Abstract
Lupus nephritis (LN) is clinically evident in 50% to 75% of lupus patients and is a significant cause of lupus-associated morbidity and mortality, including end-stage kidney disease. LN is a paradigm of immune complex–mediated kidney injury: the immune deposits that incite LN are primarily complexes of anti-double-stranded DNA antibodies directed against nucleosomal antigens. However, the pathogenesis is complex, involving abnormalities in multiple components of the immune system, including B and T cells, the complement cascade, cytokines, and clearance of apoptosis. The diagnosis of LN is suspected by changes in laboratory parameters—elevated creatinine, presence of hematuria and/or proteinuria, low serum complements—but still hinges on the kidney biopsy with glomerular changes being the major determinant of classification. The current approach to treating LN is guided by histologic findings (i.e., International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class and the degree of activity and chronicity), with appropriate consideration of presenting clinical parameters and the degree of kidney function impairment. Treatment regimens for LN typically utilize combination therapy of corticosteroids with cyclophosphamide or mycophenolate. After remission is obtained, maintenance therapy involves a tapering dose of corticosteroids combined with an antimetabolite. LN has been shown to impact clinical outcomes in systemic lupus erythematosus (SLE) both directly via target organ damage and indirectly through complications of therapy.
Keywords
lupus nephritis, immunosuppression, kidney biopsy, glomerulonephritis, systemic lupus erythematosus, antiphospholipid syndrome, mycophenolic acid, cyclophosphamide, hematuria, proteinuria
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organs, including the skin, joints, brain, peripheral nervous system, heart, gastrointestinal tract, and kidneys. Kidney involvement in SLE, generally termed lupus nephritis (LN), is a major contributor to SLE-associated morbidity and mortality. Up to 50% of SLE patients will have clinically evident kidney disease at presentation, and, during follow-up, kidney involvement occurs in up to 75% of patients, with an even greater representation among children and young adults. LN impacts clinical outcomes in SLE both directly via target organ damage and indirectly through complications of therapy.
Presentation
Most patients with SLE will have laboratory evidence of kidney involvement at some point during the course of their disease. In about one-third of SLE patients, kidney involvement first manifests with proteinuria and/or microscopic hematuria; this eventually progresses to reduction in kidney function. However, early in the course of disease, it is unusual for patients to present with decreased glomerular filtration rate (GFR), except in very aggressive cases of LN, some of which present as rapidly progressive glomerulonephritis. Instead, patients often present initially with evidence of nonkidney organ involvement, such as malar rash, arthritis, and oral ulcers. After a diagnosis of SLE is confirmed with appropriate laboratory tests, evidence of kidney disease, if present, usually emerges within the first 3 years of diagnosis.
Signs of kidney involvement tend to correlate with laboratory abnormalities. For example, patients with nephrotic range proteinuria often present with edema of the lower extremities and, if proteinuria is severe, periorbital edema in the morning. When GFR falls, as is the case with progressive forms of LN, elevated blood pressure is common. The rare development of dark or tea-colored urine is a sign of gross hematuria. A number of tools, such as the SLE Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) Index, have been developed to assess the systemic severity of lupus symptoms. Although these questionnaires are primarily used to codify symptoms for clinical trial settings, they also can be very helpful to elicit a detailed history from a patient with SLE.
Evaluation
Laboratory Findings
The American College of Rheumatology (ACR) lists 11 diagnostic criteria for SLE: antinuclear antibodies (ANA), arthritis, immunologic disorders (including anti-double-stranded DNA [dsDNA] antibody, antiphospholipid antibody, or anti-Smith antibody), malar rash, discoid rash, photosensitivity, oral ulcers, serositis, hematologic disorder, neurologic disorder, and kidney disorder ( Table 25.1 ). Ideally, four or more of these criteria should be present to diagnose SLE, including laboratory findings of a positive ANA and/or anti-dsDNA antibody. In addition to the ANA and dsDNA antibody, serum complement (C3, C4, CH50) should be checked whenever kidney involvement is suspected, because these are often low when disease is active, as is usually the case with any severe proliferative LN. Antiphospholipid and anticardiolipin antibodies are useful in gauging the risk for clotting abnormalities that can accompany SLE.
| Criteria | Description |
|---|---|
| Malar rash | Flat or raised erythematous rash over the malar eminences |
| Discoid rash | Erythematous raised patches, usually circular, with adherent keratotic scaling; atrophic scarring may occur |
| Photosensitivity | Rash upon exposure to ultraviolet light |
| Oral ulcers | Oral and/or nasopharyngeal ulcerations |
| Arthritis | Nonerosive arthritis of at least two peripheral joints, with tenderness and/or swelling |
| Serositis | Pleuritis or pericarditis |
| Kidney disorder | Proteinuria, hematuria, and/or elevated creatinine |
| Neurologic disorder | Seizures or psychosis without other etiologies |
| Hematologic disorder | Anemia (hemolytic), leukopenia, or thrombocytopenia without other etiologies |
| Immunologic disorder | Anti-dsDNA, anti-Sm, and/or antiphospholipid antibodies |
| ANA | An abnormal ANA titer in the absence of drugs known to induce ANAs |
Laboratory testing is used both to diagnose kidney involvement and to assess response to therapy in patients with SLE. Traditional parameters, such as serum creatinine and urinary protein excretion (quantified by either 24-hour collection, urine protein to creatinine ratio, or urine albumin to creatinine ratio), are supplemented by serial review of microscopic urinary sediment, changes in serum complement levels, and titers of ANA and dsDNA antibodies. Because cytopenias are often seen in active SLE, complete blood counts should be checked regularly. A number of urine and serologic tests have been studied as biomarkers for SLE and, specifically, LN disease activity. These include molecules specific to lupus (e.g., anti-C1q antibodies), mediators of chronic inflammation (e.g., TNF-like weak inducer of apoptosis [TWEAK]), and generalized markers of kidney injury (urinary neutrophil gelatinase-associated lipocalin [uNGAL]). However, the clinical utility of this approach remains unproven, and no serum or urine disease markers are able to provide as much information as a kidney biopsy. Hence, virtually all patients with SLE with suspected kidney involvement undergo one or more kidney biopsies at some point during their care.
Kidney Biopsy Findings
The classic pattern of LN is an immune complex–mediated glomerulonephritis; however, the pathology of LN can be varied and at times can cause confusion with other immune complex–mediated glomerulonephritides. Particular biopsy findings highly characteristic of LN include (1) glomerular deposits that stain dominantly for IgG with codeposits of IgA, IgM, C3, and C1q, the so-called full house immunofluorescence (IF) pattern; (2) extraglomerular immune-type deposits within tubular basement membranes, the interstitium, and blood vessels; (3) the ultrastructural finding of coexistent mesangial, subendothelial, and subepithelial electron-dense deposits; and (4) the ultrastructural finding of tubuloreticular inclusions, which represent “interferon footprints” in the glomerular endothelial cell cytoplasm ( Fig. 25.1 ).
Although lupus may affect all compartments of the kidney, including glomeruli, tubules, interstitium, and blood vessels, glomerular involvement is the best studied component and correlates well with presentation, course, and treatment response. Accordingly, disease classification is based largely on the glomerular alterations, as assessed by the combined modalities of light microscopy, IF, and electron microscopy (EM). Over the past 4 decades, there have been several attempts by different societies, particularly the World Health Organization (WHO), to classify the diverse glomerulopathies associated with SLE. Based on clinicopathologic correlations, a revised classification system of LN was developed by a working group of renal pathologists, nephrologists, and rheumatologists under the joint auspices of the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) and was published in 2004 as the ISN/RPS classification. By refining and clarifying many of the deficiencies of the older WHO classification, this revised schema has eliminated ambiguities and has achieved greater reproducibility. The ISN/RPS classification recognizes six different classes of immune complex–mediated lupus glomerulonephritis based on biopsy findings ( Table 25.2 ). These classes are not static entities but may transform from one class to another, both spontaneously and after therapy.
| Designation | Description | Characteristic Clinical Features |
|---|---|---|
| Class I: minimal mesangial lupus nephritis | No LM abnormalities; isolated mesangial IC deposits on IF and/or EM | Normal urine or microscopic hematuria |
| Class II: mesangial proliferative lupus nephritis | Mesangial hypercellularity or matrix expansion with mesangial IC deposits on IF and/or EM | Microscopic hematuria and/or low-grade proteinuria |
| Class III: focal lupus nephritis a | <50% of glomeruli on LM display segmental (<50% of glomerular tuft) or global (>50% of glomerular tuft) endocapillary and/or extracapillary proliferation or sclerosis; mesangial and focal subendothelial IC deposits on IF and EM | Nephritic urine sediment and subnephrotic proteinuria |
| Class IV: diffuse lupus nephritis a | ≥50% of glomeruli on LM display endocapillary and/or extracapillary proliferation or sclerosis; class IV-S denotes ≥50% of affected glomeruli have segmental lesions; class IV-G denotes ≥50% of affected glomeruli have global lesions; mesangial and diffuse subendothelial IC deposits on IF and EM | Nephritic and nephrotic syndromes, hypertension, reduced kidney function |
| Class V: membranous lupus nephritis b | Diffuse thickening of the glomerular capillary walls on LM with subepithelial IC deposits on IF and EM, with or without mesangial IC deposits | Nephrotic syndrome |
| Class VI: advanced sclerosing lupus nephritis | >90% of glomeruli on LM are globally sclerosed with no residual activity | Markedly reduced kidney function, hypertension |
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