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Nephritic syndrome is defined by hematuria and the presence of dysmorphic RBCs and RBC casts on microscopic examination of urinary sediment. Often ≥ 1 of the following elements are present: mild to moderate proteinuria, edema, hypertension, elevated serum creatinine, and oliguria. It has both primary and secondary causes. Diagnosis is based on history, physical examination, and sometimes renal biopsy. Treatment and prognosis vary by cause.
Nephritic syndrome is a manifestation of glomerular inflammation (glomerulonephritis [GN]) and occurs at any age. Causes differ by age (see Table 1: Glomerular Disorders: Glomerular Disorders by Age and Presentation ), and mechanisms differ by cause. The syndrome can be acute or chronic and primary (idiopathic) or secondary.
Postinfectious GN is the prototype of acute GN, but the condition may be caused by other glomerulopathies and by systemic disorders such as connective tissue disorders and hematologic dyscrasias (see Table 2: Glomerular Disorders: Causes of Glomerulonephritis). Chronic GN has features similar to those of acute GN but develops slowly and may cause mild to moderate proteinuria. Examples include IgA nephropathy and hereditary nephritis.
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Table 2
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| Causes of Glomerulonephritis |
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Type
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Examples
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Primary
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Idiopathic
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Fibrillary GN
Idiopathic crescentic GN
IgA nephropathy
Membranoproliferative GN
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Secondary
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Bacterial*
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Group A β-streptococcal infection
Mycoplasma infection
Neisseria meningitidis infection
Salmonella typhi infection
Staphylococcal infections (especially bacterial endocarditis)
Streptococcus pneumoniae infection
Visceral abscesses (due to Escherichia coli, Pseudomonas, Proteus, Klebsiella, or Clostridium sp)
Sepsis
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Parasitic*
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Malaria (due to Plasmodium falciparum or P. malariae)
Schistosomiasis (due to Schistosoma haematobium or S. mansoni)
Toxoplasmosis
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Viral*
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Coxsackievirus infection
Cytomegalovirus infection
Epstein-Barr virus infection
Hepatitis B
Hepatitis C
Herpes zoster
Measles
Mumps
Varicella
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Other infectious and postinfectious causes
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Fungal infections (due to Candida albicans or Coccidioides immitis)
Rickettsial infection
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Connective tissue disorders
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Henoch-Schönlein purpura
Microscopic polyangiitis
Polyarteritis nodosa
SLE
Wegener's granulomatosis
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Drug-induced disorders
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SLE (rarely hydralazine or procainamide)
Hemolytic-uremic syndrome (quinine, cisplatin, gemcitabine, mitomycin C, or quinine)
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Hematologic dyscrasias
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Mixed IgG-IgM cryoglobulinemia
Serum sickness
Thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome
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Glomerular basement membrane diseases
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Goodpasture's syndrome
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Hereditary disorders
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Hereditary nephritis (Alport's syndrome)
Thin basement membrane disease
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*Infectious and postinfectious causes.
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GN = glomerulonephritis.
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Hereditary Nephritis
(Alport's Syndrome)
Hereditary nephritis is a genetically heterogenous disorder characterized by hematuria, impaired renal function, sensorineural deafness, and ocular abnormalities. Cause is a gene mutation affecting type IV collagen. Symptoms and signs are those of nephritic syndrome (ie, hematuria, eventual renal insufficiency) often with sensorineural deafness and, less commonly, ophthalmologic symptoms. Diagnosis is by history, including family history, urinalysis, and biopsy (renal or skin). Treatment is the same as that of chronic kidney disease.
Hereditary nephritis is caused by a mutation in the COL4A5 gene that encodes the α-5 chain of type IV collagen and results in altered type IV collagen strands. The mechanism by which collagen alteration causes a glomerular disorder is unknown, but impaired structure and function are presumed; in most families, thickening and thinning of the glomerular and tubular basement membranes occur, with multilamination of the lamina densa in a focal or local distribution. Glomerular scarring and interstitial fibrosis eventually result.
The disorder is most commonly inherited in X-linked fashion, although autosomal recessive varieties exist. There are 2 forms: a juvenile form with onset of renal insufficiency between ages 20 and 30 yr and an adult form with onset of renal insufficiency after age 30.
Symptoms and Signs
Because of X-linked transmission, women usually are asymptomatic and have little functional impairment. Most men eventually develop renal symptoms and signs similar to those of acute nephritic syndrome (eg, microscopic hematuria, eventually gross hematuria) and progress to renal insufficiency between ages 20 and 30 (juvenile form).
Sensorineural deafness frequently is present, affecting higher frequencies; it may not be noticed during early childhood. Some men develop renal insufficiency after age 30 (adult form) with deafness that occurs late or is mild. Some patients have sensorineural deafness alone without renal disease but can transmit renal disease to their children.
Ophthalmologic abnormalities—cataracts (most common), anterior lenticonus (a regular conical protrusion on the anterior aspect of the lens due to thinning of the lens capsule), spherophakia (spherical lens deformation that can predispose to lens subluxation), nystagmus, retinitis pigmentosa, blindness—also occur but less frequently than deafness.
Other nonrenal manifestations include polyneuropathy and thrombocytopenia.
Diagnosis
Diagnosis is suggested in patients who have microscopic hematuria on urinalysis or recurrent episodes of gross hematuria, particularly if an abnormality of hearing or vision or a family history of chronic kidney disease is present.
Urinalysis and usually renal biopsy are done. The urine may contain small amounts of protein, WBCs, and casts of various types. Nephrotic syndrome occurs rarely. No distinguishing histologic changes are seen on light microscopy. The diagnosis can be confirmed by any of the following:
A combination of immunostaining and electron microscopy is often needed to distinguish hereditary nephritis from some forms of thin basement membrane disease. Although not yet widely available, molecular techniques for evaluating DNA gene mutations or mRNA may become the diagnostic techniques of choice.
Treatment
Treatment is indicated only when uremia occurs; its management is the same as that for other causes of chronic kidney disease (see Renal Failure: Treatment). Anecdotal reports suggest that ACE inhibitors or angiotensin II receptor blockers may slow progression of renal disease. Transplantation has been successful. Genetic counseling is indicated.
Immunoglobulin A Nephropathy
IgA nephropathy is deposition of IgA immune complexes in glomeruli, manifesting as slowly progressive hematuria, proteinuria, and, often, renal insufficiency. Diagnosis is based on urinalysis and renal biopsy. Prognosis is generally good. Treatment options include ACE inhibitors, angiotensin II receptor blockers, corticosteroids, immunosuppressants, and ω-3 polyunsaturated fatty acids.
IgA nephropathy is a form of chronic GN characterized by the deposition of IgA immune complexes in glomeruli. It is the most common form of GN worldwide. It occurs at all ages, with a peak onset in the teens and 20s; affects men 2 to 6 times more frequently than women; and is more common in whites and Asians than in blacks. Prevalence estimates for IgA kidney deposits are 5% in the US, 10 to 20% in southern Europe and Australia, and 30 to 40% in Asia. However, some people with IgA deposits do not develop clinical disease.
Cause is unknown, but evidence suggests that there may be several mechanisms, including increased IgA1 production, defective IgA1 glycosylation causing increased binding to mesangial cells, decreased IgA1 clearance, a defective mucosal immune system, and overproduction of cytokines stimulating mesangial cell proliferation. Familial clustering has also been observed, suggesting genetic factors at least in some cases.
Renal function is initially normal, but symptomatic renal disease may develop. A few patients present with acute renal failure or chronic kidney disease, severe hypertension, or nephrotic syndrome.
Symptoms and Signs
The most common manifestation is persistent or recurrent macroscopic hematuria (90% of involved children) or asymptomatic microscopic hematuria with mild proteinuria. Other symptoms are usually not prominent.
Gross hematuria usually begins 1 or 2 days after a febrile mucosal (upper respiratory, sinus, enteral) illness, thus mimicking acute postinfectious glomerulonephritis, except the onset of hematuria is earlier (coinciding with or immediately after the febrile illness). Rapidly progressive GN is the initial manifestation in < 10% of patients.
Diagnosis
Diagnosis is suggested by any of the following:
When manifestations are moderate or severe, diagnosis is confirmed by biopsy.
Urinalysis demonstrates microscopic hematuria, usually with dysmorphic RBCs and RBC casts. Mild proteinuria (< 1 g/day) is typical and may occur without hematuria; nephrotic syndrome develops in ≤ 20%. Serum creatinine level is usually normal.
Renal biopsy shows granular deposition of IgA and complement (C3) on immunofluorescent staining in an expanded mesangium with foci of segmental proliferative or necrotizing lesions. Importantly, mesangial IgA deposits are nonspecific and also occur in many other disorders, including Henoch-Schönlein purpura, cirrhosis, inflammatory bowel disease, psoriasis, HIV infection, lung cancer, and several connective tissue disorders. Glomerular IgA deposition is a primary feature of Henoch-Schönlein purpura, and the 2 disorders may be indistinguishable based on biopsy specimens, leading to speculation that Henoch-Schönlein purpura may be a systemic form of IgA nephropathy. However, Henoch-Schönlein purpura is clinically distinct from IgA nephropathy, usually manifesting as purpuric rash, arthralgias, and abdominal pain (see Vasculitis: Henoch-Schönlein Purpura (HSP)).
Other serum immunologic tests are usually unnecessary. Complement concentrations are usually normal. Plasma IgA concentration may be elevated and circulating IgA-fibronectin complexes are present; however, these findings are not helpful diagnostically.
Prognosis
IgA nephropathy usually progresses slowly; renal insufficiency and hypertension develop within 10 yr in 15 to 20% of patients. Progression to end-stage renal disease occurs in 25% of patients after 20 yr. When IgA nephropathy is diagnosed in childhood, prognosis is usually good. However, persistent hematuria invariably leads to hypertension, proteinuria, and renal insufficiency. Risk factors for progressive deterioration in renal function include the following:
Treatment
Normotensive patients with intact renal function (creatinine < 1.2 mg/dL) and only mild proteinuria (< 0.5 g/day) usually are not treated. Patients with renal insufficiency or more severe proteinuria and hematuria are usually offered treatment, which ideally should be started before significant renal insufficiency develops.
Angiotensin inhibition:
ACE inhibitors or angiotensin II receptor blockers are used on the premise that they reduce BP, proteinuria, and glomerular fibrosis. Patients with the DD genotype for the ACE gene may be at greater risk of disease progression but may also be more likely to respond to ACE inhibitors or angiotensin II receptor blockers. For patients with hypertension, ACE inhibitors or angiotensin II receptor blockers are the antihypertensives of choice even for relatively mild chronic kidney disease.
Corticosteroids and immunosuppressants:
Corticosteroids have been used for many years, but benefit is not well documented. One protocol uses methylprednisolone 1 g IV once/day for 3 days at the beginning of months 1, 3, and 5 plus prednisone 0.5 mg/kg po every other day for 6 mo. Because of the risk of adverse effects, corticosteroids should probably be reserved for patients with any of the following:
Combinations of corticosteroids, cyclophosphamide, and azathioprine are also used, but efficacy and safety compared with corticosteroids alone are uncertain. Mycophenolate mofetil is under investigation. None of these drugs, however, prevents recurrence in transplant patients.
Other treatments:
ω-3 Polyunsaturated fatty acids (eg, 4 to 12 g/day), available in fish oil supplements, have been used to treat IgA nephropathy, but data on efficacy are contradictory. Mechanism of effect may include alterations in inflammatory cytokines.
Other interventions have been tried to lower IgA overproduction and to inhibit mesangial proliferation. Elimination of gluten, dairy products, eggs, and meat from the diet; tonsillectomy; and immune globulin (1 g/kg IV 2 days/mo for 3 mo followed by immune globulin 0.35 mL/kg of 16.5% solution IM q 2 wk for 6 mo) all theoretically reduce IgA production. Heparin, dipyridamole, and statins are just a few examples of in vitro mesangial cell inhibitors. Data supporting any of these interventions are limited or absent, and none can be recommended for routine treatment.
Renal transplantation is better than dialysis because of excellent long-term disease-free survival. The condition recurs in ≤ 15% of graft recipients.
Postinfectious Glomerulonephritis
Postinfectious glomerulonephritis (PIGN) occurs after infection, usually with a nephritogenic strain of group A β-hemolytic streptococcus. Diagnosis is suggested by history and urinalysis and confirmed by finding a low complement level and sometimes by antibody testing. Prognosis is excellent. Treatment is supportive.
Etiology
PIGN is the most common cause of a glomerular disorder in children between 5 and 15 yr; it is rare in children < 2 yr and uncommon in adults > 40 yr.
Most cases are caused by nephritogenic strains of group A β-hemolytic streptococci, most notably type 12 (which causes pharyngitis) and type 49 (which causes impetigo); an estimated 5 to 10% of patients with streptococcal pharyngitis and about 25% of those with impetigo develop PIGN. A latency period of 6 to 21 days between infection and GN onset is typical, but latency may extend up to 6 wk.
Less common pathogens are nonstreptococcal bacteria, viruses, parasites, rickettsiae, and fungi (see Table 2: Glomerular Disorders: Causes of Glomerulonephritis). Bacterial endocarditis and ventriculoatrial shunt infections are additional important conditions in which PIGN develops; ventriculoperitoneal shunts are more resistant to infection.
The mechanism is unknown, but microbial antigens are thought to bind to the glomerular basement membrane and activate complement both directly and via interaction with circulating antibodies, causing glomerular damage, which may be focal or diffuse.
Symptoms and Signs
Symptoms and signs range from asymptomatic hematuria (in about 50%) and mild proteinuria to full-blown nephritis with microscopic or gross hematuria (cola-colored, brown, smoky, or frankly bloody urine), proteinuria, oliguria, edema, hypertension, and renal insufficiency. Severe, late disease is a relatively uncommon cause of nephrotic syndrome. Renal failure that causes fluid overload with heart failure and urgent or malignant hypertension and requires dialysis affects 1 to 2% of patients and may manifest as a pulmonary-renal syndrome with hematuria and hemoptysis (see Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome: Pulmonary-Renal Syndrome). Fever is unusual and suggests persistent infection.
Clinical manifestations of nonstreptococcal PIGN may mimic other disorders (eg, polyarteritis nodosa, renal emboli, antimicrobial drug–induced acute interstitial nephritis).
Diagnosis
Streptococcal PIGN is suggested by history of pharyngitis or impetigo plus either typical symptoms of PIGN or incidental findings on urinalysis. Tests done to confirm the diagnosis depend on clinical findings. Antistreptolysin O, antihyaluronidase, and antideoxyribonuclease (anti-DNAase) antibodies are commonly measured. Serum creatinine and complement levels (C3 and total hemolytic complement activity) are also usually measured; however, in patients with classic findings, some tests can be omitted. Sometimes other tests are done. Biopsy confirms the diagnosis but is rarely necessary; demonstration of hypocomplementemia is essentially confirmatory.
Antistreptolysin O level, the most common laboratory evidence of recent streptococcal infection, increases and remains elevated for several months in about 75% of patients with pharyngitis and in about 50% of patients with impetigo, but it is not specific. An increase in antihyaluronidase and antideoxyribonuclease titers is more specific for detecting recent streptococcal skin infection but is not widely available.
Urinalysis shows proteinuria (0.5 to 2 g/m2/day); dysmorphic RBCs; WBCs; renal tubular cells; and RBC, WBC, and granular casts. Random (spot) urinary protein/creatinine ratio may be between 0.2 and 2 (normal, < 0.2).
Serum creatinine may rise rapidly but usually peaks below a level requiring dialysis.
C3 and total hemolytic complement activity (CH50) levels fall during active disease and return to normal within 6 to 8 wk in 80% of PIGN cases; C1q, C2, and C4 levels are only minimally decreased or remain normal. Cryoglobulinemia may appear and persist for several months, whereas circulating immune complexes are detectable for only a few weeks.
Biopsy specimens show enlarged and hypercellular glomeruli, initially with neutrophilic or eosinophilic infiltration and later with mononuclear infiltration. Epithelial cell hyperplasia is a common early, transient feature. Microthrombosis may occur; if damage is severe, hemodynamic changes produce oliguria, frequently accompanied by epithelial crescents (formed within Bowman's space from epithelial cell hyperplasia). Endothelial and mesangial cells multiply, and the mesangial regions often are greatly expanded by edema and contain neutrophils, dead cells, cellular debris, and subepithelial deposits of electron-dense material. Immunofluorescence microscopy usually shows immune complex deposition with IgG and complement in a granular pattern. On electron microscopy, these deposits are semilunar or hump-shaped and are located in the subepithelial area. The presence of these deposits initiates a complement-mediated inflammatory reaction that leads to glomerular damage. Although the immune complex is presumed to contain an antigen related to streptococcal organisms, no such antigen has been found.
Prognosis
Normal renal function is retained or regained by 85 to 95% of patients. GFR usually returns to normal over 1 to 3 mo, but proteinuria may persist for 6 to 12 mo and microscopic hematuria for several years. Transient changes in urinary sediment may recur with minor URIs. Renal cellular proliferation disappears within weeks, but residual sclerosis is common. In 10% of adults and 1% of children, PIGN evolves into rapidly progressive GN.
Treatment
Treatment is supportive and may include restriction of dietary protein, Na, and fluid and, in more severe cases, treatment of edema and hypertension. Dialysis is occasionally necessary. Antimicrobial therapy is preventive only when given within 36 h of infection and before GN becomes established.
Rapidly Progressive Glomerulonephritis (RPGN)
(Crescentic Glomerulonephritis)
Rapidly progressive glomerulonephritis (RPGN) causes microscopic glomerular crescent formation with progression to renal failure within weeks to months. Diagnosis is based on history, urinalysis, serologic tests, and renal biopsy. Treatment is with corticosteroids, with or without cyclophosphamide, and sometimes plasmapheresis.
RPGN is extensive glomerular crescent formation (which can be seen in a biopsy specimen) that, if untreated, progresses to end-stage renal disease over weeks to months. It is relatively uncommon, affecting 10 to 15% of patients with GN, and occurs predominantly in patients 20 to 50 yr. Types and causes are classified by findings using immunofluorescence microscopy (see Table 3: Glomerular Disorders: Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy).
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Table 3
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| Classification of Rapidly Progressive Glomerulonephritis Based on Immunofluorescence Microscopy |
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Type
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Percentage of RPGN Cases
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Causes
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Type 1: Antiglomerular basement membrane (GBM) antibody–mediated
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≤ 10%
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Anti-GBM GN (without lung hemorrhage*)
Goodpasture's syndrome (with lung hemorrhage)
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Type 2: Immune complex
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≤ 40%
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Postinfectious causes:
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Antistreptococcal antibodies (eg, poststreptococcal GN)
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Infective endocarditis
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Vascular prosthetic nephritis
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Viral hepatitis B infection
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Visceral abscess or sepsis
Connective tissue disorders:
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Anti-DNA autoantibodies (eg, lupus nephritis)
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IgA immune complexes (eg, Henoch-Schönlein purpura GN)
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Mixed IgG-IgM cryoglobulins (eg, cryoglobulinemic GN)
Other glomerulopathies:
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IgA nephropathy
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Membranoproliferative GN
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Type 3: Pauci-immune
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≤ 50%
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Pulmonary necrotizing granulomas (eg, Wegener's granulomatosis)
Renal-limited disease (eg, idiopathic crescentic GN)
Systemic necrotizing arteritis (eg, polyarteritis nodosa)
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Type 4: Double-antibody positive
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Rare
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Same as for as types 1 and 3
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Idiopathic
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Rare
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No clear cause
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*Anti-GBM glomerulonephritis without lung hemorrhage is sometimes called Goodpasture's syndrome.
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GBM = glomerular basement membrane; GN = glomerulonephritis; RPGN = rapidly progressive glomerulonephritis.
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Anti-glomerular basement membrane (GBM) antibody disease (type 1 RPGN) is autoimmune GN and accounts for up to 10% of RPGN cases. It may arise when respiratory exposures (eg, cigarette smoke, viral URI) or some other stimulus exposes alveolar capillary collagen, triggering formation of anticollagen antibodies. The anticollagen antibodies cross-react with GBM, fixing complement and triggering a cell-mediated inflammatory response in the kidneys and usually the lungs. The term Goodpasture's syndrome usually refers to a combination of GN and alveolar hemorrhage in the presence of anti-GBM antibodies (see Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome: Goodpasture Syndrome) but sometimes refers to GN without alveolar hemorrhage in the presence of anti-GBM antibodies. Immunofluorescent staining of renal biopsy tissue demonstrates linear IgG deposits.
Immune complex RPGN (type 2 RPGN) complicates numerous infectious and connective tissue disorders and also occurs with other primary glomerulopathies. Immunofluorescent staining demonstrates nonspecific granular immune deposits. The condition accounts for up to 40% of RPGN cases. Pathogenesis is usually unknown.
Pauci-immune RPGN (type 3 RPGN) is distinguished by the absence of immune complex or complement deposition on immunofluorescent staining. It constitutes up to 50% of all RPGN cases. Almost all patients have elevated antineutrophil cytoplasmic antibodies (ANCAs, usually myeloperoxidase-ANCA) and systemic vasculitis.
Double-antibody disease (type 4 RPGN) has features of types 1 and 3, with the presence of anti-GBM and ANCA antibodies. It is rare.
Idiopathic cases are rare. They include patients with either of the following:
Symptoms and Signs
Manifestations are usually insidious, with weakness, fatigue, fever, nausea and vomiting, anorexia, arthralgia, and abdominal pain. Some patients present similarly to those with PIGN, with abrupt-onset hematuria. About 50% of patients have edema and a history of an acute influenza-like illness within 4 wk of onset of renal failure, usually followed by severe oliguria. Nephrotic syndrome is present in 10 to 30%. Hypertension is uncommon and rarely severe. Patients with anti-GBM antibody disease may have pulmonary hemorrhage, which can manifest with hemoptysis or be detectable only by finding diffuse alveolar infiltrates on chest x-ray (pulmonary-renal or diffuse alveolar hemorrhage syndrome—see Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome).
Diagnosis
Diagnosis is suggested by acute renal failure in patients with hematuria and RBC casts. Testing includes serum creatinine, urinalysis, CBC, serologic tests, and renal biopsy. Diagnosis is usually by serologic tests and renal biopsy.
Serum creatinine is almost always elevated. Hematuria and RBC casts are always present, and telescopic sediment (ie, sediment with multiple elements, including WBCs and RBCs, and WBC, RBC, granular, waxy, and broad casts) is common.
On CBC, anemia is always present, and leukocytosis is common.
Serologic testing should include anti-GBM antibodies (anti-GBM antibody disease); antistreptolysin O antibodies, anti-DNA antibodies, or cryoglobulins (immune complex RPGN); and ANCA titers (pauci-immune RPGN). Complement measurement may be useful in suspected immune complex RPGN, because hypocomplementemia is common.
Early renal biopsy is essential. The feature common to all types of RPGN is focal proliferation of glomerular epithelial cells, sometimes interspersed with numerous neutrophils, that forms a crescentic cellular mass (crescents) and that fills Bowman's space in > 50% of glomeruli. The glomerular tuft usually appears hypocellular and collapses. Necrosis within the tuft or involving the crescent may occur and may be the most prominent abnormality. In such patients, histologic evidence of vasculitis should be sought.
Immunofluorescence microscopy findings differ for each type.
Prognosis
Spontaneous remission is rare, and 80 to 90% of untreated patients progress to end-stage renal disease within 6 mo. Prognosis improves with early treatment.
Favorable prognostic factors include RPGN caused by the following:
Unfavorable prognostic factors include the following:
About 30% of patients with pauci-immune RPGN do not respond to treatment; among nonresponders, about 40% require dialysis, and 33% die within 4 yr. In contrast, among patients who respond to treatment, < 20% of patients require dialysis, and about 3% die.
Patients with double-antibody disease appear to have a renal prognosis no better than patients with anti-GBM antibody disease and worse than patients with pauci-immune RPGN.
Patients who recover normal renal function after RPGN demonstrate residual histologic changes principally in glomeruli, consisting chiefly of hypercellularity, with little or no sclerosis within the glomerular tuft or the epithelial cells and minimal fibrosis of the interstitium.
Death is usually due to infectious or cardiac causes, providing that a uremic death is prevented by dialysis.
Treatment
Treatment varies by disease type, although no regimens have been rigorously studied. Therapy should be instituted early, ideally when serum creatinine is < 5 mg/dL and before the biopsy shows crescentic involvement of all glomeruli or organizing crescents as well as fibrotic interstitium and atrophic tubules. Treatment becomes less effective as these features become more prominent and may be harmful in some patients (eg, the elderly, patients with infection).
For anti-GBM antibody disease, plasmapheresis (daily 3- to 4-L exchanges for 14 days) is recommended; the role of plasmapheresis is less well defined for immune complex and pauci-immune RPGN. Plasmapheresis is believed to be effective because it rapidly removes free antibody, intact immune complexes, and mediators of inflammation (eg, fibrinogen, complement). Prednisone and cyclophosphamide are typically started and continued to minimize new antibody formation.
For immune complex and pauci-immune RPGN, corticosteroids (methylprednisolone 1 g IV once/day over 30 min for 3 to 5 days followed by prednisone 1 mg/kg po once/day) may reduce serum creatinine levels or delay dialysis for > 3 yr in 50% of patients. Cyclophosphamide 1.5 to 2 mg/kg po once/day is usually given and may particularly benefit ANCA-positive patients; monthly pulse regimens may lessen adverse effects, but their role is not defined.
Lymphocytapheresis, a technique to remove peripheral lymphocytes from circulation, may benefit pauci-immune RPGN but requires further investigation. Patients with idiopathic disease are usually treated with corticosteroids and cyclophosphamide, but data regarding efficacy are scarce.
Renal transplantation is effective for all types, but disease may recur in the graft; risk diminishes with time. In anti-GBM antibody disease, the anti-GBM titers should be undetectable for at least 12 mo before transplantation.
Thin Basement Membrane Disease
(Benign Familial Hematuria)
Thin basement membrane disease is diffuse thinning of the glomerular basement membrane from a width of 300 to 400 nm in normal subjects to 150 to 225 nm.
Thin basement membrane disease is hereditary and usually transmitted in autosomal dominant fashion. Not all genetic mutations have been characterized, but in some families with thin basement membrane disease there is a mutation in the type IV collagen α4 gene. Prevalence is estimated to be 5 to 9%.
Most patients are asymptomatic and are incidentally noted to have microscopic hematuria on routine urinalysis, although mild proteinuria and gross hematuria are occasionally present. Renal function is typically normal, but a few patients develop progressive renal failure for unknown reasons. Recurrent flank pain, similar to that in IgA nephropathy, is a rare manifestation.
Diagnosis is based on family history and findings of hematuria without other symptoms or pathology, particularly if asymptomatic family members also have hematuria. Renal biopsy is unnecessary but is often done as part of a hematuria evaluation. Early on, thin basement membrane disease may be difficult to differentiate from hereditary nephritis because of histologic similarities.
Long-term prognosis is excellent, and no treatment is necessary in most cases. Patients with frequent gross hematuria, flank pain, or proteinuria (eg, urine protein/creatinine ratio of > 0.2) may benefit from ACE inhibitors or angiotensin receptor II blockers, which may lower intraglomerular pressure.
Last full review/revision January 2010 by James I. McMillan, MD
Content last modified February 2012
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