usually 1–2 years post-remission; agents include cyclophosphamide or rituximab; in some cases azathioprine or methotrexate.

Granulomatosis with polyangiitis (GPA) specifics

• Presentation: fever, purulent nasal discharge, sinusitis, cough, hemoptysis; hematuria and subnephrotic proteinuria common; chest imaging may show nodules or infiltrates; tissue biopsy reveals small-vessel vasculitis with noncaseating granulomas.
• Risk factors: silica exposure, α1-antitrypsin deficiency.
• Relapse common; follow-up essential; therapy-related adverse events prominent, particularly in elderly during the first year.

Microscopic polyangiitis (MPA)

• Clinically similar to GPA but without granulomas; biopsy shows pauci-immune GN.

Eosinophilic granulomatosis with polyangiitis (EGPA)

• Features: eosinophilia, asthma, allergic manifestations, eosinophilic infiltrates; kidney involvement can be pauci-immune GN or focal segmental GN without eosinophils/granulomas in some cases.

C3 glomerulopathies and MPGN patterns

• C3 glomerulopathy defined by predominant C3 deposition with little or no immunoglobulin; includes dense deposit disease (DDD, formerly MPGN type II) and C3 glomerulonephritis (C3GN).
• DDD: ribbon-like dense deposits along GBM; typically pediatric/young adults; associated with CFHR gene mutations affecting complement regulation; low C3 with normal C4; prognosis often poor with ~50% progression to ESRD.
• C3GN: variable light microscopy patterns; low C3 with normal C4; C3 nephritic factor present in many but not all cases; genetic testing for CFHR mutations and complement pathway abnormalities recommended.
• Therapies: RAAS blockade, lipid-lowering strategies; immunosuppressants with variable benefit; eculizumab (C5 inhibitor) may help in some cases; treatment remains individualized.

Membranoproliferative pattern of glomerulonephritis (MPGN) and related patterns

• MPGN is a pattern of injury characterized by mesangial/endothelial immune complexes, C3 and C4 deposition, or monoclonal deposits; basement membrane duplication (“tram-tracking”) is a hallmark.
• Patterns overlap with cryoglobulinemia, hepatitis B/C–related GN, and paraneoplastic processes; management targets underlying disease and proteinuria.
• Mesangioproliferative GN: expansion of the mesangium with mesangial deposits; seen in IgA nephropathy, malaria, lupus class II, and postinfectious GN; primary mesangioproliferative GN is rare (<15%).

Nephrotic syndrome and its major glomerular diseases

• Nephrotic syndrome defined by heavy proteinuria, hypoalbuminemia, hyperlipidemia, edema; may accompany hypertension. Edema reflects salt/water retention; hypoalbuminemia reduces capillary oncotic pressure; hyperlipidemia is a secondary response.

• General approach: treat edema and hyperlipidemia; RAAS inhibitors and SGLT2 inhibitors to reduce proteinuria; assess thrombotic risk and consider anticoagulation in nephrotic-range proteinuria.

• Minimal change disease (MCD): most common nephrotic syndrome in children; in adults, still a major cause though less frequent; light microscopy normal; immunofluorescence negative; electron microscopy shows effacement of foot processes; pathogenesis likely immune-mediated (T-cell dysfunction, permeability factors such as IL-13/IL-4, CD80 on podocytes).

  • Clinical course: abrupt edema and nephrotic-range proteinuria; selective proteinuria (predominantly albumin) in children; most children respond rapidly to steroids (prednisone) with complete remission; adults respond less consistently; relapse common in children; steroid resistance in a subset.
  • Variants and outcomes: relapses common in children; progression to chronic kidney disease is uncommon; treatment often starts with steroids; calcineurin inhibitors and rituximab reserved for resistant relapses.

• Focal segmental glomerulosclerosis (FSGS): pattern of injury with segmental scarring; can be primary or secondary; most common cause of primary glomerular disease leading to ESRD in the US.

  • Pathogenesis: multiple potential mechanisms—circulating permeability factor (primary FSGS), adaptive hyperfiltration/hypertrophy, podocyte injury from toxins or genetic mutations; APOL1 risk variants increase susceptibility, especially in people of African descent.
  • Variants: NOS (not otherwise specified) FSGS; collapsing variant; perihilar lesion; tip lesion (usually steroid-responsive); cellular variants with endocapillary hypercellularity.
  • Clinical features: proteinuria (often nephrotic-range with advanced disease), hematuria, hypertension, kidney injury.
  • Treatment: RAAS blockade and SGLT2 inhibitors; steroids may help in primary FSGS with nephrotic-range proteinuria but responses are less favorable than MCD; cyclosporine or other CNIs can induce remission in selected steroid-responsive patients but relapse is common after withdrawal; rituximab/mycophenolate data limited; recurrence after transplantation occurs in ~30%, higher in primary FSGS and can respond to plasmapheresis.
  • Secondary/Genetic FSGS: treat underlying cause; steroids often not effective.

• Membranous glomerulonephritis (MGN/MGN or membranous nephropathy)

  • Primary (antigen-associated) vs secondary membranous nephropathy: major antigens include PLA2R (dominant in ~70–80% of primary cases), THSD7A, NELL1, and others; newer antigens (Sema3B, PCDH7, EXT1/EXT2, NCAM1) explain a subset of primary MGN; secondary MGN linked to infections (HBV, HCV, syphilis, malaria, schistosomiasis), cancers (breast, colon, lung, kidney, esophagus, neuroblastoma), drugs and autoimmune diseases (SLE, RA, IgG4-related disease), and other systemic conditions.
  • Pathology: diffuse uniform GBM thickening with subepithelial deposits; silver stain may reveal spikes; IF shows diffuse granular IgG and C3; EM shows subepithelial electron-dense deposits; 70–80% primary MGNs have IgG4 class against PLA2R; THSD7A and other antigens contribute to remaining cases; in secondary MGN, antibodies to these antigens are often absent.
  • Diagnosis and management: anti-PLA2R positivity can reduce the need for biopsy in classic cases with normal creatinine and no other causes; in others, kidney biopsy remains standard.
  • Prognosis and therapy: 80% present with nephrotic syndrome; spontaneous remissions occur in 20–33%, often late; relapses common; absence of severe hypoalbuminemia portends better prognosis; initial management focuses on RAAS blockade, statins for hyperlipidemia; immunosuppressive therapy (steroids ± cyclophosphamide, CNIs, or rituximab) for persistent nephrotic-range proteinuria; risk stratification using proteinuria, GFR, albumin guides management; anticoagulation considerations for thrombotic risk due to nephrotic syndrome; PLA2R/THSD7A serology can guide prognosis and monitoring of therapy response.

• Diabetic nephropathy (DN)

  • Leading cause of CKD worldwide; progression tied to hyperglycemia effects on GBM, mesangial expansion, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and vascular changes (hyaline arteriolosclerosis).
  • Pathology: GBM thickening with loss of heparan sulfate and loss of negative charge; mesangial expansion and nodular sclerosis; occasionally linear IgG staining; arteriolar hyalinosis and chronic interstitial changes.
  • Mechanisms: hyperglycemia activates RAAS and growth factors; SGLT2 upregulation reduces distal Na delivery, promoting glomerular hyperfiltration; sustained hyperfiltration and hypertension drive matrix production and GBM changes; advanced glycation end-products (AGEs) contribute; dyslipidemia also contributes.
  • Clinical course: progression from hyperfiltration to albuminuria to declining GFR and ESRD; albuminuria is a strong predictor of kidney and cardiovascular outcomes; regression of albuminuria with therapy predicts better prognosis; normoalbuminuric CKD is seen in a substantial minority, especially with type 2 diabetes.
  • Treatment: glycemic and blood pressure control; RAAS blockade; SGLT2 inhibitors preserve GFR and reduce albuminuria; finerenone (nonsteroidal MR antagonist) adds vascular/kidney benefits in diabetics with nephropathy on ACEi/ARB; statins for ASCVD risk reduction; kidney transplantation outcomes comparable to other ESRD etiologies; early intensive therapy in type 1 diabetes prevents nephropathy.
  • Microalbuminuria monitoring: type 1 diabetes screening starts 5 years after diagnosis and annually; type 2 diabetes testing at diagnosis and annually thereafter.

• Glomerular deposition diseases

  • Light chain deposition disease (LCDD): nephrotoxic monoclonal light chains (usually κ) deposit along GBM and tubular basement membranes; casts (cast nephropathy) and LCDD differ by presence of heavy proteinuria; Congo red negative; associated with plasma cell dyscrasias (myeloma, Waldenström, lymphoma); prognosis often poor with 70% progressing to dialysis; treatment targets underlying plasma cell dyscrasia.
  • Heavy chain deposition disease (HCDD) and light+heavy chain deposition disease (LHCDD): similar to LCDD; treated by addressing the plasma cell clone.
  • Monoclonal gammopathy of renal significance (MGRS): monoclonal immunoglobulin produced by nonmalignant or premalignant clones depositing in kidney; treatment is disease-specific (chemotherapy in selected patients).
  • Renal amyloidosis
  • AL (primary) amyloidosis: light-chain–derived amyloid; systemic involvement; nephrotic-range proteinuria common; 10% have overt myeloma; prognosis variable; treatment includes melphalan and autologous stem cell transplantation; bortezomib-based regimens when not a transplant candidate.
  • AA (secondary) amyloidosis: due to serum amyloid A protein; linked to chronic inflammation/infections; nephrotic-range proteinuria common; progression to ESRD occurs in ~40–60%; treatment focuses on controlling the underlying inflammatory state; newer anti-amyloid therapies under development.
  • Fibrillary and immunotactoid glomerulopathies: rare non-amyloid glomerulopathies with non-branching fibrils (fibrillary: 12–24 nm; immunotactoid: 16–52 nm organized as microtubules); Congo red negative; DNAJB9 (in fibrillary GN) aids diagnosis; associated with monoclonal gammopathy or autoimmune diseases; treatment not standardized; rituximab reported to reduce proteinuria; often progressive; may recur post-transplant.
  • Fabry disease: X-linked lysosomal storage disease due to α-galactosidase A deficiency; glycolipid accumulation in renal, cardiac, nervous systems; kidney biopsy shows zebra bodies; presents with proteinuria, sometimes edema and hematuria; nodular glomerulosclerosis; treatment includes enzyme replacement therapy or chaperone therapy; RAAS blockade recommended; kidney transplantation viable if ESRD occurs.

Pulmonary–renal syndromes and infectious disease associations

• Catastrophic hemoptysis with glomerulonephritis seen in Goodpasture’s syndrome, GPA, MPA, EGPA, Henoch–Schönlein purpura, cryoglobulinemia.
• COVID-19 can trigger various glomerular diseases; COVAN (COVID-19–associated nephropathy) often presents as collapsing FSGS; other glomerulopathies have been reported; treatment guided by infection status and kidney disease severity; limited data on immunosuppression during infection.
• HIV-associated nephropathy (HIVAN): HIVAN typically presents as FSGS with collapsing glomerulopathy; associated with APOL1 risk variants; HIV immune complex disease (HIVICK) can mimic multiple GN patterns; RAAS blockade beneficial; ART improves survival and kidney outcomes; transplantation viable in virially suppressed patients.
• HBV/HCV–related GN: HBV commonly associated with MPGN and IgA nephropathy variants; HCV commonly associated with cryoglobulinemic GN, MPGN; antiviral therapy improves outcomes; direct-acting antivirals (DAAs) have transformed HCV-related GN prognosis.
• Malaria and schistosomiasis can cause nephritic/nephrotic syndromes; malaria (P. falciparum) often causes subendothelial deposits and mesangial GN; schistosomiasis can present with GN patterns ranging from mesangioproliferative GN to MPGN to amyloidosis; treatment of infection improves kidney disease.
• Leprosy and chronic infections can also involve the kidney via various GN patterns; treatment of infection reduces progression of renal disease.

Glomerular vascular and basement membrane disorders

• Basement membrane disorders (collagen IV family): mutations cause Alport’s syndrome or TBMD; differs by inheritance (X-linked COL4A5; autosomal COL4A3/COL4A4; often TBMD autosomal dominant); Alport’s involves hematuria, evolving proteinuria, progressive CKD, sensorineural deafness, ocular abnormalities; characteristic GBM splitting and thinning early in disease; eye and ear findings important for diagnosis; genetic testing essential for confirmation and inheritance risk assessment.
• Thin basement membrane disease (TBMD): persistent microscopic hematuria, benign course; autosomal dominant; GBM thinning; generally no proteinuria or kidney dysfunction; can be associated with COL4A3/COL4A4 variants.
• Nail-patella syndrome (LIM homeodomain transcription factor LMX1B): nephropathy with nail and skeletal abnormalities; GBM abnormalities; risk of FSGS; treatment tailored to proteinuria and hypertension; transplantation feasible if ESRD occurs.
• Glomerular vascular syndromes: nephrosclerosis and related vascular disease contribute to chronic kidney disease.
  • Atherosclerotic nephropathy: chronic ischemic changes in kidney from systemic atherosclerosis; treat cardiovascular risk factors; RAAS blockade helps.
  • Hypertensive nephrosclerosis: hypertension-driven kidney injury; ARB/ACE inhibitors are foundational; aggressive BP control reduces progression; APOL1 risk variants worsen risk in African descent populations.
  • Cholesterol emboli: showering cholesterol crystals from atherosclerotic plaques after vascular procedures or spontaneously; causes renal microvascular ischemia; no reverse therapy; manage BP and lipids; tissue biopsy can show cholesterol clefts.
  • Sickle cell disease (SCD) nephropathy: common in affected individuals; hyperfiltration early; micro/macrohematuria; concentrating defects (hyposthenuria); progression to proteinuria, CKD, ESRD; treatment includes hydroxyurea, ACE inhibitors/ARBs, blood pressure control; transplantation outcomes acceptable with good graft survival.
• Thrombotic microangiopathies (TMAs)
  • Primary TMAs: TTP (ADAMTS13 deficiency or antibodies) and Shiga toxin–mediated HUS; complement-mediated HUS (atypical HUS) caused by dysregulation of the alternative pathway.
  • Secondary TMAs: pregnancy-related (preeclampsia/HELLP), malignant hypertension, drugs (CNIs, estrogens, cocaine), infections (HIV, CMV), autoimmune diseases (lupus), etc.
  • Pathology: glomerular capillary endotheliosis, platelet thrombi, fibrin deposition; biopsy helps differentiate TTP vs HUS vs secondary TMAs.
  • Treatment:
  • TTP: urgent plasmapheresis with FFP; caplacizumab (anti-VWF) may be added in relapsed/refractory cases; steroids and rituximab as adjuncts.
  • Shiga-toxin HUS: supportive care; antibiotics may worsen toxin release and are generally avoided.
  • Complement-mediated HUS: eculizumab or ravulizumab (C5 inhibitors).

Special glomerular diseases and therapeutic implications

• HIV, HBV, HCV–related GN management emphasizes antiviral therapy; DAAs for HCV reduce GN burden; RAAS blockade and SGLT2 inhibitors reduce progression; in HIVAN, ART improves renal outcomes.
• Fabry disease: enzyme replacement therapy or chaperone therapy; RAAS blockade reduces proteinuria; kidney transplantation feasible; disease manifestations may respond variably to therapy due to antibodies or uptake differences.
• Amyloidoses: AL and AA amyloidosis have distinct systemic manifestations but similar kidney involvement; prognosis and management depend on underlying disease control and anti-amyloid therapies; autologous stem cell transplantation can yield remission in selected AL patients.
• Fibrillary and immunotactoid GN: rare non-amyloid glomerulopathies; diagnosis aided by DNAJB9 marker (fibrillary GN); rituximab may reduce proteinuria in some cases.
• Diabetic nephropathy management reiterates early and aggressive control of glucose and BP; SGLT2 inhibitors and RAAS blockade slow progression; RAAS blockade especially important in early microalbuminuria to reduce progression; lipid control and kidney replacement therapy planning as disease advances.

Practical considerations and prognosis

• Early tubulointerstitial changes are a key determinant of prognosis; tubulointerstitial nephritis on biopsy correlates better with progression to kidney failure than glomerular lesion type alone.
• Proteinuria tends to be nephrotoxic and drives tubulointerstitial injury; reducing proteinuria improves prognosis across glomerular diseases when possible.
• APOL1 risk variants influence FSGS risk and progression in African ancestry populations; genetic testing informs prognosis and family counseling.
• Kidney biopsy remains central to distinguishing glomerular diseases when clinical features are ambiguous or when therapeutic decisions hinge on precise histologic class.
• Transplant considerations vary by disease: certain diseases recur post-transplant (e.g., FSGS, MGN with antibodies to podocyte antigens) but many patients achieve good graft survival with appropriate therapy.
• The landscape of therapy is evolving: targeted biologics (rituximab, abatacept, eculizumab), SGLT2 inhibitors, nonsteroidal MR antagonists, and complement inhibitors are increasingly integrated into care for selected patients.

Quick reference values and concepts (high-yield)

• Glomerular filtration filtration capacity: approx. $120{-}180 ext{ L/day}$ of plasma filtered.
• Albumin size barrier nuance: albumin radius ~$3.6 ext{ nm}$ vs GBM/slit-pore radius ~$4 ext{ nm}$; explains albumin leakage and proximal tubule reclamation.
• Normal urinary albumin: $8{-}10 ext{ mg/day}$; 8–10 mg/day represents non-disease baseline and ~20–60% of total urinary protein.
• Microalbuminuria in diabetes screening: $30{-}300 ext{ mg/day}$ or $30{-}300 ext{ mg/g}$; sustained >$300 ext{ mg/day}$ defines frank proteinuria.
• Nephrotic-range proteinuria: >$3.0 ext{ g/day}$.
• RPGN/Crescentic GN: crescents on biopsy signify severe proliferative injury and often rapid decline in function.
• Oxford MEST-C scoring for IgA nephropathy: M (mesangial), E (endocapillary), S (segmental sclerosis), T (tubulointerstitial fibrosis), C (crescents).
• Lupus nephritis classes I–VI provide a framework for prognosis/treatment: Class III/IV proliferative lesions require aggressive immunosuppression; Class V membranous lesions often require therapy balancing nephrotic risk with systemic lupus activity.
• Key therapeutic pillars across diseases: manage proteinuria with RAAS blockade and SGLT2 inhibitors; control BP; immunosuppression (steroids, cyclophosphamide, mycophenolate mofetil, rituximab) in selected diseases; plasmapheresis for RPGN or anti-GBM; targeted therapies (eculizumab, voclosporin) in select settings; treat underlying infections in infection-associated GN.
• Important genetic and pathobiologic concepts: APOL1 risk variants; GBM composition and basement membrane switching (α3α4α5(IV) network) in Alport and related disorders; GBM thinning in TBMD; slit-pore biology in MCD; immune-complex deposition patterns define many GN phenotypes.

Summary: connections, implications, and exam-ready takeaways

• The glomerulus is a highly specialized filtration unit where structure and charge selectivity determine which molecules pass into urine; even a seemingly simple property like albumin filtration depends on size, charge, and the integrity of GBM and slit diaphragms.
• Glomerular diseases arise from a spectrum of etiologies (genetic, immune, infectious, metabolic) that converge on common downstream pathways: immune activation, complement deposition, cytokine signaling, and fibrogenesis; despite diverse triggers, many diseases share overlapping histologic patterns and respond to similar therapeutic principles when guided by histology and serology.
• Diagnosis integrates clinical syndrome (nephritic vs nephrotic vs mixed), serology (complement levels, ANCA, anti-GBM, PLA2R etc.), imaging, and kidney biopsy with light/IF/EM to tailor therapy and prognosis.
• Management is disease-specific but centers on reducing proteinuria, controlling blood pressure, and mitigating fibrosis; newer therapies targeting specific pathways (complement, podocyte antigens, immune cells) are increasingly used, offering improved outcomes for select patients.
• A practical approach to a patient with suspected glomerulonephritis includes: assess for acute vs chronic presentation, evaluate hematuria/proteinuria, check renal function, screen for systemic disease and infections, and consider biopsy when results will influence therapy or prognosis.
• Ethical and practical implications include balancing immunosuppression risks (infection, malignancy) against disease activity, individualizing therapy based on histology and serology, and recognizing the potential genetic contributors to disease progression and treatment response (e.g., APOL1, COL4A mutations).