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Kidney Diseases
A reference to diseases affecting the kidneys, covering causes, symptoms, affected structures, diagnostic methods, treatment approaches and prognosis.
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A reference to diseases affecting the kidneys, covering causes, symptoms, affected structures, diagnostic methods, treatment approaches and prognosis.
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| # | TextNo. | TextDisease Name | TextCategory | TextPrimary Cause / Etiology | TextPrevalence | TextAge of Onset | TextKey Symptoms | TextAffected Organ(s) | TextDiagnostic Method | TextTreatment Approach | TextPrognosis | TextICD-10 Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 01 | 1 | ANCA-Associated Vasculitis (Renal) | Glomerular Diseases | ANCA-associated vasculitis (AAV) encompasses granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss), all of which can cause pauci-immune necrotizing and crescentic glomerulonephritis. The pathogenesis involves anti-neutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA, more common in GPA) or myeloperoxidase (MPO-ANCA, more common in MPA and EGPA). ANCA activate primed neutrophils by binding to PR3 or MPO expressed on the neutrophil surface, triggering degranulation, release of reactive oxygen species, and formation of neutrophil extracellular traps (NETs). Activated neutrophils adhere to glomerular endothelium, causing necrotizing vasculitis of glomerular capillaries with fibrinoid necrosis, GBM rupture, and crescent formation. The pauci-immune pattern (absence of significant immunoglobulin deposits) distinguishes AAV from immune complex-mediated crescentic GN. Alternative complement pathway activation through C5a-C5aR axis amplifies neutrophil recruitment and plays a critical role in disease pathogenesis, providing the rationale for complement-targeted therapies. Environmental triggers including silica exposure, infections, and certain medications (hydralazine, propylthiouracil, levamisole-adulterated cocaine) have been associated with ANCA formation. | AAV has an annual incidence of approximately 15-25 per million and a prevalence of approximately 200-400 per million in Western countries. GPA and MPA are the most common forms, with GPA predominating in Northern Europe and MPA in Southern Europe and Asia. Renal involvement occurs in 70-85% of MPA and 40-60% of GPA patients. The mean age at diagnosis is 55-65 years, with a slight male predominance (1.5:1). AAV is more common in Caucasians, though it occurs in all racial groups. Renal involvement is a major determinant of morbidity and mortality and is the presenting feature in many patients. AAV accounts for approximately 3-5% of ESRD. | AAV predominantly affects middle-aged and elderly adults, with peak incidence in the sixth to seventh decades of life. It is uncommon in children but can occur at any age. PR3-ANCA positive GPA tends to present at a younger age (mean 50 years) than MPO-ANCA positive MPA (mean 60-65 years). Childhood AAV is rare but may present with more aggressive renal disease. Drug-induced ANCA vasculitis (e.g., from propylthiouracil) may occur at younger ages depending on medication exposure. | Renal manifestations range from asymptomatic urinary abnormalities to fulminant RPGN. Active urinary sediment with microscopic hematuria, dysmorphic RBCs, RBC casts, and proteinuria (usually non-nephrotic) is the hallmark. Rapidly progressive renal failure with rising creatinine over days to weeks occurs in 30-50% of patients at presentation. Hypertension is present in 30-50% but is often mild. Systemic symptoms include constitutional symptoms (fever, weight loss, fatigue, malaise) in 70-90% of patients. GPA-specific features include upper airway disease (sinusitis, epistaxis, saddle nose deformity, subglottic stenosis), pulmonary nodules or cavitary lesions, and orbital pseudotumor. MPA-specific features include diffuse alveolar hemorrhage (occurring in 10-30%) presenting with hemoptysis, dyspnea, and bilateral infiltrates. Skin manifestations (palpable purpura in 30-50%), peripheral neuropathy (mononeuritis multiplex in 20-30%), and musculoskeletal symptoms (arthralgia, myalgia) are common in both GPA and MPA. | Kidneys (glomeruli - pauci-immune necrotizing crescentic GN); lungs (alveolar hemorrhage, nodules, cavities); upper airways (sinuses, nasal septum, subglottic region); skin (purpura, ulcers); peripheral nerves (mononeuritis multiplex); eyes (scleritis, orbital pseudotumor); joints | ANCA testing by ELISA for PR3 and MPO antibodies is the initial diagnostic step, with sensitivity of 85-95% and specificity of >95% for active AAV with renal involvement. Renal biopsy is essential for confirming the diagnosis and assessing severity. Biopsy shows necrotizing and crescentic GN with pauci-immune immunofluorescence pattern (no or minimal immunoglobulin deposits). The Berden histologic classification grades renal biopsies into focal, crescentic, mixed, and sclerotic classes, with prognostic implications. Urinalysis shows active nephritic sediment. Chest CT evaluates for pulmonary involvement (nodules, cavities, ground-glass opacities). CRP and ESR are typically markedly elevated. Complete blood count may show anemia and leukocytosis. Serum creatinine at presentation and the percentage of normal glomeruli on biopsy are the strongest predictors of long-term renal outcome. | Induction therapy for severe AAV (organ-threatening, including renal involvement): rituximab (375 mg/m2 IV weekly x 4) is non-inferior and often preferred over cyclophosphamide based on RAVE and RITUXVAS trials, particularly for PR3-ANCA positive disease, relapsing disease, and when cyclophosphamide is contraindicated. Alternatively, IV cyclophosphamide (15 mg/kg every 2 weeks x 3, then every 3 weeks x 3-6, per Euro-Vasculitis Study Group protocol) combined with glucocorticoids. Avacopan (30 mg twice daily), a C5a receptor antagonist, is FDA-approved as add-on therapy replacing or reducing glucocorticoids based on the ADVOCATE trial showing superior sustained remission rates. IV methylprednisolone (500-1000 mg x 3 days) followed by oral prednisone (0.5-1 mg/kg/day tapered to off by 3-6 months). Plasma exchange is considered for severe disease with creatinine >5.8 mg/dL or pulmonary hemorrhage. Maintenance therapy: rituximab (500 mg IV every 6 months for at least 2-4 years) is preferred over azathioprine (2 mg/kg/day) based on MAINRITSAN trials. Trimethoprim-sulfamethoxazole (800/160 mg three times weekly) for Pneumocystis prophylaxis during immunosuppression. | Variable - With modern treatment, 1-year survival exceeds 85-90% and 5-year survival is 70-80%. Renal survival at 5 years is approximately 75-85% with prompt treatment. Complete remission is achieved in 70-90% with induction therapy. Relapse rates remain significant: 40-60% for PR3-ANCA positive disease and 20-30% for MPO-ANCA positive disease over 5 years without maintenance therapy; maintenance rituximab reduces relapse rates to 10-15%. Factors predicting poor renal outcome include high serum creatinine at diagnosis, high percentage of sclerotic glomeruli on biopsy, and delayed treatment. AAV accounts for approximately 3-5% of ESRD; dialysis-dependent patients at diagnosis have a 30-50% chance of renal recovery with aggressive treatment. Five-year transplant graft survival is comparable to other causes of ESRD (>85%), with relapse in transplant occurring in 10-15%. | M31.7 |
| 02 | 2 | Alport Syndrome | Glomerular Diseases | Alport syndrome is a hereditary nephritis caused by mutations in genes encoding type IV collagen alpha chains, specifically COL4A5 (X-linked form, 80% of cases), or COL4A3/COL4A4 (autosomal recessive form, 15%, and autosomal dominant form, 5%). The alpha-3, alpha-4, and alpha-5(IV) chains form the alpha-3-4-5(IV) collagen network, which is the major structural component of the mature GBM, cochlear basement membranes, and lens capsule. In Alport syndrome, mutations prevent proper assembly and incorporation of the alpha-3-4-5 network, and the GBM retains the fetal alpha-1-1-2(IV) network, which is thinner, more susceptible to proteolytic degradation, and less resistant to mechanical stress. The GBM progressively deteriorates, showing characteristic alternating thinning and thickening with lamellation and basket-weave splitting of the lamina densa on electron microscopy. This progressive GBM damage leads to hematuria, proteinuria, and eventual glomerulosclerosis with interstitial fibrosis. In the X-linked form, affected males (hemizygous) have more severe disease than affected females (heterozygous), who have a mosaic pattern of normal and abnormal GBM due to random X-inactivation. The same alpha-3-4-5(IV) network is present in the cochlear basement membrane and lens capsule, explaining the characteristic extrarenal manifestations of sensorineural hearing loss and ocular anomalies. | Alport syndrome affects approximately 1 in 5,000 to 1 in 10,000 people, accounting for approximately 1-2% of all ESRD. X-linked Alport syndrome (XLAS) accounts for approximately 80% of cases, autosomal recessive for 15%, and autosomal dominant for 5%. Males with XLAS inevitably develop ESRD, typically by age 20-30 (severe phenotype with truncating mutations) or by age 40-60 (milder phenotype with missense mutations). Approximately 12% of females heterozygous for XLAS develop ESRD, usually after age 40. Alport syndrome is found worldwide with no significant racial or ethnic predilection. | Microscopic hematuria is present from birth in males with XLAS and is typically the first manifestation. Proteinuria develops in the first to second decade. Sensorineural hearing loss typically becomes detectable in late childhood to early adolescence (age 6-15) in severe XLAS. Renal failure develops in the second to third decade in severe XLAS (truncating mutations) and in the fourth to fifth decade in milder forms (missense mutations). Females with XLAS may develop hematuria and proteinuria at any age. Autosomal recessive Alport syndrome presents similarly to severe XLAS in both sexes. | Persistent microscopic hematuria from birth is the earliest manifestation in affected males and is present in nearly 100% of XLAS males. Episodes of gross hematuria triggered by upper respiratory infections occur in 60-70% during childhood. Progressive proteinuria develops over the first to second decade, eventually reaching nephrotic range in many patients. Bilateral sensorineural hearing loss (initially high-frequency, eventually affecting conversational frequencies) develops in 80-90% of XLAS males, typically becoming clinically apparent between ages 6 and 15. Anterior lenticonus (conical protrusion of the anterior lens capsule, pathognomonic for Alport syndrome) is found in 15-30% of XLAS males and may cause progressive myopia. Perimacular retinal flecks (dot-and-fleck retinopathy) are found in 40-60%. Hypertension develops as CKD progresses. Progressive CKD manifests with fatigue, growth retardation, anemia, and uremic symptoms. Heterozygous XLAS females have a spectrum from asymptomatic hematuria to progressive CKD. | Kidneys (GBM - progressive deterioration and sclerosis); cochlea (sensorineural hearing loss); eyes (anterior lenticonus, retinal flecks, posterior polymorphous corneal dystrophy); rarely leiomyomatosis of esophagus and tracheobronchial tree (associated with COL4A5-COL4A6 deletions) | Genetic testing of COL4A3, COL4A4, and COL4A5 is the gold standard for diagnosis and should be performed first-line in suspected cases. Renal biopsy shows non-specific findings on light microscopy in early stages but progressive glomerulosclerosis and interstitial fibrosis in advanced disease. Electron microscopy demonstrates the characteristic GBM changes: alternating thinning and thickening with lamellation and basket-weave splitting of the lamina densa. Immunohistochemistry of the biopsy or skin biopsy for type IV collagen alpha chains is useful: in XLAS males, alpha-5(IV) is absent from the GBM and Bowman's capsule, and alpha-3 and alpha-4 are also absent from the GBM. In XLAS females, alpha-5(IV) staining is mosaic. Audiometry should be performed at diagnosis and regularly thereafter to monitor hearing loss. Ophthalmologic examination for anterior lenticonus and retinal flecks. Urinalysis shows persistent hematuria and progressive proteinuria. Family pedigree analysis helps determine the inheritance pattern. | ACE inhibitors are the cornerstone of therapy and should be initiated at the earliest sign of proteinuria (even microalbuminuria), as they significantly delay progression to ESRD. Ramipril (2.5-10 mg daily, pediatric dose 0.05-0.1 mg/kg/day) has the strongest evidence from the EARLY PRO-TECT Alport trial, which showed that ACE inhibitor initiation before CKD stage 3 delays ESRD by an average of 10-13 years. ARBs (losartan 25-100 mg daily) may be used as alternatives. Addition of an ARB to an ACE inhibitor (dual RAS blockade) is used by some centers for persistent proteinuria, though this approach is debated. Aldosterone receptor antagonists (spironolactone 25-50 mg daily or eplerenone 25-50 mg daily) may provide additional antiproteinuric benefit when added to ACE inhibitor/ARB therapy. SGLT2 inhibitors (dapagliflozin 10 mg daily) are increasingly being studied in Alport syndrome. Hearing aids are prescribed for significant hearing loss. Anterior lenticonus causing visual impairment may require lens replacement surgery. Kidney transplantation is the preferred renal replacement modality, with excellent outcomes and no recurrence of disease in the allograft; however, 3-5% of XLAS males develop post-transplant anti-GBM nephritis due to immune response against the 'novel' alpha-3-4-5(IV) network in the allograft. | Moderate - Males with XLAS and truncating COL4A5 mutations develop ESRD by a median age of 25 years, while those with missense mutations develop ESRD by a median age of 40-50 years. Early ACE inhibitor therapy significantly improves prognosis, delaying ESRD by 10-13 years or more. Approximately 12% of heterozygous XLAS females develop ESRD, usually after age 40, and up to 40% develop CKD. Autosomal recessive Alport syndrome progresses to ESRD by age 20-30 in both sexes. Hearing loss is progressive and bilateral; cochlear implants may be needed in severe cases. Kidney transplant outcomes are excellent (5-year graft survival >90%), with post-transplant anti-GBM disease occurring in 3-5% of XLAS males (most episodes are mild and self-limited). Gene therapy and chaperone therapy for Alport syndrome are in early research stages. | Q87.81 |
| 03 | 3 | Anti-GBM Disease (Goodpasture Syndrome) | Glomerular Diseases | Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune condition caused by circulating autoantibodies directed against the non-collagenous 1 (NC1) domain of the alpha-3 chain of type IV collagen, a structural component of the glomerular and alveolar basement membranes. The target epitopes (designated EA and EB) are normally sequestered within the collagen IV hexameric network and become accessible through environmental triggers including pulmonary injury from cigarette smoking, inhaled hydrocarbons, cocaine, infections, or high oxygen concentrations. The anti-GBM antibodies (predominantly IgG1 and IgG3 subclasses) bind the alpha-3(IV)NC1 domain in a linear pattern along the GBM, activate complement via the classical pathway (C1q, C3, C5b-9), recruit neutrophils and monocytes, and cause severe necrotizing and crescentic glomerulonephritis. Pulmonary hemorrhage occurs when anti-GBM antibodies also bind the alveolar basement membrane, which is more accessible when the alveolar-capillary barrier is disrupted (explaining the association with smoking and hydrocarbon exposure). When both renal and pulmonary involvement are present, it is termed Goodpasture syndrome. Strong HLA association exists with HLA-DRB1*1501 (relative risk 8-16). The disease may overlap with ANCA positivity (double-positive disease) in 20-30% of cases. | Anti-GBM disease is rare, with an incidence of approximately 0.5-1.0 per million per year. It accounts for less than 5% of all crescentic glomerulonephritis and approximately 1-2% of all glomerulonephritis in biopsy series. There is a bimodal age distribution with peaks in the third decade (predominantly young males with pulmonary-renal disease) and sixth to seventh decades (predominantly renal-limited disease in both sexes). No significant racial or ethnic predilection has been established, though the disease appears rare in Sub-Saharan African populations. The disease may be triggered by environmental factors in genetically susceptible individuals. | Anti-GBM disease has a bimodal age distribution. The first peak occurs in young adults aged 20-30 years, predominantly males, who often present with pulmonary-renal syndrome (Goodpasture syndrome) and frequently have a history of smoking or hydrocarbon exposure. The second peak occurs in adults aged 60-70 years, with a more equal sex distribution, who more commonly present with renal-limited disease without pulmonary involvement. Pediatric cases are very rare. The elderly peak may overlap with ANCA-positive disease (double positivity). | Rapidly progressive glomerulonephritis is the hallmark, with rapidly rising serum creatinine, oliguria or anuria, and active urinary sediment with dysmorphic red blood cells and red blood cell casts developing over days to weeks. Pulmonary hemorrhage occurs in 40-60% of patients (Goodpasture syndrome), presenting with hemoptysis (ranging from mild to massive and life-threatening), dyspnea, cough, and diffuse alveolar infiltrates on chest imaging. Pulmonary hemorrhage may precede renal manifestations and can be fatal from asphyxiation. Constitutional symptoms including malaise, fatigue, weight loss, fever, and myalgias are common. Hypertension is variable and may be absent initially. Nausea, vomiting, and uremic symptoms develop rapidly in untreated patients. Anemia may be disproportionate to the degree of renal failure due to pulmonary blood loss. | Kidneys (glomerular basement membrane - crescentic GN); lungs (alveolar basement membrane - diffuse alveolar hemorrhage); rare involvement of choroid plexus, cochlea, and retina | Anti-GBM antibody testing (ELISA or chemiluminescent immunoassay) is the cornerstone of diagnosis, with sensitivity of 95-100% and specificity of >97%. False negatives may occur rarely, and if clinical suspicion is high despite negative serologic testing, renal biopsy should be performed. Renal biopsy shows necrotizing and crescentic glomerulonephritis with linear IgG deposition along the GBM on immunofluorescence (pathognomonic finding). Crescents are present in >50% (usually >80%) of glomeruli. ANCA testing should be performed simultaneously, as 20-30% of anti-GBM patients are double-positive (usually MPO-ANCA). Urinalysis shows nephritic sediment with dysmorphic RBCs, RBC casts, and proteinuria. Chest X-ray or CT shows bilateral alveolar infiltrates in pulmonary hemorrhage. Bronchoalveolar lavage (BAL) confirms alveolar hemorrhage with progressively hemorrhagic return and hemosiderin-laden macrophages. Serum creatinine at presentation is the strongest predictor of renal outcome. | Treatment is a medical emergency and should be initiated immediately upon clinical suspicion, before biopsy results are available. Plasmapheresis (daily 4L exchanges using 5% albumin replacement for 14 days or until anti-GBM antibodies are undetectable) rapidly removes circulating antibodies. Concurrent immunosuppressive therapy with IV methylprednisolone (500-1000 mg/day for 3 days) followed by oral prednisolone (1 mg/kg/day tapered over 6-9 months) and oral cyclophosphamide (2-3 mg/kg/day for 2-3 months) suppresses new antibody production. Rituximab (375 mg/m2 weekly x 4) may be used as an alternative to cyclophosphamide, particularly in patients with contraindications. Dialysis-dependent patients at presentation with 100% crescents on biopsy and no pulmonary hemorrhage have minimal chance of renal recovery (<5-8%), and aggressive immunosuppression may not be justified for renal benefit alone, though pulmonary hemorrhage still warrants treatment. Pulmonary hemorrhage is managed with supplemental oxygen, mechanical ventilation if needed, and avoidance of fluid overload. Smoking cessation and avoidance of hydrocarbon exposure are critical to prevent pulmonary hemorrhage recurrence. | Variable - Renal prognosis is heavily dependent on serum creatinine at presentation: patients presenting with creatinine <5.7 mg/dL have 80-90% renal survival at 1 year; those presenting with creatinine 5.7-7.5 mg/dL have 50-60% renal survival; those requiring dialysis at presentation have <8-15% chance of renal recovery. Pulmonary hemorrhage mortality has decreased from 50% to <10% with modern treatment but remains the primary cause of early death. With prompt and adequate treatment, patient survival exceeds 80-90% at 1 year. The disease is typically monophasic with less than 5% relapse rate (unlike ANCA vasculitis). Anti-GBM disease does not recur in kidney transplants if transplantation is delayed 6-12 months after antibodies become undetectable. Double-positive (anti-GBM + ANCA) patients may have a slightly better renal prognosis than anti-GBM alone but have higher relapse risk from the ANCA component. | M31.0 |
| 04 | 4 | C3 Glomerulopathy | Glomerular Diseases | C3 glomerulopathy (C3G) is a group of rare glomerular diseases defined by dominant C3 deposition on immunofluorescence with absent or scanty immunoglobulin staining, resulting from dysregulation of the alternative complement pathway. C3G comprises two entities based on electron microscopy findings: dense deposit disease (DDD, formerly MPGN type II) characterized by ribbon-like highly electron-dense intramembranous deposits transforming the GBM, and C3 glomerulonephritis (C3GN) characterized by mesangial and/or subendothelial deposits without the dense intramembranous deposits of DDD. The underlying pathogenesis involves uncontrolled activation of the alternative complement pathway, which may be caused by acquired autoantibodies (C3 nephritic factor/C3NeF in 50-80%, which stabilizes C3 convertase; anti-factor H antibodies in 10-15%) or by genetic mutations in complement regulatory genes (CFH in 10-20%, CFI, CFB, C3, CFHR gene rearrangements). The resulting persistent C3 activation and consumption leads to low serum C3 levels (found in 40-70% of patients) and C3 fragment deposition in glomeruli. Dense deposit disease derives its name from the osmiophilic transformation of the lamina densa of the GBM by C3 breakdown products. Monoclonal gammopathy may drive C3G through production of monoclonal immunoglobulins that interfere with complement regulation. | C3 glomerulopathy is very rare, with an estimated incidence of 1-2 per million per year. DDD is rarer than C3GN. C3G accounts for approximately 1-3% of all glomerulonephritis in renal biopsy series. It may be underdiagnosed, as some cases previously classified as MPGN or post-infectious GN may represent C3G. There is no significant gender predilection. C3G occurs in all ethnic groups. The association with monoclonal gammopathy increases with age, and patients over 50 should be screened for underlying paraproteinemia. | C3G can present at any age but has distinct age-related patterns. DDD predominantly presents in children and young adults (median age of diagnosis 10-15 years). C3GN presents more commonly in adults (median age 30-50 years). C3G associated with monoclonal gammopathy typically presents in adults over 50 years. The disease may present acutely or be discovered incidentally during evaluation of proteinuria or hematuria. | Clinical presentation is variable and non-specific. Proteinuria is present in nearly all patients, with nephrotic-range proteinuria in 30-50%. Microscopic hematuria is found in 70-90% of patients. Nephrotic syndrome (edema, hypoalbuminemia, hyperlipidemia) occurs in 30-50%. Acute nephritic syndrome with gross hematuria, hypertension, and renal impairment may be the presenting feature. Hypertension is present in 30-50%. Progressive CKD develops in many patients over time. Low serum C3 (reflecting alternative pathway consumption) is found in 40-70% of patients, while C4 is typically normal. DDD is uniquely associated with acquired partial lipodystrophy (loss of subcutaneous fat from the face and upper body) in 20-30% of cases, and retinal drusen (basal laminar deposits in Bruch's membrane) in 10-40%. | Kidneys (glomeruli - mesangium, GBM, capillary walls); eyes (retinal drusen in DDD); subcutaneous fat (acquired partial lipodystrophy in DDD); complement system (systemic alternative pathway dysregulation) | Renal biopsy is essential for diagnosis. Immunofluorescence shows dominant C3 deposition (C3 intensity ≥2 orders of magnitude greater than any immunoglobulin) with absent or scanty immunoglobulin staining. Light microscopy patterns vary and may include MPGN pattern (most common), mesangial proliferative, endocapillary proliferative, or crescentic patterns. Electron microscopy distinguishes DDD (pathognomonic dense intramembranous deposits) from C3GN (mesangial and subendothelial deposits). Serum C3 is low in 40-70% with normal C4 (alternative pathway). C3NeF is positive in 50-80% of DDD and 40-50% of C3GN. Anti-factor H antibodies should be tested. Serum and urine protein electrophoresis/immunofixation should be performed to exclude monoclonal gammopathy, especially in patients >50. Genetic testing of complement regulatory genes (CFH, CFI, CFB, C3, CFHR1-5) should be performed. Serum factor H, factor I, and factor B levels may be measured. Ophthalmologic examination for drusen is recommended in DDD. | There is no established standard therapy for C3G, and treatment is guided by limited evidence from case series and small studies. Supportive therapy with ACE inhibitors or ARBs for proteinuria and blood pressure control is the foundation. Mycophenolate mofetil (1-2 g/day) has shown benefit in observational studies, particularly for C3GN with active proliferative lesions. Corticosteroids alone have limited efficacy. Complement-targeted therapy with eculizumab (anti-C5 monoclonal antibody, 900 mg IV every 2 weeks) has shown variable results, with benefit primarily in patients with active proliferative disease and high C5b-9 levels. Iptacopan (LNP023, oral factor B inhibitor) and danicopan (factor D inhibitor) are under investigation in clinical trials for C3G. For C3G driven by monoclonal gammopathy, clone-directed therapy (rituximab for B-cell clones, bortezomib-based regimens for plasma cell clones) targeting the underlying dysproteinemia is essential. Plasma infusion (providing normal complement regulators) has been attempted in genetic factor H deficiency. Antiplatelet and anticoagulant therapy may be considered for MPGN-pattern disease. | Poor - C3G generally has a progressive course with significant risk of ESRD. DDD has a particularly poor prognosis, with approximately 50% of patients progressing to ESRD within 10 years. C3GN has a somewhat better prognosis but is still progressive, with 30-40% reaching ESRD by 10 years. Factors predicting poor outcome include crescentic histology, interstitial fibrosis, nephrotic-range proteinuria, and elevated creatinine at presentation. Post-transplant recurrence is very high, particularly for DDD (80-100% histologic recurrence, with 50% graft loss within 10 years) and C3GN (50-70% recurrence). Treatment of the underlying complement dysregulation (autoantibodies or genetic mutations) may improve transplant outcomes. Novel complement-targeted therapies offer hope for improved outcomes, but long-term efficacy data are awaited. | N05.8 |
| 05 | 5 | Collapsing Glomerulopathy | Glomerular Diseases | Collapsing glomerulopathy is a histologic variant of focal segmental glomerulosclerosis characterized by global or segmental collapse (wrinkling and retraction) of the glomerular capillary tuft with prominent hyperplasia and hypertrophy of overlying visceral epithelial cells (podocytes). Unlike other FSGS variants where podocytes are lost, collapsing glomerulopathy features podocyte dedifferentiation and proliferation, re-entering the cell cycle and losing mature podocyte markers (WT1, synaptopodin) while gaining proliferative markers (Ki-67, cyclin D1) and parietal epithelial cell markers. The etiology includes viral infections (HIV-1 is the prototypical cause, termed HIV-associated nephropathy/HIVAN; more recently SARS-CoV-2/COVID-19-associated collapsing glomerulopathy has been recognized), APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2, present in the vast majority of HIV-associated and idiopathic cases in African Americans), interferon therapy, bisphosphonate (pamidronate) use, and idiopathic causes. In HIVAN, HIV-1 directly infects podocytes and tubular epithelial cells, and viral gene products (Nef, Vpr) drive podocyte proliferation and apoptosis. The APOL1 risk variants encode gain-of-function protein that is toxic to podocytes through mechanisms involving mitochondrial dysfunction, inflammasome activation, and disruption of endolysosomal trafficking. Histologically, the collapsed capillary tuft is surrounded by swollen, vacuolated, proliferating podocytes that fill Bowman's space, creating the characteristic 'pseudocrescent' appearance. | Collapsing glomerulopathy is relatively uncommon but disproportionately affects individuals of African ancestry due to the high frequency of APOL1 risk variants (12-13% of African Americans carry two risk alleles). HIVAN historically occurred in 3-10% of HIV-infected African Americans before effective antiretroviral therapy (ART), and its incidence has decreased dramatically with widespread ART use. Idiopathic and viral-associated (non-HIV) collapsing glomerulopathy accounts for a smaller proportion. During the COVID-19 pandemic, collapsing glomerulopathy was reported as a complication of SARS-CoV-2 infection, almost exclusively in individuals with APOL1 high-risk genotypes. Collapsing FSGS accounts for approximately 10-15% of all FSGS cases in biopsy series. | HIVAN typically presents in adults aged 20-50 years, reflecting the demographics of HIV infection. Idiopathic collapsing glomerulopathy presents over a wider age range but most commonly in adults aged 30-50 years. COVID-19-associated collapsing glomerulopathy was reported in adults of all ages during the pandemic. The disease is rare in children but has been reported in perinatally HIV-infected children and in children with APOL1 high-risk genotypes. | Severe nephrotic syndrome with heavy proteinuria (often >10 g/day) is the hallmark presentation, typically with marked peripheral edema, anasarca, severe hypoalbuminemia (<2.0 g/dL), and hyperlipidemia. Rapid decline in renal function is characteristic, with elevated creatinine at presentation in 60-80% of patients. The combination of heavy proteinuria and renal insufficiency distinguishes collapsing glomerulopathy from minimal change disease clinically. Kidneys are typically enlarged (rather than small) on ultrasound due to parenchymal edema, which is an important distinguishing feature. Microscopic hematuria may be present. In HIVAN, the nephrotic syndrome may be the initial presentation of HIV infection, and HIV testing should be performed in any patient with collapsing FSGS. Systemic signs of HIV infection or COVID-19 may accompany the renal presentation. | Kidneys (podocytes - proliferation and dedifferentiation; glomerular capillary tuft - collapse); in HIVAN: also tubular epithelium (microcystic tubular dilation is characteristic), immune system | Renal biopsy is diagnostic. Light microscopy shows global or segmental collapse (wrinkling) of the glomerular capillary tuft with prominent podocyte hypertrophy and hyperplasia filling Bowman's space (pseudocrescents). Microcystic tubular dilation with proteinaceous casts is characteristic of HIVAN. Tubulointerstitial inflammation and fibrosis are often prominent. Immunofluorescence is typically negative or shows non-specific IgM/C3 trapping. Electron microscopy shows extensive podocyte foot process effacement, podocyte detachment, endothelial tubuloreticular inclusions (particularly in HIVAN, indicating interferon exposure), and absence of organized deposits. HIV testing (fourth-generation HIV-1/2 antigen/antibody combination test) should be performed in all cases of collapsing FSGS. APOL1 genotyping may be performed, particularly in patients of African ancestry. SARS-CoV-2 testing should be considered during pandemics. | For HIVAN, antiretroviral therapy (ART) is the cornerstone of treatment and should be initiated immediately; ART has dramatically reduced the incidence and improved the prognosis of HIVAN, converting it from a rapidly progressive disease to a manageable condition. ACE inhibitors or ARBs are recommended for proteinuria reduction in HIVAN. For non-HIV collapsing glomerulopathy, treatment is challenging and often disappointing. Immunosuppressive therapy with corticosteroids (prednisone 1 mg/kg/day), calcineurin inhibitors (cyclosporine 3-5 mg/kg/day or tacrolimus 0.05-0.1 mg/kg/day), or rituximab has been tried with limited success rates (20-40% partial remission). Supportive care with ACE inhibitors/ARBs, diuretics, and statin therapy is essential. For COVID-19-associated collapsing FSGS, treatment of the acute infection combined with supportive care is the primary approach. Given the role of APOL1 in disease pathogenesis, APOL1 inhibitors (inaxaplin) are in clinical development and represent a potential targeted therapy for APOL1-mediated kidney diseases. | Poor - Collapsing glomerulopathy has the worst prognosis among all FSGS variants. Without treatment, the median time to ESRD is approximately 1-2 years, with >50% reaching ESRD within 3 years. HIVAN prognosis has improved dramatically with ART, with renal survival increasing from <1 year (pre-ART era) to >5-10 years with effective viral suppression. Non-HIV collapsing FSGS remains highly resistant to therapy, with fewer than 30% achieving partial remission and >60% progressing to ESRD within 3-5 years. Post-transplant recurrence of idiopathic collapsing FSGS is high (30-50%), often occurring within days to weeks. APOL1 high-risk genotype in the recipient (but not the donor) is associated with worse graft outcomes. COVID-19-associated collapsing FSGS has variable outcomes, with some patients recovering renal function as the acute infection resolves. Novel APOL1-targeted therapies may transform the prognosis for APOL1-mediated collapsing glomerulopathy. | N04.1 |
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