Approach Considerations
Evaluating kidney function in patients with systemic lupus erythematosus (SLE) to detect any kidney involvement early is important because early detection and treatment can significantly improve renal outcome. [24]
Kidney biopsy should be considered in any patient with SLE who has clinical or laboratory evidence of active nephritis, especially upon the first episode of nephritis. [24, 30]
Lupus nephritis is staged according to the classification revised by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) in 2013. This classification is based on light microscopy, immunofluorescence, and electron microscopy findings from kidney biopsy specimens.
Laboratory Tests for Kidney Function in SLE
Laboratory tests to evaluate kidney function in SLE patients include the following:
-
Blood urea nitrogen (BUN) testing
-
Serum creatinine assessment
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Urinalysis (to check for protein, red blood cells [RBCs], and cellular casts)
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A spot urine test for creatinine and protein concentration (normal creatinine excretion is 1000 mg/24 h/1.75 m2; normal protein excretion is 150-200 mg/24 h/1.75 m2; normal urinary protein-to-creatinine ratio is < 0.2)
-
A 24-hour urine test for creatinine clearance and protein excretion
In an international study, Smith and colleagues reported that a panel of novel urinary biomarkers can accurately identify active lupus nephritis in children. [31] These authors concluded that the optimal biomarker panel would include the following:
-
Alpha-1-acid glycoprotein (AGP)
-
Ceruloplasmin
-
Lipocalin-like prostaglandin D synthase (LPGDS)
-
Transferrin (area under the curve [AUC] 0.920)
Laboratory Tests for SLE Disease Activity
SLE disease activity can be evaluated by assessing antibodies to double-stranded DNA (dsDNA), complement (C3, C4, and CH50), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels.
The CRP level is generally not elevated in patients with SLE, even with active disease, unless the patient has significant arthritis or infection. [24] Generally, elevated ESR and anti-dsDNA and depressed C3 and C4 levels are associated with active nephritis, especially focal and diffuse lupus nephritis. Clinically relevant lupus nephritis is associated with a 30% decrease in creatinine clearance, proteinuria of greater than 1000 mg/d, and/or renal biopsy findings indicating active lupus nephritis.
Anti-nucleosome antibodies appear early in the course of the autoimmune response in SLE, they have high sensitivity and specificity for a diagnosis of SLE, and the titers correlate with disease activity. [32, 33, 34] Anti-C1q antibodies are associated with lupus nephritis; higher titers correlate with active renal disease. [35, 36]
Anti-C1q antibodies have a sensitivity of 44-100% and a specificity of 70-92% in active renal disease (SLE); in combination with low C3 and C4 levels, these may be the predictors of renal flares in patients with SLE. [37] Although anti-DNA antibodies were more sensitive than anti-C1q antibodies for active lupus nephritis (75% vs 53%, respectively), anti-C1q antibodies were more specific (84% vs 49%, respectively); the negative predictive value of negative anti-DNA and anti-C1q antibodies for active lupus nephritis was 91%. [38]
Kidney Biopsy
Kidney biopsy may be useful in patients with recurrent episodes of nephritis, depending on the clinical circumstances. By revealing the histologic pattern and stage of disease (activity and chronicity), kidney biopsy is useful in determining prognosis and treatment. Findings from a thorough clinical and laboratory evaluation can be used to predict the histologic type of lupus nephritis in approximately 70-80% of patients; however, this is not accurate enough, in view of the toxicity of some of the treatment protocols.
A good rule is to perform a kidney biopsy if the findings will potentially alter patient management. If a particular patient has other manifestations of SLE (eg, severe central nervous system [CNS] or hematologic involvement) and will be treated with cyclophosphamide, biopsy may not be necessary but should still be considered because it may help predict renal outcome.
Sampling error can occur during a kidney biopsy. Thus, the results of the biopsy should always be evaluated for consistency with the clinical and laboratory presentation of the patient.
The experience of pathologists in reading lupus nephritis biopsy specimens varies considerably. Studies have suggested that the most consistent readers are in larger medical centers with substantial populations of patients with SLE. [39]
Staging
The classification of lupus nephritis was revised by the International Society of Nephrology and the Renal Pathology Society (ISN/RPS) in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from kidney biopsy specimens. The ISN/RPS classification itself is based on earlier classifications by the World Health Organization (WHO) in 1974 and 1982 (see Table 2 below). [40] Further revision of the ISN/RPS classification, proposed in 2018, includes elimination of the class IV-S and IV-G subdivisions of class IV lupus nephritis and replacement of the active and chronic designations for class III/IV lesions by a proposal for activity and chronicity indices to be applied to all classes. [41]
Table 2. International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis (Open Table in a new window)
Class I Minimal mesangial lupus nephritis |
Light microscopy findings |
Normal |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits |
|
Clinical manifestations |
Mild proteinuria |
|
Class II Mesangial proliferative lupus nephritis |
Light microscopy findings |
Purely mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits; few immune deposits in subepithelial or subendothelial deposits possible |
|
Clinical manifestations |
Mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy |
|
Class III Focal lupus nephritis Class III (A) Active lesions - Focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions - Focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions - Focal sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive focal, segmental, or global glomerulonephritis involving < 50% of all glomeruli |
Immunofluorescence electron microscopy findings |
Subendothelial and mesangial immune deposits |
|
Clinical manifestations |
Active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria in many patients; worsening renal function in significant minority, potentially progressing to class IV lupus nephritis |
|
Class IV Diffuse lupus nephritis Class IV-S (A) Active lesions - Diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions - Diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions - Diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions - Diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars - Diffuse global sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive diffuse, segmental or global glomerulonephritis involving = 50% of all glomeruli; subdivided into diffuse segmental (class IV-S) when = 50% of involved glomeruli have segmental lesions (involving less than half of glomerular tuft) and diffuse global (class IV-G) when = 50% of involved glomeruli have global lesions |
Immunofluorescence electron microscopy findings |
Subendothelial immune deposits |
|
Clinical manifestations |
Clinical evidence of renal disease including hypertension, edema, active urinary sediment, worsening renal function, and nephrotic range proteinuria in most cases; active extrarenal SLE in many patients |
|
Class V Membranous lupus nephritis |
Light microscopy findings |
Diffuse thickening of glomerular basement membrane without inflammatory infiltrate; possibly, subepithelial deposits and surrounding basement membrane spikes on special stains, including silver and trichrome; may occur in combination with class II or IV; may show advanced sclerosis |
Immunofluorescence electron microscopy findings |
Subepithelial and intramembranous immune deposits; subendothelial deposits present only when associated proliferative component is present |
|
Clinical manifestations |
Clinical and laboratory features of nephrotic syndrome, usually without manifestations of active SLE |
|
Class VI Advanced sclerosis lupus nephritis |
Light microscopy findings |
Advanced glomerular sclerosis involving = 90% of glomeruli, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury |
Clinical manifestations |
Significant renal insufficiency or end-stage renal disease in most cases; unlikely to respond to medical therapy |
|
SLE = systemic lupus erythematosus. |
||
In addition to the pathologic classification, activity and chronicity indices are scored pathologically and predict the renal prognosis—that is, the progression of renal disease (see Table 3 below). The activity index reflects the state of active inflammation observed at biopsy, which may be reversible with medical therapy. The chronicity index reflects the amount of fibrosis and scarring, which are unlikely to respond to therapy. Renal lesions with a high activity index are more likely to respond to aggressive therapy, whereas renal lesions with high chronicity are not.
These indices in the table below serve as a prognostic tool and a general guide to therapy. Signs of activity justify aggressive medical therapy because such therapy may arrest or reverse the pathologic changes. Signs of chronicity suggest irreversibility, and aggressive therapy is less likely to affect the outcome. The activity and chronicity indices are evaluated at a single point in time, and renal lesions may transform from one class to another either spontaneously or as a result of treatment.
Table 3. Active and Chronic Glomerular Lesions (Open Table in a new window)
Activity Index |
Chronicity Index |
• Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction • Karyorrhexis • Fibrinoid necrosis • Rupture of glomerular basement membrane • Cellular or fibrocellular crescents • Subendothelial deposits on light microscopy • Intraluminal immune aggregates |
• Glomerular sclerosis; segmental, global • Fibrous adhesion • Fibrous crescents |
See the images below.
Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).
Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).
-
Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
-
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).
-
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
-
Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
-
Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
-
Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
-
Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).
-
Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
-
Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).
Tables
Gene Locus |
Gene Name |
Gene Product |
1p13.2 |
PTPN22 |
Lymphoid-specific protein tyrosine phosphatase |
1q21-q23 |
CRP |
CRP |
1q23 |
FCGR2A, FCGR2B |
FcγRIIA (R131), FcγRIIB |
1q23 |
FCGR3A, FCGR3B |
FcγRIIIA (V176), FcγRIIIB |
1q31-q32 |
IL10 |
IL-10 |
1q36.12 |
C1QB |
C1q deficiency |
2q32.2-q32.3 |
STAT4 |
Signal transducer and activator of transcription 4 |
2q33 |
CTLA4 |
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) |
6p21.3 |
HLA-DRB1 |
HLA-DRB1: DR2/*1501, DR3/*0301C1q deficiency |
6p21.3 |
C2, C4A, C4B |
C2, C4 deficiencies |
6p21.3 |
TNF |
TNF-a (promoter, -308) |
10q11.2-q21 |
MBL2 |
Mannose-binding lectin |
CRP = C-reactive protein; HLA = human leukocyte antigen; IL = interleukin; TNF = tumor necrosis factor. |
||
Class I Minimal mesangial lupus nephritis |
Light microscopy findings |
Normal |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits |
|
Clinical manifestations |
Mild proteinuria |
|
Class II Mesangial proliferative lupus nephritis |
Light microscopy findings |
Purely mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits; few immune deposits in subepithelial or subendothelial deposits possible |
|
Clinical manifestations |
Mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy |
|
Class III Focal lupus nephritis Class III (A) Active lesions - Focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions - Focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions - Focal sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive focal, segmental, or global glomerulonephritis involving < 50% of all glomeruli |
Immunofluorescence electron microscopy findings |
Subendothelial and mesangial immune deposits |
|
Clinical manifestations |
Active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria in many patients; worsening renal function in significant minority, potentially progressing to class IV lupus nephritis |
|
Class IV Diffuse lupus nephritis Class IV-S (A) Active lesions - Diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions - Diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions - Diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions - Diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars - Diffuse global sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive diffuse, segmental or global glomerulonephritis involving = 50% of all glomeruli; subdivided into diffuse segmental (class IV-S) when = 50% of involved glomeruli have segmental lesions (involving less than half of glomerular tuft) and diffuse global (class IV-G) when = 50% of involved glomeruli have global lesions |
Immunofluorescence electron microscopy findings |
Subendothelial immune deposits |
|
Clinical manifestations |
Clinical evidence of renal disease including hypertension, edema, active urinary sediment, worsening renal function, and nephrotic range proteinuria in most cases; active extrarenal SLE in many patients |
|
Class V Membranous lupus nephritis |
Light microscopy findings |
Diffuse thickening of glomerular basement membrane without inflammatory infiltrate; possibly, subepithelial deposits and surrounding basement membrane spikes on special stains, including silver and trichrome; may occur in combination with class II or IV; may show advanced sclerosis |
Immunofluorescence electron microscopy findings |
Subepithelial and intramembranous immune deposits; subendothelial deposits present only when associated proliferative component is present |
|
Clinical manifestations |
Clinical and laboratory features of nephrotic syndrome, usually without manifestations of active SLE |
|
Class VI Advanced sclerosis lupus nephritis |
Light microscopy findings |
Advanced glomerular sclerosis involving = 90% of glomeruli, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury |
Clinical manifestations |
Significant renal insufficiency or end-stage renal disease in most cases; unlikely to respond to medical therapy |
|
SLE = systemic lupus erythematosus. |
||
Activity Index |
Chronicity Index |
• Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction • Karyorrhexis • Fibrinoid necrosis • Rupture of glomerular basement membrane • Cellular or fibrocellular crescents • Subendothelial deposits on light microscopy • Intraluminal immune aggregates |
• Glomerular sclerosis; segmental, global • Fibrous adhesion • Fibrous crescents |
