Nephritic Syndrome: Glomerular Diseases: Merck Manual Professional

Nephritic syndrome is defined by hematuria and RBC casts on microscopic examination of urinary sediment. Often one or more elements of mild to moderate proteinuria, edema, hypertension, elevated serum creatinine, and oliguria are also present. 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 Diseases: Glomerular Diseases by Age and Presentation

), and mechanisms differ by cause. Acute and chronic forms exist. Postinfectious GN is the prototype of acute GN, but the condition may be caused by other glomerulopathies and by systemic diseases such as connective tissue disorders and paraproteinemias (see Table 2: Glomerular Diseases: Causes of Glomerulonephritis

). Chronic GN has features similar to acute GN but develops slowly and may display mild to moderate proteinuria. Examples include IgA nephropathy and hereditary nephritis.

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 with sensorineural deafness and, less commonly, those of ophthalmologic diseases. Diagnosis is by family history and urinalysis. Treatment is that of chronic renal failure.

Hereditary nephritis is caused by a mutation in the COL4A5 gene that encodes the α-5 chain of type IV collagen and produces altered type IV collagen strands. The mechanism by which this causes glomerular disease 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. Although autosomal recessive varieties exist, the disease is most commonly inherited in X-linked fashion.

Hereditary Nephritis

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 and progress to renal insufficiency between ages 20 and 30. Sensorineural deafness frequently is present, affecting higher frequencies. Some patients have nerve deafness alone without renal disease but can transmit the renal disease to a subsequent generation. Ophthalmologic abnormalities—cataracts (most common), anterior lenticonus, spherophakia, nystagmus, retinitis pigmentosa, blindness—also occur but less frequently than deafness. Other nonrenal manifestations include polyneuropathy and thrombocytopenia.

Diagnosis is suggested by personal and family history and by findings of microscopic hematuria on urinalysis or recurrent episodes of gross hematuria, particularly if abnormalities of hearing or vision are present. 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 or immunofluorescence microscopy. Although not widely available, immunohistochemistry for the α-5 chain in skin and, in particular, genetic analysis may become the diagnostic techniques of choice.

Treatment is indicated only when uremia occurs; its management is the same as for other causes of chronic renal failure (see Renal Failure: Prognosis). Transplantation has also been successful. Genetic counseling is indicated.

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, corticosteroids, 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 are 5% in the US, 10 to 20% in southern Europe and Australia, and 30 to 40% in Asia.

Cause is unknown, but evidence suggests that IgA nephropathy may arise through multiple pathogenetic 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 or chronic renal failure, severe hypertension, or nephrotic syndrome.

The most common presentation 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 in IgA nephropathy usually begins 1 or 2 days after a febrile mucosal (upper respiratory, sinus, enteral) illness, thus mimicking acute GN, except the onset of hematuria is earlier, coinciding with or immediately after the febrile illness and may be accompanied by loin pain. Hypertension is unusual at diagnosis.

Diagnosis is suggested by urinalysis and 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 devel-ops in ≤ 20%.

Serum creatinine and complement concentrations are usually normal. Plasma IgA concentration may be increased, and circulating IgA-fibronectin complexes are present; however, these findings are of dubious value.

IgA Nephropathy (Mesangial IgA Deposition)

IgA Nephropathy (Mesangial Expansion)

Renal biopsy shows granular deposition of IgA and 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 diseases, including Henoch-Schönlein purpura (HSP), hepatic cirrhosis, inflammatory bowel disease, psoriasis, HIV infection, lung cancer, and multiple connective tissue diseases. Glomerular IgA deposition is a primary feature of HSP, and the 2 disorders may be indistinguishable on biopsy, leading to the proposal that HSP may be a systemic form of IgA nephropathy. However, HSP is clinically distinct from IgA nephropathy, usually manifesting as purpuric rash, arthralgias, and abdominal pain (see Vasculitis: Henoch-Schönlein Purpura (HSP)).

IgA nephropathy usually progresses slowly; renal insufficiency and hypertension develop within 10 yr in 15 to 20% of cases. 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. Older age at onset, hypertension, persistent severe proteinuria, absence of recurrent macroscopic hematuria, elevated serum creatinine, and advanced glomerular sclerosis or crescent formation and tubulointerstitial disease are risk factors for progression to renal failure.

Normotensive patients with intact renal function (creatinine < 1.2 mg/dL) and only mild proteinuria (< 1 g/day) usually are not treated unless renal function worsens or proteinuria progresses. Patients with renal insufficiency and more severe proteinuria and hematuria are usually offered treatment, which ideally should be started before significant renal insufficiency.

ACE inhibitors are used on the premise that they reduce BP and proteinuria, but data on efficacy are contradictory. Patients with the DD genotype for the ACE gene may be at greater risk of disease progression and more likely to respond. For patients with hypertension, ACE inhibitors or angiotensin receptor blockers are the antihypertensives of choice even for relatively mild renal disease. Combination ACE inhibitor–angiotensin receptor blocker therapy should be given if monotherapy does not control hypertension or reduce proteinuria.

Corticosteroids have been used for many years, but benefit is not well documented. One protocol uses methylprednisolone Some Trade Names
MEDROL
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1 g IV once/day for 3 days at the beginning of months 1, 3, and 5 plus prednisone Some Trade Names
DELTASONE
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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 whose disease progresses, as shown by worsening proteinuria or renal function, or for patients who present with heavy proteinuria (> 2 g/24 h) or significant renal insufficiency (creatinine clearance < 60 mL/min). Combinations of corticosteroids, cyclophosphamide Some Trade Names
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, and azathioprine Some Trade Names
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are also used, but efficacy and safety compared with corticosteroids alone are uncertain. Mycophenolate is also under investigation. None of these drugs, however, prevents recurrence in transplant patients.

ω-3 Polyunsaturated fatty acids, 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 Some Trade Names
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, dipyridamole Some Trade Names
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, 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 GN occurs after infection, usually with a nephritogenic strain of group A β-hemolytic streptococcus. Diagnosis is suggested by history and urinalysis and confirmed by low complement. Prognosis is excellent. Treatment is supportive.

Postinfectious GN (PIGN) is the most common cause of glomerular disease in children between 5 and 15 yr; it is rare in children < 2 yr and in adults > 40 yr.

Most cases are caused by nephritogenic strains of group A β-hemolytic streptococcus, most notably types 12 (pharyngitis) and 49 (impetigo); an estimated 5 to 10% of patients with streptococcal pharyngitis and about 25% of those with impetigo develop the condition. 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 Diseases: 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 of disease 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 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), proteinuria, oliguria, edema, hypertension, and renal insufficiency. Severe, late disease is a relatively uncommon cause of nephrotic syndrome. Flank pain may be attributable to stretching of the renal capsule. 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 present 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 diseases (eg, polyarteritis nodosa, renal emboli, antimicrobial drug–induced acute interstitial nephritis).

Streptococcal PIGN is suggested by history of pharyngitis or impetigo and urinalysis. Biopsy confirms the diagnosis but is rarely necessary; demonstration of hypocomplementemia is essentially confirmatory. Serum creatinine may rise rapidly but usually peaks below a level requiring dialysis.

Antistreptolysin O, the most common test 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 urinary protein/creatinine ratio may be < 2 (normal, < 0.2).

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 shows 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.

Postinfectious Glomerulonephritis (Hypercellularity With Neutrophilic Infiltration)

Postinfectious Glomerulonephritis (Epithelial Crescents)

Postinfectious Glomerulonephritis (Immunofluorescent Staining)

Postinfectious Glomerulonephritis (Immune Complex Deposits)

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 (see below).

No specific treatment exists. Treatment is supportive and may include restriction of dietary protein, Na, and fluid and treatment of edema and hypertension in more severe cases. Dialysis is occasionally necessary. Antimicrobial therapy is preventive only when given within 36 h of infection and before GN becomes established.

Rapidly progressive GN 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.

Rapidly progressive GN (RPGN) is extensive glomerular crescent formation seen on biopsy 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 on immunofluorescence microscopy (see Table 4: Glomerular Diseases: Serologic Classification of Rapidly Progressive Glomerulonephritis

Anti-glomerular basement membrane (GBM) antibody disease (type 1 RPGN) is autoimmune GN and accounts for 10% of RPGN cases. It may arise when respiratory exposures (eg, cigarette smoke, viral URI) expose 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 lungs. The combination of GN and alveolar hemorrhage in the presence of anti-GBM antibodies is called Goodpasture's syndrome (see Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome: Goodpasture's Syndrome). 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 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 50% of all RPGN cases. Almost all patients have elevated antineutrophil cytoplasmic antibodies (ANCAs) and systemic vasculitis.

Presentation is 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 present with hemoptysis or be detectable only by diffuse alveolar infiltrates on chest x-ray (pulmonary-renal or diffuse alveolar hemorrhage syndrome—see Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome).

Diagnosis is suggested by history and urinalysis and confirmed 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 granular, waxy, and broad casts) is common. 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), depending on clinical presentation; and ANCA titers (pauci-immune RPGN). Complement measurement may be of use 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 differs for the 3 RPGN types. In anti-GBM antibody disease, linear or ribbon-like deposition of IgG along the GBM is most prominent and is often accompanied by linear and sometimes granular deposition of C3. In immune complex RPGN, immunofluorescence reveals diffuse irregular mesangial IgG and C3 deposits, commonly with proliferation of intraglomerular cells and crescent formation. In pauci-immune RPGN, immune staining and deposits are not detected. However, fibrin occurs within the crescents, regardless of the fluorescence pattern.

Rapidly Progressive Glomerulonephritis (Type 1)

Rapidly Progressive Glomerulonephritis (Type 3)

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; predictors of response include early anti-GBM disease (before oliguria, creatinine < 7 mg/dL [616 μmol/L]) and PIGN, SLE, Wegener's granulomatosis, or polyarteritis nodosa as an underlying cause. Prognosis with or without treatment is poorest in patients > 60 yr, those with oliguric renal failure or higher serum creatinine, and those in whom > 75% of glomeruli contain circumferential crescents. About 30% of patients with pauci-immune RPGN do not respond to treatment; about 40% of nonresponders require dialysis, and 33% die within 4 yr. In contrast, < 20% of those who respond to treatment require dialysis, and about 3% die. Patients who recover normal renal function 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 varies by disease type, although no regimens have been rigorously studied. Therapy should be instituted early, ideally when serum creatinine is < 5 mg/dL (< 440 μmol/L) 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 populations (eg, the elderly and 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 Some Trade Names
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and cyclophosphamide Some Trade Names
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are typically started and continued to minimize new antibody formation.

For immune complex and pauci-immune RPGN, corticosteroids ( methylprednisolone Some Trade Names
MEDROL
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1 g IV once/day over 30 min for 3 to 5 days followed by prednisone Some Trade Names
DELTASONE
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1 mg/kg po once/day) may reduce serum creatinine or delay dialysis for > 3 yr in 50% of patients. Cyclophosphamide Some Trade Names
CYTOXAN
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1.5 to 2 mg/kg po once/day may also 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.

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 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 some families with thin basement membrane disease have been identified with mutation in the type IV collagen alpha 4 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 presentation.

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 performed as part of a hematuria evaluation. Early on, thin basement membrane disease may be difficult to differentiate from hereditary nephritis because of histologic similarities. Anti-GBM antibodies are usually present in thin basement membrane disease.

Thin Basement Membrane Lesion

Long-term prognosis is excellent, and no treatment is necessary in most cases. Patients with frequent gross hematuria or flank pain may benefit from ACE inhibitors, which may lower intraglomerular pressure.