Sections

DDx

Diagnostic Considerations

Lupus nephritis usually arises within 5 years of diagnosis of systemic lupus erythematosus (SLE); however, renal failure rarely occurs before American College of Rheumatology criteria for classification are met.

Besides the conditions listed in the differential diagnosis, other problems to be considered include the following:

Mesangial glomerulonephritis
Glomerulosclerosis

Differential Diagnoses

Workup

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Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treatment in lupus nephritis patients. Clin Kidney J. 2016 Aug. 9 (4):552-5. [QxMD MEDLINE Link].
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Media Gallery

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).

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Table 1. Genes Associated With Systemic Lupus Erythematosus

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.

Table 2. International Society of Nephrology/Renal Pathology Society 2003 Classification of Lupus Nephritis

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
Class VI Advanced sclerosis lupus nephritis	Clinical manifestations	Significant renal insufficiency or end-stage renal disease in most cases; unlikely to respond to medical therapy
SLE = systemic lupus erythematosus.

Table 3. Active and Chronic Glomerular Lesions

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

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Author

Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology

Disclosure: Stock ownership for: Johnson & Johnson.

Coauthor(s)

Arati S Karhadkar, MD Consulting Physician, Rheumatology Associates, Ltd

Disclosure: Nothing to disclose.

Eric Bloom, MD Division Chief of Nephrology, Nephrology Fellowship Program Director, Attending Physician, Division of Nephrology, Department of Internal Medicine, Albert Einstein Medical Center

Eric Bloom, MD is a member of the following medical societies: American Society of Nephrology, National Kidney Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ajay K Singh, MB, MRCP, MBA Associate Professor of Medicine, Harvard Medical School; Director of Dialysis, Renal Division, Brigham and Women's Hospital; Director, Brigham/Falkner Dialysis Unit, Faulkner Hospital

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Interim Chair, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Carlos J Lozada, MD Director of Rheumatology Fellowship Training Program, Professor of Clinical Medicine, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Received honoraria from Pfizer for consulting; Received grant/research funds from AbbVie for other; Received honoraria from Heel for consulting.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Irene Viola, MD, to the development and writing of the source article.

Lupus Nephritis Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

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