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Several glomerular disorders typically manifest with features of both nephritic and nephrotic syndromes. These disorders include fibrillary and immunotactoid glomerulopathies, membranoproliferative glomerulonephritis (GN), and lupus nephritis.
Fibrillary and Immunotactoid Glomerulopathies
Fibrillary and immunotactoid glomerulopathies are rare conditions defined pathologically by organized deposition of nonamyloid microfibrillar or microtubular structures within the renal mesangium and basement membrane.
Fibrillary and immunotactoid glomerulopathies are thought by some experts to be related disorders. They are found in about 0.6% of renal biopsy specimens, occur equally in men and women, and have been described in patients ≥ 10 yr. Average age at diagnosis is about 45. Mechanism is unknown, although deposition of immunoglobulin, particularly IgG κ and λ light chains and complement (C3), suggests immune system dysfunction. Patients may have accompanying paraproteinemia, cryoglobulinemia, plasma cell dyscrasia, hepatitis C infection, or SLE, or they may have a primary renal disease without evidence of systemic disease.
All patients have proteinuria, > 60% in the nephrotic range. Microscopic hematuria is present in about 60%; hypertension, in about 70%. Slightly > 50% have renal insufficiency at presentation.
Diagnosis
Diagnosis is suggested by laboratory data and confirmed by renal biopsy. If nephrotic syndrome is present, testing is done as for other cases of nephrotic syndrome. Urinalysis usually shows features of nephritic and nephrotic syndromes. Serum C3 and C4 are usually measured and are occasionally decreased. Light microscopy of a biopsy specimen shows mesangial expansion by amorphous eosinophilic deposits and mild mesangial hypercellularity. Various other changes may be present on light microscopy (eg, crescent formation, membranoproliferative patterns). Congo red staining is negative for amyloid. Immunostaining reveals IgG and C3 and sometimes κ and λ light chains in the area of the deposits. Electron microscopy shows glomerular deposits consisting of extracellular, elongated, nonbranching microfibrils or microtubules. The diameter of the microfibrils and microtubules varies from 9 nm to > 50 nm. Some experts distinguish immunotactoid from fibrillary glomerulopathy by the presence of microtubular (as opposed to smaller microfibrillar) structures in the deposits; others distinguish them by the presence of a related systemic illness such as a paraproteinemia, cryoglobulinemia, or SLE in immunotactoid GN.
Prognosis
The condition is usually slowly progressive with renal insufficiency, progressing to end-stage renal disease in 50% of patients within 2 to 4 yr. A more rapid decline is predicted by the presence of hypertension, nephrotic-range proteinuria, and renal insufficiency at presentation.
Treatment
Evidence to support specific treatments is lacking. Immunosuppressants have been used based on anecdotal evidence; success may be greater with corticosteroids when serum complement is decreased.
Membranoproliferative Glomerulonephritis
(Mesangiocapillary Glomerulonephritis; Lobular Glomerulonephritis)
Membranoproliferative GN is a heterogeneous group of disorders that share mixed nephritic and nephrotic features and microscopic findings. They mostly affect children. Cause is immune complex deposition that is idiopathic or secondary to a systemic disorder. Diagnosis is by renal biopsy. Prognosis is generally poor. Treatment, when indicated, is with corticosteroids and antiplatelet drugs.
Membranoproliferative GN is a group of immune-mediated disorders characterized histologically by glomerular basement membrane (GBM) thickening and proliferative changes on light microscopy. There are 3 types, each of which may have primary (idiopathic) or secondary causes. Primary forms affect children and young adults between ages 8 and 30 and account for 10% of cases of nephrotic syndrome in children; secondary causes tend to affect adults > 30. Men and women are affected equally. Reported familial cases of some types suggest genetic factors play a role in at least some cases. Many factors contribute to hypocomplementemia.
Type I (mesangial proliferation with immune deposits) accounts for 80 to 85% of cases. The idiopathic form is rare. Type I most commonly occurs secondary to one of the following:
Type II (similar to type I with less mesangial proliferation and with GBM dense deposits) accounts for 15 to 20%. It is probably an autoimmune disorder in which an IgG autoantibody (C3 nephritic factor) binds C3 convertase, rendering C3 resistant to inactivation; immunofluorescent staining identifies C3 around dense deposits and in mesangium.
Type III is thought to be a disorder similar to type I and accounts for few cases. Cause is unknown but may be related to immune complex (IgG, C3) deposition. An IgG autoantibody against the terminal component of complement is found in 70% of patients. Subepithelial deposits can occur focally and appear to disrupt the GBM.
Symptoms and Signs
Symptoms and signs are those of nephrotic syndrome in 60 to 80% of cases. Symptoms and signs of nephritic syndrome (acute GN) are presenting features in 15 to 20% of cases of type I and III disease and in a higher percentage of type II disease. At diagnosis, 30% of patients have hypertension and 20% have renal insufficiency; hypertension often develops even before GFR declines. Patients with type II disease have a greater incidence of ocular abnormalities (basal laminar drusen, diffuse retinal pigment alterations, diskiform macular detachment, choroidal neovascularization), which ultimately impair vision.
Diagnosis
Diagnosis is confirmed by renal biopsy, but other tests are done.
Serum complement profiles are more frequently abnormal in membranoproliferative GN than in other glomerular disorders and provide supportive evidence of the diagnosis. C3 levels are often low. In type I disease, C3 is depressed more often than C4 at diagnosis and decreases further during follow-up, but eventually normalizes. In type II disease, C3 is more frequently and severely reduced. In type III disease, C3 is reduced but C4 is normal. C3 nephritic factor is detectable in 80% of patients with type II and in some patients with type I disease. Terminal complement nephritic factor is detectable in 20% of patients with type I, rare patients with type II, and 70% of patients with type III disease.
Serologic tests (eg, for SLE, hepatitis B and C virus, and cryoglobulinemia) are warranted to check for secondary causes of type I disease.
CBC, often obtained in the course of diagnostic evaluation, demonstrates normochromic-normocytic anemia, often out of proportion to the stage of renal insufficiency (possibly because of hemolysis), and thrombocytopenia from platelet consumption.
Prognosis
Prognosis is good if a condition causing secondary membranoproliferative GN is successfully treated. Idiopathic type I membranoproliferative GN often progresses slowly; type II progresses more rapidly. In general, the long-term prognosis is poor. End-stage renal disease occurs in 50% of patients at 10 yr and in 90% at 20 yr. Spontaneous remission occurs in < 5% with type II. Type I membranoproliferative GN recurs in 30% of kidney transplantation patients; type II recurs in 90%. Outcome tends to be worse if proteinuria is in the nephrotic range.
Treatment
Underlying disorders are treated when possible. Specific therapy is probably not indicated in patients with non-nephrotic–range proteinuria because the disorder usually progresses slowly.
Among children with nephrotic-range proteinuria, treatment with corticosteroids, eg, prednisone 2.5 mg/kg po once/day on alternate days (maximum 80 mg/day) for 1 yr, followed by tapering to a maintenance dose of 20 mg on alternate days for 3 to 10 yr, may stabilize renal function. However, corticosteroid treatment may retard growth and cause hypertension.
Among adults, dipyridamole (225 mg po once/day) with aspirin (975 mg po once/day) for 1 yr may stabilize renal function at 3 to 5 yr, but at 10 yr there is no difference from placebo. Studies of antiplatelet therapy yield inconsistent results.
Alternate therapies are sometimes substituted for the usual treatments (eg, corticosteroids could exacerbate underlying hepatitis C). Alternative therapies include pegylated interferon alfa 2A or 2B (with addition of ribavirin if creatinine clearance is > 50 mL/min) for hepatitis C virus–associated disease and plasmapheresis with corticosteroids for concomitant severe cryoglobulinemia or rapidly progressive GN. ACE inhibitors may decrease proteinuria and help control hypertension.
Lupus Nephritis
Lupus nephritis is GN caused by SLE. Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis is based on renal biopsy. Treatment is of the underlying disorder and usually involves corticosteroids and cytotoxic or other immunosuppressant drugs.
Lupus nephritis is diagnosed in about 50% of SLE patients (see Autoimmune Rheumatic Disorders: Systemic Lupus Erythematosus (SLE)) and typically develops within 1 yr of diagnosis. However, the total incidence is probably > 90%, because renal biopsy in patients with suspected SLE without clinical evidence of renal disease shows changes of GN.
Pathophysiology
Pathophysiology involves immune complex deposition with development of GN. The immune complexes consist of nuclear antigens (especially DNA), high-affinity complement-fixing IgG antinuclear antibodies, and antibodies to DNA. Subendothelial, intramembranous, subepithelial, or mesangial deposits are characteristic. Wherever immune complexes are deposited, immunofluorescence staining is positive for complement and for IgG, IgA, and IgM in varying proportions. Epithelial cells may proliferate, forming crescents. Classification of lupus nephritis is based on histologic findings (see Table 6: Glomerular Disorders: Classification of Lupus Nephritis ).
Antiphospholipid syndrome nephropathy:
This syndrome may occur with or without lupus nephritis in up to one third of patients with SLE. In the antiphospholipid antibody syndrome, circulating lupus anticoagulant (see Thrombotic Disorders: Antiphospholipid Antibody Syndrome) causes microthrombi, endothelial damage, and cortical ischemic atrophy. Antiphospholipid syndrome nephropathy increases a patient's risk of hypertension and renal insufficiency or failure compared with lupus nephritis alone.
Symptom and Signs
The most prominent symptoms and signs are those of SLE; patients who present with renal disease may have edema, foaming urine, hypertension, or a combination.
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Table 6
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| Classification of Lupus Nephritis |
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Class
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Description
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Histologic Findings*
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Clinical Findings
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Renal Prognosis
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I
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Minimal mesangial
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Normal (although immune complexes are sometimes visible using immunofluorescence or electron microscopy)
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None
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Excellent
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II
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Mesangial proliferative
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Immune complexes in the mesangium only and mesangial hypercellularity
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Possibly microscopic hematuria, proteinuria, or both
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Excellent
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III
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Focal proliferative
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Endocapillary and extracapillary cellular proliferation and inflammation in < 50% of glomeruli, usually in a segmental distribution
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Usually hematuria and proteinuria
Possibly hypertension, nephrotic syndrome, and elevated serum creatinine
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Variable
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IV
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Diffuse proliferative†
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Endocapillary and extracapillary cellular proliferation and inflammation in > 50% of glomeruli
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Usually hematuria and proteinuria
Frequently hypertension, nephrotic syndrome, and elevated serum creatinine
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Variable
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V
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Membranous
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Thickening of the glomerular basement membrane with subepithelial and intramembranous immune complex deposition
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Usually nephrotic syndrome
Sometimes microscopic hematuria or hypertension
Serum creatinine usually normal or slightly elevated
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Poorly defined
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VI
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Sclerosing
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Sclerosis of > 90% of glomerular capillaries
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Bland urinary sediment and end-stage renal disease or slowly increasing serum creatinine
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Poor
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* Using light microscopy.
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†Most common form.
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Diagnosis
Diagnosis is suspected in all patients with SLE, particularly in patients who have proteinuria, microscopic hematuria, RBC casts, or hypertension. Diagnosis is also suspected in patients with unexplained hypertension, elevated serum creatinine levels, or abnormalities on urinalysis who have clinical features suggesting SLE.
Urinalysis is done and serum creatinine is measured. If either is abnormal, renal biopsy is usually done to confirm the diagnosis and classify the disorder histologically. Histologic classification helps determine prognosis and direct treatment.
Some of the histologic subtypes are similar to other glomerulopathies; eg, membranous and diffuse proliferative lupus nephritis are histologically similar to idiopathic membranous GN and type I membranoproliferative GN, respectively. Overlap between these categories is substantial, and patients may progress from one class to another over time.
Renal function and SLE activity should be monitored regularly. A rising serum creatinine level reflects deteriorating renal function, while a falling serum complement level or a rising anti-DNA antibody titer suggests increased disease activity.
Prognosis
Class of nephritis influences renal prognosis (see Table 6: Glomerular Disorders: Classification of Lupus Nephritis), as do other renal histologic features. Renal biopsies are scored with a semiquantitative activity score and with a chronicity index.
The activity score describes the degree of inflammation. The score is based on cellular proliferation, fibrinoid necrosis, cellular crescents, hyaline thrombi, wire loop lesions, glomerular leukocyte infiltration, and interstitial mononuclear cell infiltration.
The chronicity index describes the degree of scarring. It is based on presence of glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The chronicity index predicts progression of lupus nephritis to renal failure. A mild to moderate chronicity score suggests at least partially reversible disease, whereas more severe chronicity scores may indicate irreversible disease. The activity score is less well correlated with disease progression, perhaps because it is based on the degree of inflammation, which is more reversible with treatment.
Patients with lupus nephritis are at high risk of cancers, primarily B-cell lymphomas. Risk of atherosclerotic complications (eg, coronary artery disease, ischemic stroke) is also high, because of frequent vasculitis, hypertension, hyperlipidemia, and use of corticosteroids.
Treatment
Immunosuppression:
Treatment is toxic and thus is reserved for nephritis that has the following characteristics:
Activity is estimated by the activity score as well as clinical criteria (eg, urine sediment, increasing urine protein, increasing serum creatinine). Many experts believe that a mild to moderate chronicity score, because it suggests reversibility, should provoke more aggressive therapy than a more severe chronicity score. Nephritis with the potential for deterioration and for reversibility is usually class III or IV; it is unclear whether class V nephritis warrants aggressive treatment.
Treatment usually combines cytotoxic drugs, corticosteroids, and sometimes other immunosuppressants. Induction is with cyclophosphamide, which is usually given in IV boluses (monthly for up to 6 mo) beginning with 0.75 g/m2 in a saline solution over 30 to 60 min and, assuming a WBC count > 3000/μL, increasing to a maximum of 1 g/m2. Oral or IV fluid administration to create rapid urine flow minimizes the bladder toxicity of cyclophosphamide, as does mesna (see Autoimmune Rheumatic Disorders: Protocol for Chemotherapy With Cyclophosphamide and IV Mesna). Prednisone is begun at 60 to 80 mg po once/day and tapered according to response to 20 to 25 mg every other day over 6 to 12 mo. The amount of prednisone is determined by the extrarenal manifestations and number of relapses. Relapses are usually treated with increasing doses of prednisone.
Many experts are replacing the more toxic cyclophosphamide maintenance regimens (after induction with 6 or 7 monthly IV cyclophosphamide doses) with protocols using mycophenolate mofetil (500 mg to 1 g po bid) or azathioprine (2 mg/kg po once/day, maximum 150 to 200 mg/day). Chlorambucil, cyclosporine, and tacrolimus have also been used, but relative efficacies are not clear. Low-dose prednisone (0.05 to 0.2 mg/kg po once/day) is continued and titrated based on disease activity. Duration of maintenance therapy is at least 1 yr.
Other treatments:
Angiotensin inhibition with an ACE inhibitor or angiotensin II receptor blocker is indicated for patients with even mild hypertension (eg, BP > 130/80 mm Hg) or proteinuria. Also, hyperlipidemia and risk factors for atherosclerosis should be treated aggressively.
Anticoagulation is of theoretical benefit for patients with antiphospholipid syndrome nephropathy, but the value of such treatment has not been established.
Last full review/revision January 2010 by James I. McMillan, MD
Content last modified February 2012
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