Glomerular Diseases¶
Chapter 326 | Harrison's 22e · Part 9 – Renal & Urinary Tract Disorders · Chapter 326
Key Clinical Points¶
- The glomerular filtration barrier consists of three layers: fenestrated endothelium, glomerular basement membrane (GBM), and podocyte foot processes.
- Albumin is a large protein (radius 3.6 nm) that occasionally crosses the barrier because pores in the GBM and slit-pore membranes have a larger radius (4 nm).
- Nephritic syndromes are characterized by proteinuria (+/++), hematuria (++/+++), and no vascular injury (-).
- Nephrotic syndromes are characterized by heavy proteinuria (+++), minimal hematuria (+), and no vascular injury (-).
- Post-streptococcal glomerulonephritis (PSGN) is identified by subendothelial deposits and pathognomonic 'humps' on the GBM surface.
- Thrombotic microangiopathies (TMA) can be primary (TTP, Shiga-toxin HUS, Complement-mediated HUS) or secondary (pregnancy-related, drug-induced, etc.).
- Membranous glomerulonephritis (MGN) has a wide range of causes including primary (autoimmune/antigen-associated) and secondary (infection, cancer, drugs).
- Focal segmental glomerulosclerosis (FSGS) can be primary (genetic mutations like NPHS1, NPHS2) or secondary (hyperfiltration, drugs, infections).
CLINICAL CONTEXT: TRANSPLANT COMPLICATIONS¶
• Hypertension: ◦ Common in transplant patients due to (1) native kidney disease, (2) rejection activity, (3) renal artery stenosis, or (4) CNI toxicity. ◦ Management goal: 120–130/70–80 mmHg. ◦ Treatment: Calcium channel blockers shown to improve long-term mortality. • Hypercalcemia: ◦ Indicates failure of hyperplastic parathyroid glands to regress. ◦ Risk: Aseptic necrosis of the head of the femur (often due to preexisting hyperparathyroidism exacerbated by glucocorticoid treatment). • Anemias: ◦ Common in post-transplant period due to bone marrow-suppressant medications such as azathioprine, mycophenolic acid, and mTOR inhibitors. ◦ Gastrointestinal bleeding is a common side effect of high-dose and long-term steroid administration. ◦ Management: Patients with GFR 30–50 mL/min → consider supplementation of erythropoietin. • Infection: ◦ Hepatitis B and C are concerns; however, the introduction of direct-acting antiviral medications has significantly reduced this risk.
DEFINITION & CLASSIFICATION¶
• Glomerular Filtration Barrier: ◦ Composed of three layers: fenestrated endothelial cells, glomerular basement membrane (GBM), and podocyte foot processes. ◦ Function: Filters 120–180 L/d of plasma water while excluding most large proteins and cells based on a physicochemical barrier governed by pore size and negative electrostatic charge. • Albumin Filtration: ◦ Albumin has a radius of 3.6 nm; however, pores in the GBM and slit-pore membranes have a radius of 4 nm. ◦ Result: Variable amounts of albumin cross the barrier and are reclaimed by megalin and cubilin receptors along the proximal tubule. ◦ Normal excretion: 8–10 mg/day (approximately 20–60% of total excreted protein). ◦ Pathological state: Levels can rise to gram quantities following glomerular injury. • Glomerular Anatomy: ◦ Two human kidneys harbor nearly 1.8 million glomerular capillary tufts.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Pathogenesis Mechanisms: ◦ Genetic mutations (e.g., NPHS1, NPHS2). ◦ Infection, toxin exposure, autoimmunity. ◦ Atherosclerosis, hypertension, emboli, thrombosis. ◦ Idiopathic: Cases where the specific cause remains unknown. • Genetic Factors: ◦ Congenital nephrotic syndrome (mutations in NPHS1/nephrin and NPHS2/podocin). ◦ APOL1 mutations: Risk factor for nearly 70% of African Americans with non-diabetic end-stage kidney disease (ESKD), particularly FSGS.
CLINICAL FEATURES¶
• Nephritic vs. Nephrotic Syndromes (Table 326-2): ◦ Nephritic Syndromes: Characterized by proteinuria (+/++), hematuria (++/+++), and no vascular injury (-). ◦ Nephrotic Syndromes: Characterized by heavy proteinuria (+++), minimal hematuria (+), and no vascular injury (-). • Vascular Injury Indicators: ◦ Significant vascular injury (++++) is associated with conditions such as ANCA small-vessel vasculitis (Granulomatosis with polyangiitis, Microscopic polyangiitis, Churg-Strauss syndrome), Henoch-Schönlein purpura, and Cryoglobulinemia. ◦ Other conditions like IgA nephropathy or Anti-GBM disease do not typically present with significant vascular injury (-).
DIAGNOSTIC APPROACH¶
- Urinary Protein Assessment (Table 326-1): ◦ Normal: 8–10 mg/24h albumin; <30 mg/g albumin/creatinine ratio; Dipstick: -. ◦ Microalbuminuria: 30–300 mg/24h albumin; 30–300 mg/g albumin/creatinine ratio; Dipstick: -/Trace/1+. ◦ Proteinuria: >300 mg/24h albumin; >300 mg/g albumin/creatinine ratio; Dipstick: Trace–3+.
- Clinical Syndrome Identification (Table 326-2): ◦ Categorize based on proteinuria, hematuria, and presence of vascular injury to distinguish between Nephritic, Nephrotic, and Vascular syndromes.
MANAGEMENT & TREATMENT¶
- Hypertension Management: ◦ Target: 120–130/70–80 mmHg. ◦ Intervention: Calcium channel blockers shown to improve long-term mortality.
- Anemia Management: ◦ Criteria: GFR 30–50 mL/min → consider erythropoietin supplementation.
KEY PEARLS & HIGH-YIELD POINTS¶
• Lupus Nephritis Classification (Table 326-3): ◦ Class I: Minimal mesangial; Normal histology with mesangial deposits. ◦ Class II: Mesangial; Mesangial hypercellularity with expansion of the mesangial matrix. ◦ Class III: Focal nephritis; Focal endocapillary ± extracapillary hypercellularity with focal subendothelial immune deposits and mild mesangial expansion ± fibrinoid necrosis. ◦ Diffuse nephritis: Diffuse endocapillary ± extracapillary hypercellularity with diffuse subendothelial immune deposits and mesangial alterations ± crescents ± fibrinoid necrosis. ◦ Class V: Membranous nephritis; Thicked basement membranes with diffuse subepithelial immune deposits (may occur with class III or IV lesions). ◦ Sclerotic nephritis: Global sclerosis of nearly all glomerular capillaries. • Focal Segmental Glomerulosclerosis (Table 326-4): ◦ Primary causes: Genetic mutations (NPHS1, NPHS2, PLCE1, INF2, WT1, TRPC6, ACTN4), α-Galactosidase A deficiency (Fabry’s disease), and N-Acetylneuraminic acid hydrolase deficiency (nephrosialidosis). ◦ Secondary causes: Hyperfiltration/reduced kidney mass, obesity, infections (HIV, Hep B, Parvovirus, SARS-CoV-2), hypertension, reflux nephropathy, cholesterol emboli, drugs (Heroin, analgesics, bisphosphonates, ecstasy, interferon, anabolic steroids), oligomeganephronia, sickle cell disease, and radiation nephritis. • Membranous Glomerulonephritis (Table 326-5): ◦ Primary/Antigen-associated: PLA2R, NELL1, THSD7A, Sema3B, PCDH7, HTRA1, EXT1, EXT2, NCAM1. ◦ Secondary: Infections (Hep B and C, syphilis, malaria, schistosomiasis, leprosy, filariasis), Cancers (Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma), Drugs (Gold, mercury, penicillamine, NSAIDs, probenecid, anti-TNF agents), Autoimmune diseases (SLE, RA, PBC, DH, BP, MG, Sjögren’s, Hashimoto’s, IgG4 disease), and other conditions (Fanconi’s, Sickle cell, Diabetes, Crohn’s, Sarcoidosis, GBS, Weber-Christian, ANLH). • Thrombotic Microangiopathies (Table 326-6): ◦ Primary: TTP, Shiga-toxin HUS, Complement-mediated HUS. ◦ Secondary: Pregnancy-related (preeclampsia, HELLP), Drug-induced (OCPs, quinine, CNIs, antiplatelets [ticlopidine, clopidogrel], drugs of abuse [cocaine, oxycodone]), Kidney transplant patients given OKT3, Malignant hypertension, Autoimmune (APS, lupus, scleroderma), Infections (HIV, pneumococcal, CMV), and Cobalamin deficiency.
Reference Tables¶
TABLE 326-1 Urine Assays for Albuminuria/Proteinuria Normal Microalbuminuria Proteinuria a¶
Harrison's 22e, p.2414
| 24-h ALBUMINa (mg/24 h) | ALBUMINa/CREATININE RATIO (mg/g) | DIPSTICK PROTEINURIA | 24-h URINE PROTEINb (mg/24 h) | |
|---|---|---|---|---|
| Normal | 8–10 | <30 | – | <150 |
| 30–300 | 30–300 | –/Trace/1+ | ||
| Proteinuria | >300 | >300 | Trace–3+ | >150 |
TABLE 326-2 Patterns of Clinical Glomerulonephritis¶
Harrison's 22e, p.2415
| GLOMERULAR SYNDROMES | PROTEINURIA | HEMATURIA | VASCULAR INJURY |
|---|---|---|---|
| Acute Nephritic Syndromes | |||
| Poststreptococcal glomerulonephritisa | +/++ | ++/+++ | – |
| Subacute bacterial endocarditisa | +/++ | ++ | – |
| Lupus nephritisa | +/++ | ++/+++ | + |
| Antiglomerular basement membrane diseasea | ++ | ++/+++ | – |
| IgA nephropathya | +/++ | +++c | – |
| ANCA small-vessel vasculitisa | |||
| Granulomatosis with polyangiitis (Wegener’s) | +/++ | ++/+++ | ++++ |
| Microscopic polyangiitis | +/++ | ++/+++ | ++++ |
| Churg-Strauss syndrome | +/++ | ++/+++ | ++++ |
| Henoch-Schönlein purpuraa | +/++ | ++/+++c | ++++ |
| Cryoglobulinemiaa | +/++ | ++/+++ | ++++ |
| Membranoproliferative glomerulonephritisa | ++ | ++/+++ | – |
| C glomerulopathies 3 |
++ | ++/+++ | – |
| Mesangioproliferative glomerulonephritis | + | +/++ | – |
| Pulmonary-Renal Syndromes | |||
| ++ +/++ +/++ +/++ +/++ +/++ |
++/+++ ++/+++ ++/+++ ++/+++ ++/+++c ++/+++ |
||
| Nephrotic Syndromes | |||
| Minimal change disease | ++++ | – | – |
| Focal segmental glomerulosclerosis | +++/++++ | + | – |
| Membranous glomerulonephritis | ++++ | + | – |
| Diabetic nephropathy | ++/++++ | –/+ | – |
| AL and AA amyloidosis | +++/++++ | + | +/++ |
| Light chain deposition disease | +++ | + | – |
| Fibrillary-immunotactoid disease | +++/++++ | + | + |
| Fabry’s disease | + | + | – |
| Basement Membrane Syndromes | |||
| ++ ++ + ++/+++ |
++/+++ ++ ++ ++ |
||
| Glomerular Vascular Syndromes | |||
| Atherosclerotic nephropathy | + | + | +++ |
| Hypertensive nephropathyb | +/++ | +/++ | ++ |
| Cholesterol emboli | +/++ | ++ | +++ |
| Sickle cell disease | +/++ | +++c | +++ |
| Thrombotic microangiopathies | ++ | ++ | +++ |
| Antiphospholipid syndrome | ++ | ++ | +++ |
| ANCA small-vessel vasculitisa | |||
| Granulomatosis with polyangiitis (Wegener’s) | +/++ | ++/+++ | ++++ |
| Microscopic polyangiitis | +/++ | ++/+++ | ++++ |
| Churg-Strauss syndrome | +++ | ++/+++ | ++++ |
| Henoch-Schönlein purpuraa | +/++ | ++/+++c | ++++ |
| Cryoglobulinemiaa | +/++ | ++/+++ | ++++ |
| AL and AA amyloidosis | +++/++++ | + | +/++ |
| Infectious Disease–Associated Syndromes | |||
| +/++ +/++ +++ |
++/+++ ++ +/++ |
TABLE 326-3 Classification for Lupus Nephritis Class I Class II Class III¶
Harrison's 22e, p.2418
| Class I | Minimal mesangial | Normal histology with mesangial deposits |
|---|---|---|
| Mesangial proliferation |
Mesangial hypercellularity with expansion of the mesangial matrix |
|
| Class III | Focal nephritis | Focal endocapillary ± extracapillary hypercellularity with focal subendothelial immune deposits and mild mesangial expansion ± fibrinoid necrosis |
| Diffuse nephritis | Diffuse endocapillary ± extracapillary hypercellularity with diffuse subendothelial immune deposits and mesangial alterations ± crescents ± fibrinoid necrosis |
|
| Class V | Membranous nephritis |
Thickened basement membranes with diffuse subepithelial immune deposits; may occur with class III or IV lesions and is sometimes called mixed membranous and proliferative nephritis |
| Sclerotic nephritis | Global sclerosis of nearly all glomerular capillaries |
TABLE 326-4 Focal Segmental Glomerulosclerosis Primary focal segmental glomerulosclerosis Yet to be identified…¶
Harrison's 22e, p.2422
- Primary focal segmental glomerulosclerosis
Yet to be identified circulating permeable factor
Secondary focal segmental glomerulosclerosis
Adaptive response to hyperfiltration/reduced kidney mass, obesity
Viruses: HIV/hepatitis B/parvovirus/SARS-CoV-2
Hypertensive nephropathy
Reflux nephropathy
Cholesterol emboli
Drugs: Heroin/analgesics/bisphosphonates/ecstasy/interferon/anabolic steroids
Oligomeganephronia
Sickle cell disease
Radiation nephritis
Familial podocytopathies
NPHS1 mutation/nephrin
NPHS2 mutation/podocin
PLCE1 mutation/phospholipase Cε1
INF2 mutation/inverted formin 2
WT1 mutation/Wilms tumor
TRPC6 mutation/cation channel
ACTN4 mutation/actinin
α-Galactosidase A deficiency/Fabry’s disease
N-Acetylneuraminic acid hydrolase deficiency/nephrosialidosis
Uncertain cause
TABLE 326-5 Membranous Glomerulonephritis Primary/antigen-associated membranous glomerulonephritis¶
Harrison's 22e, p.2423
- Primary/antigen-associated membranous glomerulonephritis
PLA2R, NELL1, THSD7A, Sema3B, PCDH7, HTRA1, EXT1, EXT2, NCAM1
Secondary membranous glomerulonephritis
Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy, filariasis
Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma
Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents,
probenecid, antitumor necrosis factor agents
Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis,
primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid,
myasthenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis, IgG4 disease
Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes,
Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian disease,
angiofollicular lymph node hyperplasia
TABLE 326-6 Thrombotic Microangiopathies Primary thrombotic microangiopathy¶
Harrison's 22e, p.2428
- Primary thrombotic microangiopathy
TTP
Shiga-toxin HUS
Complement-mediated HUS - Secondary thrombotic microangiopathy
Pregnancy related: preeclampsia, HELLP (hemolysis, elevated liver enzymes,
and low platelet count syndrome), postpartum (thought to be complement
mediated)
Drug induced: oral contraceptives or quinine, calcineurin inhibitors,
antiplatelet agents (ticlopidine and clopidogrel), drugs of abuse (cocaine, IV
use of oxycodone)
Kidney transplant patients given OKT3 for rejection
Malignant hypertension
Autoimmune: antiphospholipid syndrome, lupus, scleroderma
Infections: HIV, pneumococcal, CMV
Cobalamin deficiency