Genetics of Lupus Nephritis: Clinical Implications

doi:10.1016/j.semnephrol.2015.08.002

Seminars in Nephrology

Volume 35, Issue 5, September 2015, Pages 396-409

https://doi.org/10.1016/j.semnephrol.2015.08.002 Get rights and content

Summary

Systemic lupus erythematosus is a heterogeneous autoimmune disease marked by the presence of pathogenic autoantibodies, immune dysregulation, and chronic inflammation that may lead to increased morbidity and early mortality from end-organ damage. More than half of all systemic lupus erythematosus patients will develop lupus nephritis. Genetic-association studies have identified more than 50 polymorphisms that contribute to lupus nephritis pathogenesis, including genetic variants associated with altered programmed cell death and defective immune clearance of programmed cell death debris. These variants may support the generation of autoantibody-containing immune complexes that contribute to lupus nephritis. Genetic variants associated with lupus nephritis also affect the initial phase of innate immunity and the amplifying, adaptive phase of the immune response. Finally, genetic variants associated with the kidney-specific effector response may influence end-organ damage and the progression to end-stage renal disease and death. This review discusses genetic insights of key pathogenic processes and pathways that may lead to lupus nephritis, as well as the clinical implications of these findings as they apply to recent advances in biologic therapies.

Section snippets

Extrarenal Etiology

The pathogenesis of LN largely is related to that of SLE: complex dysregulation of immune responses to nuclear autoantigens, including inhibition of regulatory mechanisms, chronic inflammation, accumulation of autoantibody specificities, and formation of pathogenic immune complexes (ICs). Here, we discuss the phases of the autoimmune response and those genes that may contribute to the downstream pathogenesis of LN.

Intrarenal Etiology

The development and renal deposition of ICs in LN has been studied extensively because renal deposits are found in almost all patients with SLE (Figure 3).⁹⁶ Recent studies have indicated that ICs containing antinuclear autoantibodies interact with trapped nucleosomes in an antigen-specific manner, particularly in SLE patients with autoantibody specificities to nucleosome components, such as chromatin and dsDNA.¹ In addition, a large number of SLE patients carry anti-C1q antibodies, which are

Clinical Implications and Opportunities

Considerable advances have been made in our understanding of the genetic basis of SLE, and novel approaches and studies that explore the relationship between genetics, cellular function, and clinical sequelae are moving forward. Given the renewed interest in personalized, precision medicine, there is a strong push to use what we know about the presence of genetic variants and altered immune pathways to make treatment decisions for SLE patients on an individual basis.118, 119 The significant

Acknowledgments

The authors would like to thank Rebecka Bourn, PhD, and Jennifer Kelly for critical reading of the manuscript.

References (129)

A.T. Borchers et al.
Lupus nephritis: a critical review
Autoimmun Rev
(2012)
J.M. Kelley et al.
Pathways: strategies for susceptibility genes in SLE
Autoimmun Rev
(2010)
L.L. Teichmann et al.
Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus
Immunity
(2013)
P. Li et al.
Association of genetic variations in the STAT4 and IRF7/KIAA1542 regions with systemic lupus erythematosus in a Northern Han Chinese population
Hum Immunol
(2011)
R.M. Tavares et al.
The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity
Immunity
(2010)
M.J. Lewis et al.
UBE2L3 polymorphism amplifies NF-kappaB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases
Am J Hum Genet
(2015)
F.B. Karassa et al.
FcgammaRIIIa-SLE Meta-Analysis Investigators. The Fc gamma RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis
Kidney Int
(2003)
L.A. Haseley et al.
Antibodies to C1q in systemic lupus erythematosus: characteristics and relation to Fc gamma RIIA alleles
Kidney Int
(1997)
M. MacPherson et al.
A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis
J Biol Chem
(2011)
S. Sigurdsson et al.
Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
Am J Hum Genet
(2005)

T. Vang et al.

The autoimmune-predisposing variant of lymphoid tyrosine phosphatase favors T helper 1 responses

Hum Immunol

(2013)

S.K. Lee et al.

Interferon-gamma excess leads to pathogenic accumulation of follicular helper T cells and germinal centers

Immunity

(2012)

C.J. Lessard et al.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study

Am J Hum Genet

(2012)

J.M. Guthridge et al.

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription

Am J Hum Genet

(2014)

A.L. Peters et al.

A novel polymorphism of the human CD40 receptor with enhanced function

Blood

(2008)

I.B. Richman et al.

European genetic ancestry is associated with a decreased risk of lupus nephritis

Arthritis Rheum

(2012)

O.J. Rullo et al.

Recent insights into the genetic basis of systemic lupus erythematosus

Ann Rheum Dis

(2013)

K. Fenton

The effect of cell death in the initiation of lupus nephritis

Clin Exp Immunol

(2015)

L.E. Munoz et al.

The role of defective clearance of apoptotic cells in systemic autoimmunity

Nat Rev Rheumatol

(2010)

YGJJ Bollain et al.

Soluble fas and the -670 polymorphism of fas in lupus nephritis

Int J Nephrol

(2014)

B. Moudi et al.

Association of FAS and FAS ligand genes polymorphism and risk of systemic lupus erythematosus

Sci World J

(2013)

F. Martinez-Valle et al.

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

Rheumatol Int

(2010)

D. Panneer et al.

Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients

Lupus

(2013)

J.B. Harley et al.

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Nat Genet

(2008)

X.J. Zhou et al.

Brief report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy

Arthritis Rheum

(2014)

T. Robinson et al.

Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients

J Immunol

(2011)

T. Imaizumi et al.

Melanoma differentiation-associated gene 5 regulates the expression of a chemokine CXCL10 in human mesangial cells: implications for chronic inflammatory renal diseases

Tohoku J Exp Med

(2012)

C. Enevold et al.

Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

Rheumatol Int

(2014)

J. Pothlichet et al.

A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

EMBO Mol Med

(2011)

B. Namjou et al.

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

Genes Immun

(2011)

T. Imaizumi et al.

Toll-like receptor 3 signaling contributes to the expression of a neutrophil chemoattractant, CXCL1 in human mesangial cells

Clin Exp Nephrol

(2014)

J. Tian et al.

The TLR7 7926A>G polymorphism is associated with susceptibility to systemic lupus erythematosus

Mol Med Rep

(2012)

R. Ramachandran et al.

Association between -1486 T>C and +1174 G>A single nucleotide polymorphisms in TLR9 gene and severity of lupus nephritis

Indian J Nephrol

(2012)

B. Namjou et al.

Evaluation of TRAF6 in a large multiancestral lupus cohort

Arthritis Rheum

(2012)

C.O. Jacob et al.

Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Proc Natl Acad Sci U S A

(2009)

K.M. Kaufman et al.

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Ann Rheum Dis

(2013)

K. Bolin et al.

Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis

PLoS One

(2013)

R. Salloum et al.

Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients

Arthritis Rheum

(2010)

T.B. Niewold et al.

Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients

Arthritis Rheum

(2008)

J.S. Bates et al.

Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations

Genes Immun

(2009)

L. Verstrepen et al.

The biology of A20-binding inhibitors of NF-kappaB activation (ABINs)

Adv Exp Med Biol

(2014)

D.J. Caster et al.

ABIN1 dysfunction as a genetic basis for lupus nephritis

J Am Soc Nephrol

(2013)

X.J. Zhou et al.

Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort

Clin J Am Soc Nephrol

(2014)

S.A. Chung et al.

Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

PLoS Genet

(2011)

A. Jonsen et al.

Association between SLE nephritis and polymorphic variants of the CRP and FcgammaRIIIa genes

Rheumatology (Oxford)

(2007)

R.A. Floto et al.

Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts

Nat Med

(2005)

F.B. Karassa et al.

FcgammaRIIa-SLE Meta-Analysis Investigators. Role of the Fcgamma receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis

Arthritis Rheum

(2002)

A.P. Gelmetti et al.

Polymorphism of the FcgammaRIIalpha IgG receptor in patients with lupus nephritis and glomerulopathy

J Rheumatol

(2006)

R. Zuniga et al.

Identification of IgG subclasses and C-reactive protein in lupus nephritis: the relationship between the composition of immune deposits and FCgamma receptor type IIA alleles

Arthritis Rheum

(2003)

J.E. Salmon et al.

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans

J Clin Invest

(1996)

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El lupus eritematoso sistémico (LES) es una enfermedad crónica, autoinmune, de etiología desconocida, que afecta a cualquier órgano o tejido. La nefritis lúpica (NL) es la causa más frecuente de compromiso renal en LES. Aproximadamente el 50% de los pacientes con LES presentan NL en algún momento de su enfermedad, siendo un factor de riesgo para morbimortalidad.
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Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease of unknown aetiology that affects any organ or tissue. Lupus Nephritis (LN) is the most common cause of kidney involvement in SLE. Approximately 50% of patients with SLE suffer LN at some point in their disease, being a risk factor for morbidity and mortality.
To provide updated information on LN, evaluating the pathophysiology, clinical manifestations and placing special emphasis on the diagnosis and therapeutic strategies used in clinical practice.
A narrative review was carried out regarding patients with SLE who developed LN in the Google Scholar, Embase, SciELO, Scopus and Medline databases using the MeSH terms lupus nephritis, biopsy, systemic lupus erythematosus, treatment.
A total of 50 studies were chosen that met the search requirements. These included 18 original articles, 11 reviews, 9 cases and controls, 7 cohort studies, and 5 experimental studies. The pathophysiology is heterogeneous and genetic and environmental factors contribute to it. Proteinuria, haematuria, and tubular abnormalities are among the main clinical manifestations. There is no single way to treat LN, it varies according to the severity of the disease and the risk of progressive kidney damage; according to the renal biopsy result, standardized by the ISN / RPS classification.
The purpose of treatment is to improve kidney function, decrease proteinuria, correct immunological markers, avoiding the appearance of complications. To improve the prognosis, new techniques must be developed that will allow us to evaluate the onset of kidney disease activity or its relapse to initiate early management, generating a reduction in mortality and improving quality of life.
Reframing health disparities in SLE: A critical reassessment of racial and ethnic differences in lupus disease outcomes
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Health disparities in the prevalence and outcomes of systemic lupus erythematosus (SLE) are well documented across racial and ethnic groups. Similar to other chronic diseases, differences in disease severity among individuals with SLE are likely influenced by both genetic predisposition and multiple social determinants of health. However, research in SLE that jointly examines the genetic and environmental contributions to the disease course is limited, resulting in an incomplete understanding of the biologic and social mechanisms that underly health disparities. While research on health disparities can reveal inequalities and inform resource allocation to improve outcomes, research that relies on racial and ethnic categories to describe diverse groups of people can pose challenges. Additionally, results from research comparing outcomes across socially constructed groups without considering other contributing factors can be misleading. We herein comprehensively examine existing literature on health disparities in SLE, including both clinical studies that examine the relationship between self-reported race and ethnicity and disease outcomes and studies that explore the relationships between genomics and lupus outcomes. Having surveyed this body of research, we propose a framework for research examining health disparities in SLE, including ways to mitigate bias in future studies.
Polymeric dexamethasone prodrugs attenuate lupus nephritis in MRL/lpr mice with reduced glucocorticoid toxicity
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Citation Excerpt :
Previously, we successfully designed and tested two polymeric dexamethasone prodrug nanomedicines (P-Dex and ZSJ-0228) that showed significant therapeutic efficacy and decreased toxicity in treating LN in the NZB/W F1 mouse model of lupus. Recognizing the highly heterogeneous nature of SLE38, we have extended these initial studies to assess the therapeutic efficacy and safety of monthly P-Dex or ZSJ-0228 in the MRL/lpr mouse model, which in addition to nephritis, exhibits multiple other lupus associated pathologies. Both monthly P-Dex or ZSJ-0228 were effective in ameliorating LN after 8-weeks of treatment in MRL/lpr mice.
Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.
Lupus nephritis – An update on disparities affecting african americans
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Lupus Nephritis is a complex clinical manifestation of systemic lupus erythematosus (SLE) associated with significant morbidity and mortality. It disproportionately affects minorities, especially African Americans (AA) with higher rates of progression to end stage kidney disease. Several factors are implicated including genetic predisposition to both SLE and chronic kidney disease, social determinants of health such as income inequality, education disparities, social isolation/lack of support, health care access and affordability. Clinically, AA may have higher auto-antibody titers, including several antibodies occurring simultaneously. AA are more prone to severe disease such as Class III and IV lupus nephritis. Fortunately, clinical trials have shown a favorable benefit/response among African Americans to mycophenolate mofetil. However, newer and alternative agents such as Rituximab, Belimumab and Voclosporin are widely unaffordable, and AA remain underrepresented in these clinical trials. The current state of disparities affecting LN patients of AA ancestry is a call for better access to healthcare and social support systems, greater inclusion/representation in clinical trials, and making new and alternative regimens more affordable and cost effective.
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Glomerulonephritis is a heterogeneous group of disorders that present with a combination of haematuria, proteinuria, hypertension, and reduction in kidney function to a variable degree. Acute presentation with full blown nephritic syndrome or rapidly progressive glomerulonephritis is uncommon and is mainly restricted to patients with post-infectious glomerulonephritis, anti-neutrophil cytoplasmic antibodies-associated vasculitis, and anti-glomerular basement membrane disease. Most frequently, patients present with asymptomatic haematuria and proteinuria with or without reduced kidney function. All glomerulonephritis disorders can show periods of exacerbation, but disease flairs characteristically occur in patients with IgA nephropathy or C3 glomerulopathy. The gold standard for the diagnosis of a glomerulonephritis is a kidney biopsy, with a hallmark glomerular inflammation that translates into various histopathological patterns depending on the location and severity of the glomerular injury. Traditionally, glomerulonephritis was classified on the basis of the different histopathological patterns of injury. In the last few years, substantial progress has been made in unravelling the underlying causes and pathogenetic mechanisms of glomerulonephritis and a causal approach to the classification of glomerulonephritis is now favoured over a pattern-based approach. As such, glomerulonephritis can be broadly classified as immune-complex glomerulonephritis (including infection-related glomerulonephritis, IgA nephropathy, lupus nephritis, and cryoglobulinaemic glomerulonephritis), anti-neutrophil cytoplasmic antibodies-associated (pauci-immune) glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-associated glomerulonephritis. We provide an overview of the clinical presentation, pathology, and the current therapeutic approach of the main representative disorders in the spectrum of glomerulonephritis.
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^☆: Financial support: Supported by the National Institutes of General Medical Sciences (U54GM104938 and P30GM103510), Arthritis and Musculoskeletal and Skin Diseases (P30AR053483), and Allergy and Infectious Diseases (U19AI082714 and U01AI101934). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

^☆☆: Conflict of interest statement: none.

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Genetics of Lupus Nephritis: Clinical Implications☆,☆☆

Summary

Section snippets

Extrarenal Etiology

Intrarenal Etiology

Clinical Implications and Opportunities

Acknowledgments

Autoimmun Rev

Autoimmun Rev

Immunity

Hum Immunol

Immunity

Am J Hum Genet

Kidney Int

Kidney Int

J Biol Chem

Am J Hum Genet

Hum Immunol

Immunity

Am J Hum Genet

Am J Hum Genet

Blood

European genetic ancestry is associated with a decreased risk of lupus nephritis

Arthritis Rheum

Recent insights into the genetic basis of systemic lupus erythematosus

Ann Rheum Dis

The effect of cell death in the initiation of lupus nephritis

Clin Exp Immunol

The role of defective clearance of apoptotic cells in systemic autoimmunity

Nat Rev Rheumatol

Soluble fas and the -670 polymorphism of fas in lupus nephritis

Int J Nephrol

Association of FAS and FAS ligand genes polymorphism and risk of systemic lupus erythematosus

Sci World J

DNase1 activity in systemic lupus erythematosus patients with and without nephropathy

Rheumatol Int

Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients

Lupus

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Nat Genet

Brief report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy

Arthritis Rheum

Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-alpha and serologic autoimmunity in lupus patients

J Immunol

Melanoma differentiation-associated gene 5 regulates the expression of a chemokine CXCL10 in human mesangial cells: implications for chronic inflammatory renal diseases

Tohoku J Exp Med

Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

Rheumatol Int

A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients

EMBO Mol Med

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

Genes Immun

Toll-like receptor 3 signaling contributes to the expression of a neutrophil chemoattractant, CXCL1 in human mesangial cells

Clin Exp Nephrol

The TLR7 7926A>G polymorphism is associated with susceptibility to systemic lupus erythematosus

Mol Med Rep

Association between -1486 T>C and +1174 G>A single nucleotide polymorphisms in TLR9 gene and severity of lupus nephritis

Indian J Nephrol

Evaluation of TRAF6 in a large multiancestral lupus cohort

Arthritis Rheum

Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Proc Natl Acad Sci U S A

Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Ann Rheum Dis

Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis

PLoS One

Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha activity in lupus patients

Arthritis Rheum

Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients

Arthritis Rheum

Meta-analysis and imputation identifies a 109 kb risk haplotype spanning TNFAIP3 associated with lupus nephritis and hematologic manifestations

Genes Immun

The biology of A20-binding inhibitors of NF-kappaB activation (ABINs)

Adv Exp Med Biol

ABIN1 dysfunction as a genetic basis for lupus nephritis

J Am Soc Nephrol

Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort

Clin J Am Soc Nephrol

Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

PLoS Genet