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Several glomerular diseases typically present with both nephritic and nephrotic features. These 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, found in about 0.6% of renal biopsies, occur equally in men and women and have been described in patients ≥ 10 yr. Mechanism is unknown, although deposition of immunoglobulin, particularly IgG κ and λ light chains and complement, suggests immune system dysfunction. Patients may have accompanying paraproteinemia, cryoglobulinemia, plasma cell dyscrasia, 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 > ½ have renal insufficiency at presentation.
Diagnosis is suggested by laboratory data and confirmed by renal biopsy. Urinalysis usually shows a mixed nephritic and nephrotic picture. Serum complement is occasionally decreased. Light microscopy of a biopsy specimen shows mesangial expansion by eosinophilic deposits and mild mesangial hypercellularity. Congo red staining is negative for amyloid. Immunostaining reveals IgG and complement 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 microfibrillar) structures in the deposits; others distinguish it by the absence of a related systemic illness such as a paraproteinemia, cryoglobulinemia, or SLE.
The condition is usually slowly progressive with renal insufficiency, progressing to end-stage renal disease in 50% of patients by 2 to 4 yr. A more rapid decline is predicted by the presence of hypertension, nephrotic-range proteinuria, and renal insufficiency at presentation.
Immunosuppressants have been used without documented success except anecdotally; success may be greater with corticosteroids when serum complement is decreased.
Membranoproliferative Glomerulonephritis
(Mesangiocapillary Glomerulonephritis; Lobular Glomerulonephritis)
Membranoproliferative
GN is a heterogeneous group of diseases 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 systemic disease. Diagnosis is by renal biopsy. Prognosis
is generally poor. Treatment 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 NS in children, while 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.
Type
I (mesangial proliferation with immune deposits) accounts for 80 to 85% of cases. It most commonly occurs secondary to systemic immune complex disease (eg, SLE, mixed cryoglobulinemia, Sjögren's syndrome), chronic infection (eg, bacterial endocarditis, HIV, hepatitis B and C, visceral abscess, ventriculoatrial shunt), malignancy (eg, chronic lymphocytic leukemia, lymphomas, melanoma), and other disorders (eg, partial lipodystrophy, C2 or C3 deficiencies, sarcoidosis, thrombotic microangiopathies).
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 disease 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. 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.
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 by renal biopsy. Serum complement profiles are more frequently abnormal in membranoproliferative GN than in other glomerular diseases and provide supportive evidence of the diagnosis; hypocomplementemia is multifactorial in origin and is considered a marker, not a cause. In type I disease, C3 is depressed more often than C4 at diagnosis, decreases further during follow-up, but eventually normalizes. C3 is more frequently and severely reduced in type II disease. C3 is reduced but C4 is normal in type III disease. 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 type I, rare cases of type II, and 70% of cases of type III disease.
Serologic tests (eg, for SLE, hepatitis B and C, 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
and Treatment
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 3 to 5 yr and in 75% at 10 yr; at 5 yr, only 25% have normal renal function. Spontaneous remission occurs in < 5%. Type I membranoproliferative GN recurs in 30% of kidney transplantation patients; type II recurs in 90%.
Specific therapy is probably not indicated in patients with non-nephrotic–range proteinuria because the disease usually progresses slowly. In nephrotic children, treatment with prednisone 2.5 mg/kg po once/day on alternate days (maximum 80 mg) 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. In adults, dipyridamole (225 mg po once/day) with aspirin (975 mg po once/day) for 1 yr seems to stabilize renal function at 3 to 5 yr, but at 10 yr there is no difference from placebo. Prolonged therapy may be required.
Alternate therapies include α-interferon (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 azotemia in more advanced stages.
Diagnosis is based on renal biopsy. Treatment is of the underlying
disorder and usually involves corticosteroids, cytotoxic
drugs, and immune-modifying antimetabolites.
Lupus nephritis is diagnosed in about 50% of SLE patients (see Autoimmune Rheumatic Disorders: Systemic Lupus Erythematosus (SLE)). 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 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, or subepithelial deposits are characteristic. Wherever immune complexes are deposited, immunofluorescence staining is positive for complement and for IgG, IgA, and IgM in varying proportions.
Lupus nephritis should be distinguished from antiphospholipid syndrome nephropathy, which may occur independently or coexist in up to 1⁄3 of patients with lupus. 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.
Symptoms,
Signs, and Diagnosis
The most prominent symptoms and signs are those of SLE; patients who present with renal disease may have edema, foaming urine, and/or hypertension.
Diagnosis is suspected by proteinuria, with or without microscopic hematuria and RBC casts, in a patient with SLE. Lupus nephritis usually develops within 1 yr of diagnosis of SLE, and a search for renal disease with urinalysis and serum creatinine is indicated whenever SLE is diagnosed or suspected.
Diagnosis is confirmed by renal biopsy. Histology is classified (WHO criteria) as normal (class I); immune complexes in the mesangium only (mesangial proliferative—class II—10 to 20% of cases); cellular proliferation and inflammation in < 50% of glomeruli usually in a segmental distribution (focal proliferative—class III—10 to 20%); cellular proliferation and inflammation in > 50% of glomeruli (diffuse proliferative—class IV—40 to 70%); and thickening of the glomerular basement membrane with subepithelial and intramembranous immune complex deposition (membranous—class V—10 to 20%). Some of these 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, but the classification system is useful because clinical and prognostic features differ by category.
Renal function and SLE activity should be monitored regularly. A rising serum creatinine reflects deteriorating renal function, while a falling serum complement level or a rising anti-DNA antibody titer suggests increased disease activity.
Prognosis
Renal biopsies are scored with a semiquantitative “activity” and a “chronicity” index, which describe the degree of inflammation and scarring, respectively; the chronicity index (based on presence of glomerular sclerosis, fibrous crescents, tubular atrophy, or interstitial fibrosis) predicts progression of lupus nephritis to renal failure. Many experts believe that a mild to moderate chronicity index should provoke more aggressive therapy (eg, with cytotoxic drugs), whereas more severe chronicity scores may indicate irreversible disease, suggesting that the risk/benefit ratio of aggressive treatment might be unacceptable. The activity score (based on cellular proliferation, fibrinoid necrosis, cellular crescents, hyaline thrombi, wire loop lesions, glomerular leukocyte infiltration, or interstitial mononuclear cell infiltration) is less well correlated with disease progression, perhaps because it is based on more inflammatory disease that is more reversible with treatment.
Prognosis and indications for treatment of membranous lupus nephritis are poorly defined and controversial.
Treatment
Treatment usually combines cytotoxic drugs, antimetabolites, and corticosteroids. Induction is with cyclophosphamide , which is usually given in IV boluses (monthly for up to 6 mo) beginning with 0.75 g/m2 and, assuming a WBC count > 3000/μL, increasing to a maximum of 1 g/m2 in a saline solution over 30 to 60 min. Oral or IV fluid administration to create rapid urine flow minimizes the bladder toxicity of cyclophosphamide . Prednisone 60 to 80 mg po once/day is 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. Recurrences 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 (500 mg to 1 g po bid) or azathioprine (2 mg/kg po once/day, maximum 150 to 200 mg/day). Low-dose prednisone is continued (0.05 to 0.20 mg/kg once/day) and titrated based on disease activity. Duration of maintenance therapy is minimally 1 yr.
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 November 2005
Content last modified November 2005
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