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Sex and Gender in Glomerular Disease

      Summary

      There is increasing understanding that a multifaceted interplay of sex-dependent genetic and immune dysregulation underpins the development of glomerular disorders. Regional and ethnic variations in glomerular disease incidence make delineating the effects of sex and gender on disease pathophysiology more complex, but there is a marked paucity of research in this area. This review article presents a summary of the current understanding of sex and gender in glomerular disease, highlighting the broader effects of sex and gender on autoimmunity, clinical presentations, and pathophysiology of individual glomerular diseases, as well as exploring sex, gender, and glomerular disease within a wider socioenvironmental context. It is important to specifically consider the effects of sex and gender when presenting and analyzing clinical and scientific studies on glomerular disease. Failure to do so risks promoting disparities within health care provision, neglecting opportunities to identify sex-specific biomarkers, and potentially hindering the development of sex-specific therapies.

      Keywords

      Sex differences in developmental, physiological, and pathologic processes have been recorded for more than 150 years.
      • Darwin C.
      The Descent of Man, and Selection in Relation to Sex.
      In human beings, sex differences exert multiple influences on disease, affecting susceptibility, presentation, outcomes, and experience. As yet, the molecular mechanisms that underlie sex differences in autoimmune and glomerular disease are not completely understood. There is, however, increasing understanding that a multifaceted interplay of sex-dependent genetic and immune regulation underpins these complex disorders.
      Although the terms sex and gender often are used interchangeably, there are important differences between the two.
      • Bairey Merz CN
      • Dember LM
      • Ingelfinger JR
      • et al.
      Sex and the kidneys: current understanding and research opportunities.
      For the purpose of this review, sex will refer to characteristics that are biologically defined and assigned at birth, as according to the World Health Organization definition.

      Organisation WH. Gender and Health, https://www.who.int/health-topics/gender#tab=tab_1 (accessed 22/12/2021 2021).

      Gender will refer to the more socially constructed features, the “sense of self,” which may not match sex assigned at birth.

      Organisation WH. Gender and Health, https://www.who.int/health-topics/gender#tab=tab_1 (accessed 22/12/2021 2021).

      Both sex and gender may impact significantly on health and disease: with sex potentially modulating disease progression and therapeutic responses; and gender influencing interpersonal communication, nonpharmacologic disease management, and desire or ability to access health care.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      This review explores why sex and gender are important in glomerulonephritis, and the impact that sex has on autoimmunity and glomerular disease, before exploring individual disorders in detail. Finally, it explores the effects of sex and gender on socioenvironmental aspects of glomerular disease.

      WHY SEX AND GENDER ARE IMPORTANT IN GLOMERULAR DISEASE

      It is important to examine the role of sex and gender within disease because they can influence pathophysiology, clinical outcomes, and experiences of illness (Fig. 1). This is particularly true for glomerulonephritis, for which the effects of sex on disease frequency, distribution, and severity are well recognized.
      • O'Shaughnessy MM
      • Hogan SL
      • Thompson BD
      • et al.
      Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
      ,
      Anonymous
      The New Zealand Glomerulonephritis Study: introductory report.
      Glomerular disease as a single entity has a marked male preponderance, and males outnumber females affected in all of the primary glomerulonephritides.
      • O'Shaughnessy MM
      • Hogan SL
      • Thompson BD
      • et al.
      Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
      Anonymous
      The New Zealand Glomerulonephritis Study: introductory report.

      Cattran DC, Reich HN, Beanlands HJ, et al. The impact of sex in primary glomerulonephritis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2008;23:2247-2253. 2008/01/10. https://doi.org/10.1093/ndt/gfm919.

      Lupus nephritis is the only glomerular disease in which more females are affected,

      Cattran DC, Reich HN, Beanlands HJ, et al. The impact of sex in primary glomerulonephritis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2008;23:2247-2253. 2008/01/10. https://doi.org/10.1093/ndt/gfm919.

      although sex differences in anti–neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be changing as occupational and recreational exposure to environmental hazards evolve.
      • O'Shaughnessy MM
      • Hogan SL
      • Thompson BD
      • et al.
      Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
      These epidemiologic variations highlight the important role that gender also plays in the development of glomerular disease. Given that sex frequencies in glomerulonephritides also differ in prevalence geographically,
      • Deng W
      • Tan X
      • Zhou Q
      • et al.
      Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy.
      while genetic modifiers may have key roles to account for the geo-ethnic differences, the effect of different cultures and environments on perceived sex/gender roles also should be considered.
      Figure 1
      Figure 1Influences of sex and gender on glomerular disease.
      There are many challenges to untangling the biological and nonbiological factors that influence outcomes in glomerular disease because data presented in research studies often are incomplete, and historically have usually focused on the influence of sex and biological processes on disease pathogenesis and outcome.
      In animal research, a disproportionate number of models exclusively use males, thus limiting our ability to extrapolate research findings to both sexes. For example, in a study of high-impact renal journals, for every experiment performed with female animals, there are between 5 and 16 studies conducted solely in males, a figure that disappointingly has not improved over the past decade.
      • Sandberg K
      • Pai AV
      • Maddox T.
      Sex and rigor: the TGF-β blood pressure affair.
      Similarly, effects of sex and gender often are not considered or recorded when reporting outcomes in clinical trials. Historic literature primarily will have considered sex rather than gender (even when described as the latter) and focused on biological differences or mechanisms. Alongside this, it also is rare for studies to report the menopausal status of patients, or whether there is a history of oral contraceptive or hormone therapy use among participants, yet these medications may significantly impact disease progression and severity.
      It has been shown repeatedly that women have an increased incidence of chronic kidney disease (CKD), but are less likely to progress to end-stage kidney disease (ESKD).
      • Ricardo AC
      • Yang W
      • Sha D
      • et al.
      Sex-Related Disparities in CKD Progression.
      There are no significant differences in the rate of progression of CKD in women compared with men, so why women are less likely to undergo renal replacement therapy has not been answered satisfactorily. Women with CKD are less likely to have seen a nephrologist, and have lower education and income levels than their male counterparts,
      • Ricardo AC
      • Yang W
      • Sha D
      • et al.
      Sex-Related Disparities in CKD Progression.
      raising important questions on equity and access to health care.
      Finally, negative experiences because of health care professionals failing to consider sex or gender can adversely impact clinician–patient relationships and disease trajectories. Glomerular diseases often are chronic, long-term conditions, requiring multidisciplinary care and frequent hospital attendances: damaged clinician–patient relationships can have long-lasting repercussions.
      Ignoring the effects of sex and gender on glomerular disease when presenting and analyzing clinical and scientific studies risks promoting disparities within health care provision, and neglecting opportunities to identify and develop sex-specific biomarkers or therapies, which may prevent the implementation of personalized medicine in glomerulonephritis (GN) in the future.

      IMPACT OF SEX ON AUTOIMMUNITY

      Although diverse pathogenic processes underpin the different forms of GN, in common they share an autoimmune mechanism of kidney injury. The marked female bias in autoimmune disease is striking.
      • Whitacre CC.
      Sex differences in autoimmune disease.
      It is estimated that nearly 80% of those affected by autoimmune disease are women
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      and that female sex carries a risk of autoimmunity far higher than any other identified susceptibility locus from genome-wide association studies and meta-analyses.
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      ,
      • Lim SS
      • Bayakly AR
      • Helmick CG
      • et al.
      The incidence and prevalence of systemic lupus erythematosus, 2002-2004: The Georgia Lupus Registry.
      Early work in this area focused on the influence of sex hormones, encouraged by the finding that many autoimmune diseases (particularly Th1-associated, or inflammatory autoimmune diseases such as rheumatoid arthritis or multiple sclerosis) improve significantly during pregnancy. This is particularly marked in the third trimester when estrogen and progesterone levels are at their highest.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      However, this is too simplistic a view because in antibody-mediated autoimmune diseases (T helper (Th) 2-associated), the effects of pregnancy are more variable, challenging the idea that sex hormones are solely responsible for sex differences in autoimmunity. Symptoms of myasthenia gravis can vary from pregnancy to pregnancy in the same women, and pregnancy can improve, worsen, or result in no change in myasthenia gravis symptoms.
      • Batocchi AP
      • Majolini L
      • Evoli A
      • et al.
      Course and treatment of myasthenia gravis during pregnancy.
      Systemic lupus erythematosus (SLE), another antibody-mediated disease, frequently has been reported to worsen during pregnancy, although the severity of relapse is widely variable.
      • Lateef A
      • Petri M.
      Management of pregnancy in systemic lupus erythematosus.
      Furthermore, sex hormones alone cannot explain the sexual dimorphism seen in autoimmune disease because a female sex bias also is observed in childhood when estrogen levels are similar in both sexes, and in postmenopausal women.
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      The presence of an additional X chromosome (or lack thereof) is another proposed driver for observed sex differences, as is the potential role of gut microbiota given the marked differences seen between male and female microbiomes. Intestinal microbiome abnormalities have been seen in most immune-mediated diseases.
      • Billip-Tomecka Z
      • Gellert R
      • Zaleska M
      • et al.
      [Renal biopsy in the aged].
      Demonstrating a causal role for the gut microbiota has been challenging, but associations between the gut and glomerular disease have long been recognized. A genome-wide association study in IgA nephropathy (IgAN) showed that most loci associated with IgAN also are associated with immune-mediated inflammatory bowel diseases, and maintenance of the intestinal barrier and response to gut pathogens,
      • Coppo R.
      The Gut-Renal Connection in IgA Nephropathy.
      highlighting the gut–renal connection in glomerular disease.

      Sex Hormones

      Sex hormones have been postulated as a contributary factor to the female sex bias seen in autoimmune diseases (Table 1). Progesterone is thought to be an important driver of the immune tolerance seen during pregnancy, reducing proinflammatory mediators and inhibiting immune cell activation.
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      Progesterone decreases activation of natural killer cells, macrophages, and dendritic cells, and promotes a shift from Th1 to Th2-type T-cell responses,
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      all of which are thought to contribute to the beneficial impacts of pregnancy on some diseases, as well as promoting maternal immune tolerance to the semi-allogenic fetus.
      • Lissauer D
      • Eldershaw SA
      • Inman CF
      • et al.
      Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.
      Table 1Sex Hormones in Autoimmunity
      Effects on AutoimmunityHormoneEffects
      InhibitoryProgesterone
      • Reduces proinflammatory mediators (18)
      • Inhibits immune cell activation (18)
      • Promotes a shift from Th1 to Th2 type T cell responses (12)
      Androgens
      • Inhibitory effects on immune cell proliferation, activation and response (26)
      VariableEstrogen
      • Upregulates immune regulatory factors (20)
      • Dose dependent response on white blood cells (22,23,24)
      • At lower concentrations promotes a Th1 response, at higher concentrations promotes a Th2 shift. (12)
      StimulatoryProlactin
      • Inhibits negative selection of autoreactive B cells increasing antibody production (28)
      Th1, T helper 1; Th2, T helper 2.
      Effects of estrogen on autoimmunity are more challenging to untangle. Estrogen levels vary across the menstrual cycle, are high during pregnancy, and decrease significantly after menopause. Estrogen receptors (ERs) are expressed in immune cells, with ERα highly expressed in T cells, and ERβ highly expressed in B cells. Estrogen has a plethora of biological effects, acting directly to up-regulate various immune regulatory factors, via ERs,
      • Dragin N
      • Bismuth J
      • Cizeron-Clairac G
      • et al.
      Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.
      via estrogen response elements on target genes, and through interaction with estrogen response element–independent transcription factors in immune cells.
      • Kovats S.
      Estrogen receptors regulate innate immune cells and signaling pathways.
      Effects of estrogens on white blood cells are dose-dependent and vary according to cell type. Estrogens increase neutrophil number, but overall inhibit their activation and migration
      • Bereshchenko O
      • Bruscoli S
      • Glucocorticoids Riccardi C.
      ; enhance natural killer cell cytotoxicity and interferon-γ production, but down-regulate natural killer cell granzyme B secretion and cell surface activation markers
      • Hao S
      • Zhao J
      • Zhou J
      • et al.
      Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors.
      ; enhance production of proinflammatory cytokines at low concentrations, and suppress their production at higher concentrations.
      • Karpuzoglu E
      • Phillips RA
      • Gogal Jr, RM
      • et al.
      IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12.
      In summary, at lower estrogen concentrations, immunostimulatory responses promote a Th1 response, but at high concentrations, a Th2 response is stimulated.
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      To further support the role of estrogen in influencing sex differences in autoimmunity, performing oophorectomy is protective against the development of disease in lupus-prone mice.
      • Cunningham MA
      • Wirth JR
      • Scott JL
      • et al.
      Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+ Spleen Cells and Impacts Disease Expression in Murine Lupus.
      Androgens can be considered primarily anti-inflammatory mediators, exerting inhibitory effects on immune cell proliferation, activation, and responses.
      • Trigunaite A
      • Dimo J
      • Jørgensen TN.
      Suppressive effects of androgens on the immune system.
      As such, they have been shown to provide protective effects in various models of autoimmune disease.
      • Zhu ML
      • Bakhru P
      • Conley B
      • et al.
      Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.
      In contrast, prolactin is considered immunostimulatory and increases autoantibody production by inhibiting the negative selection of autoreactive B cells.
      • Borba VV
      • Zandman-Goddard G
      • Shoenfeld Y.
      Positive correlations between circulating prolactin levels and disease activity in patients with SLE have been reported, but causality has yet to be shown.
      • Song GG
      • Lee YH.
      Circulating prolactin level in systemic lupus erythematosus and its correlation with disease activity: a meta-analysis.

      Sex Chromosomes

      Many genes responsible for immune function are located on the X chromosome.
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      These genes code for proteins including pattern recognition receptors (such as TLR7 and TLR8), cytokine receptors (eg, IL2RG and IL13RA2), and transcriptional factors (eg, FOXP3).
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      Several of these show a female expression bias or are hypomethylated in female but not male patients with SLE.
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.
      The inherited disorder Klinefelter syndrome also highlights the importance of X dosage in autoimmunity. Klinefelter syndrome occurs when males have an additional X chromosome (karyotype XXY), causing low testosterone, increased gonadotrophins, and increased estrogen levels. Males with Klinefelter syndrome have an immune profile more similar to that of females, with higher levels of immunoglobulin, B cells, CD4+ T cells, and CD4/CD8 ratios compared with XY male controls,
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      and an increased risk of SLE.
      • Scofield RH
      • Bruner GR
      • Namjou B
      • et al.
      Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome.
      Treatment with testosterone therapy reverses many of the immunologic effects seen in Klinefelter syndrome.
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      Similarly, females with Turner syndrome (karyotype XO, or those who have significant X chromosomal deletions) have lower immunoglobulin levels and T and B cells compared with XX females,
      • Klein SL
      • Flanagan KL.
      Sex differences in immune responses.
      highlighting the importance of the X chromosome in modulating autoimmunity.
      The X chromosome is enriched in microRNAs (miRNAs), transcripts that are not translated into proteins but that regulate gene expression and are essential for maintaining a balance between immune tolerance and immune response.
      • Lam IKY
      • Chow JX
      • Lau CS
      • et al.
      MicroRNA-mediated immune regulation in rheumatic diseases.
      miRNAs are thought to control the development and activation of T and B cells, and are expressed differentially between the two sexes. The high density of miRNAs seen on the X chromosome means that females may express more as a result of incomplete X inactivation. In females with SLE, a subset of X-linked miRNAs were found to be overexpressed,
      • Hewagama A
      • Gorelik G
      • Patel D
      • et al.
      Overexpression of X-linked genes in T cells from women with lupus.
      possibly contributing to the sex differences in disease susceptibility seen.

      Gut Immunology and the Microbiota

      The gut microbiota plays a fundamental role in the maturation and modulation of innate and adaptive immunity, and is itself shaped by the immune system.
      • Pickard JM
      • Zeng MY
      • Caruso R
      • et al.
      Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease.
      Both gut immunology and microbiota show sex differences, with a trend to enhanced innate immunity and attenuated adaptive immunity in males and increased microbiota diversity in females.
      • Markle JG
      • Frank DN
      • Mortin-Toth S
      • et al.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      There is increasing evidence for a role of the gut microbiota in initiating sexually dimorphic autoimmunity. Female nonobese diabetic mice develop spontaneous autoimmune type 1 diabetes at twice the frequency of male mice, a sex difference that is removed when housing the mice under germ-free conditions. Furthermore, when male intestinal microbiota was transferred into these females, they were safeguarded against development of type 1 diabetes, signifying a protective role for the (less-diverse) male microbiome.
      • Markle JG
      • Frank DN
      • Mortin-Toth S
      • et al.
      Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
      Together, animal data suggest that sex and androgens regulate gut microbiota diversity and function, which reciprocally influences the immune response and development of autoimmunity.
      • Billi AC
      • Kahlenberg JM
      • Gudjonsson JE.
      Sex bias in autoimmunity.

      IMPACT OF SEX AND GENDER ON GLOMERULAR DISEASE

      In addition to the systemic effects of sex and gender on autoimmune disease, female sex is reported to be a protective factor in renal disease in general.
      • Bairey Merz CN
      • Dember LM
      • Ingelfinger JR
      • et al.
      Sex and the kidneys: current understanding and research opportunities.
      Animal studies have suggested that estrogens exert renoprotective effects.
      • Tanaka R
      • Tsutsui H
      • Kobuchi S
      • et al.
      Protective effect of 17β-estradiol on ischemic acute kidney injury through the renal sympathetic nervous system.
      ,
      • Mankhey RW
      • Bhatti F
      • Maric C.
      17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.
      Administering estrogen to male Imai rats resulted in attenuated progression of glomerular injury by significantly reducing proteinuria and glomerular sclerosis.
      • Sakemi T
      • Toyoshima H
      • Shouno Y
      • et al.
      Estrogen attenuates progressive glomerular injury in hypercholesterolemic male Imai rats.
      In further support, knockout of ERα protects female mice from developing nephritis, despite the presence of immune complexes, the production of proinflammatory cytokines in the kidneys, and normal humoral responses to immunization.
      • Corradetti C
      • Jog NR
      • Cesaroni M
      • et al.
      Estrogen Receptor alpha Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity.
      In contrast, testosterone has been shown repeatedly to exacerbate renal injury and dysfunction: as such, after castration, proteinuria in hypertensive rats was reduced by 80% and glomerular sclerosis was reversed.
      • Fortepiani LA
      • Yanes L
      • Zhang H
      • et al.
      Role of androgens in mediating renal injury in aging SHR.
      However, as with systemic differences, the influence of sex on glomerular disease may not be solely attributable to the influence of sex hormones, and very few studies have explored the role of sex chromosomes or sex-specific autosome gene expression in glomerulonephritides. In the context of hypertension, the limited studies that have explored these factors showed that in addition to the effects of gonadal hormones on blood pressure, X- and Y-linked genes, parental imprinting, and X chromosome mosaicism all contributed to sex differences in hypertension-associated renal injury
      • Ji H
      • Zheng W
      • Wu X
      • et al.
      Sex chromosome effects unmasked in angiotensin II-induced hypertension.
      : it is likely that similar cellular and molecular mechanisms underlie sex differences in glomerular disease.
      Women consistently are under-represented in randomized clinical trials, and clinical data exploring the association between biological sex and progression of glomerular disease are conflicting, representing the complex interactions between biological, cultural, and socioeconomic factors.
      • De La Mata NL
      • Rosales B
      • MacLeod G
      • et al.
      Sex differences in mortality among binational cohort of people with chronic kidney disease: population based data linkage study.
      For example, using development of ESKD as a primary outcome (a common end point in nephrology studies) may be influenced by nonbiological factors such as differences in timing of dialysis initiation between men and women, and disparities in access to renal replacement therapy or transplantation. Even studies that use change in slope of estimated glomerular filtration rate to measure disease progression might not accurately capture biological differences between sexes, or psychosocial, economic, or cultural factors that are affected by gender.
      • Ricardo AC
      • Yang W
      • Sha D
      • et al.
      Sex-Related Disparities in CKD Progression.
      A detailed review of pharmacokinetics and pharmacodynamics is beyond the scope of this review, but it is clear that sex differences in drug metabolism also could account for sex differences seen in treatment responses in glomerulonephritis.
      In addition to effects of sex on disease pathobiology and the interpretation of clinical research outcomes, sex and gender significantly can influence perceptions of illness and quality of life. A study by the Cure Glomerulonephropathy Network (which included 1,115 adults and 478 children with glomerular disease) found that female sex correlated with reductions in health-related quality-of-life domains,
      • Canetta PA
      • Troost JP
      • Mahoney S
      • et al.
      Health-related quality of life in glomerular disease.
      and the association of negative self-reported quality of life and subsequent mortality is well recognized.
      • Phyo AZZ
      • Freak-Poli R
      • Craig H
      • et al.
      Quality of life and mortality in the general population: a systematic review and meta-analysis.
      Moreover, sex can have significant effects on associated diseases: females with nephrotic disease are more likely to be anemic than their male counterparts,
      • Mahr N
      • Neyer U
      • Prischl F
      • et al.
      Proteinuria and hemoglobin levels in patients with primary glomerular disease.
      and, compared with males, females have lower proteinuria in primary kidney disease and are less hypertensive, regardless of whether they have underlying CKD.

      Coggins CH, Breyer Lewis J, Caggiula AW, et al. Differences between women and men with chronic renal disease. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 1998;13:1430-1437. 1998/06/26. https://doi.org/10.1093/ndt/13.6.1430.

      ,
      • Reckelhoff JF.
      Gender differences in the regulation of blood pressure.
      Furthermore, sex has distinct associations with cardiovascular disease, the risk of which is increased significantly in many patients with glomerular disease.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Lastly, in a long-term study of childhood Henoch-Schoenlein purpura (IgA vasculitis), despite the majority of included females having a good outcome (defined as healthy or minor urinary abnormalities only), 70% of subsequent pregnancies were complicated by hypertension, proteinuria, or both, with potential consequences for both the mother and her child(ren).
      • Ronkainen J
      • Nuutinen M
      • Koskimies O.
      The adult kidney 24 years after childhood Henoch-Schönlein purpura: a retrospective cohort study.
      These are risks traditionally overlooked in many glomerular disease long-term outcome reports. It is unknown if glomerular disease in males has a similar effect on progeny.

      SEX AND GENDER DIFFERENCES IN SPECIFIC GLOMERULAR DISEASES

      Different glomerular diseases have distinct underlying pathophysiology, and, consequently, distinct sex and gender differences can be seen (Table 2). The following sections review individual glomerular diseases, including both primary and secondary glomerulonephropathies, with a particular focus on sex and gender differences.
      Table 2Sex and Gender Differences in Specific Glomerular Diseases
      DiseaseSex dominanceDetails
      IgA NephropathyMale (8)
      • Increased antibody activity (and removal) against aberrantly glycosylated IgA in females (4, 48)
      • Gender-specific gene polymorphisms confer increased risk (49)
      • Higher blood pressure seen in males (50)
      • No gender differences in proteinuria, disease activity or outcomes (8, 50)
      Membranous NephropathyMale (50, 55)
      • Higher blood pressure and proteinuria seen in males (50)
      • Better prognosis in females: higher renal survival, more likely to achieve complete remission and lower relapse rate (4, 50)
      Minimal Change Nephropathy and FSGSMale (5, 50, 56, 57)
      • MCN: No gender differences in clinical phenotype or remission rates (57)
      • FSGS: higher levels of proteinuria, increased risk of relapse and less likely to achieve remission in males (7, 50, 58)
      • Reduced levels of renal survival and increased risk of death in males (50, 59)
      Anti- GBM diseaseEqual (4, 63)
      • Clinical presentation more dependent on age and smoking status than gender (64,65)
      • Concurrent ANCA positivity more common in females (4, 69)
      • No gender differences in long term renal outcomes (63)
      Lupus NephritisFemale (13)
      • Increased disease activity and more aggressive histopathological findings in males (70-72)
      • Males less likely to achieve complete remission (73, 75)
      • No gender differences in long term renal outcomes or mortality (73,76,77)
      ANCA associated vasculitisYounger males and older females (79, 80)
      • MPO-ANCA vasculitis associated with female sex (81)
      • No gender differences in clinical presentations or disease activity (84)
      • Conflicting long term outcome data; likely no differences between genders (80, 85-88)
      ANCA, anti–neutrophil cytoplasmic antibody; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; MCN, minimal change nephropathy; MPO, myeloperoxidase.

      IgAN

      IgAN is the most common primary glomerulonephritis, and a major cause of ESKD. It is defined pathologically by IgA deposition in the glomerular mesangium, accompanied by a mesangial proliferative glomerulonephritis that varies widely in severity.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Although there is a clear male predominance worldwide, sex differences in prevalence differ geographically, ranging from a male to female ratio of 1.4:1 in Asians, to as high as 6:1 in Caucasians.
      • Deng W
      • Tan X
      • Zhou Q
      • et al.
      Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy.
      The pathophysiology of IgAN remains uncertain, but an important hypothesis involves the development of antibodies against aberrantly glycosylated O-linked oligosaccharide(s) on the IgA1 hinge region.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Nakamura et al
      • Nakamura I
      • Iwase H
      • Arai K
      • et al.
      Detection of gender difference and epitope specificity of IgG antibody activity against IgA1 hinge portion in IgA nephropathy patients by using synthetic hinge peptide and glycopeptide probes.
      measured antibody activity against synthetic hinge peptides and glycopeptides and found that antibody activity was significantly higher in females against all probes tested. They postulated that this might underlie a protective mechanism in females (to remove aberrantly glycosylated molecules), and potentially explain why the incidence of IgAN is higher in males.
      Despite many studies exploring immunogenetic associations, a clear cause for susceptibility to IgAN has not yet been identified. Genome-wide association studies have highlighted strongly associated risk alleles within HLA coding regions, but these do not appear to be sex-specific. Reports have suggested that IgAN is familial in less than 10% of cases,

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      • Magistroni R
      • D’Agati VD
      • Appel GB
      • Kiryluk K
      New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
      but the true frequency is unknown and likely under-reported because there are no reliable serologic or urinary markers for the disease. Sex-specific gene polymorphisms have been found to be associated with IgAN: the NTN4 rs1362970 A/A and GNG2 rs3204008 G/G genotype are associated with increased IgAN risk in males, and PHLDB1 rs7389 G/T genotype is associated with higher risk in females.
      • Feng Y
      • Su Y
      • Ma C
      • et al.
      3′UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.
      Clinical features vary between the sexes in IgAN. Documented blood pressure in males was higher, despite increased use of antihypertensive medication, but there was no difference in proteinuria between the sexes at either diagnosis or during follow-up evaluation.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      Several studies have shown more progressive disease in males,
      • Goto M
      • Wakai K
      • Kawamura T
      • et al.
      A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
      but others showed no difference.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      ,
      • Moriyama T
      • Tanaka K
      • Iwasaki C
      • et al.
      Prognosis in IgA nephropathy: 30-year analysis of 1,012 patients at a single center in Japan.
      Similarly, data examining the effect of sex on development of ESKD in IgAN are mixed, with some studies showing no differences between the sexes
      • Deng W
      • Tan X
      • Zhou Q
      • et al.
      Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy.
      ,
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      and another study reporting poorer outcomes in females.
      • Donadio JV
      • Bergstralh EJ
      • Grande JP
      • et al.
      Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.

      Membranous Nephropathy

      Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults and is characterized by the presence of subepithelial immune deposits on biopsy.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Disturbance of the podocyte structure by immune complex deposition and membrane attack complex formation results in large amounts of proteinuria.
      Recent technological advances in combining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins has resulted in an explosion of putative autoantigens,
      • Ronco P
      • Beck L
      • Debiec H
      • et al.
      Membranous nephropathy.
      which has challenged the traditional classification of MN into primary MN and secondary MN forms. Some antigens [eg, Phospholipase A2 receptor (PLA2R) or thrombospondin type-1 domain-containing 7A (THSD7A)] can be associated with both primary MN or a specific cause of secondary MN (eg, lupus or cancer), and so an antigen-based classification may be considered in the future.
      MN is historically male dominant, affecting twice as many males as females, but data on the incidence of MN and MN subtypes are old, limited, and predominantly from North America and Europe.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      ,
      • Hogan SL
      • Muller KE
      • Jennette JC
      • et al.
      A review of therapeutic studies of idiopathic membranous glomerulopathy.
      Again, differences in clinical presentation can be seen between sexes. Men have significantly higher levels of proteinuria both at presentation and during follow-up evaluation, as well as higher recorded blood pressure.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      Females have a better prognosis in MN: they are more likely to achieve complete remission and have a lower relapse rate,

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      as well as having higher levels of renal survival.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      Given new understanding of disease pathogenesis, we suggest the gender distribution should be reviewed in large representative cohorts, accounting for antigen subclass. It is very conceivable that the gender prevalence may have changed, particularly because infectious precipitants of secondary MN have decreased significantly with vaccination, whereas drug exposure and lupus have increased.
      • Ronco P
      • Beck L
      • Debiec H
      • et al.
      Membranous nephropathy.

      Minimal Change Nephropathy and Focal Segmental Glomerulosclerosis

      In adults, minimal change nephropathy (MCN) and focal segmental glomerulosclerosis (FSGS) together are responsible for a third of cases of nephrotic syndrome, and both conditions can be primary or secondary.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Whether primary MCN and FSGS represent two different disease entities or a continuation of the same disease process continues to be debated; hence, we consider them together. Both disorders are characterized by diffuse foot process effacement on electron microscope, absent immune deposits, and a severe functional defect in glomerular permselectivity.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      MCN and FSGS are thought to be caused by circulating factor(s) and there is a male sex bias in both diseases.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      ,
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      ,
      • Lee H
      • Yoo KD
      • Oh YK
      • et al.
      Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease.
      ,
      • Fenton A
      • Smith SW
      • Hewins P.
      Adult minimal-change disease: observational data from a UK centre on patient characteristics, therapies, and outcomes.
      There are no gender differences in clinical phenotype in MCN,
      • Fenton A
      • Smith SW
      • Hewins P.
      Adult minimal-change disease: observational data from a UK centre on patient characteristics, therapies, and outcomes.
      whereas men with FSGS have higher levels of proteinuria at presentation.

      Cattran DC, Reich HN, Beanlands HJ, et al. The impact of sex in primary glomerulonephritis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2008;23:2247-2253. 2008/01/10. https://doi.org/10.1093/ndt/gfm919.

      This increase in proteinuria in males continues throughout follow-up evaluation, and men with FSGS are less likely to achieve remission of the disease.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      Although no differences in rates of achieving remission in gender in MCN have been reported, one study found there was an increased risk of early relapse in females.
      • Fenton A
      • Smith SW
      • Hewins P.
      Adult minimal-change disease: observational data from a UK centre on patient characteristics, therapies, and outcomes.
      This has not been found consistently: another study found no difference in relapse rates between the sexes.
      • Lee H
      • Yoo KD
      • Oh YK
      • et al.
      Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease.
      In contrast, in FSGS, male gender was associated with an increased risk of relapse.
      • Troyanov S
      • Wall CA
      • Miller JA
      • et al.
      Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.
      We did not find studies examining sex as a variable when describing disease outcomes in adult MCN. Men with FSGS have been found to have a more rapid deterioration in renal function when presenting with high rates of proteinuria
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      and poorer renal survival compared with females.
      • Cattran DC
      • Reich HN
      • Beanlands HJ
      • et al.
      The impact of sex in primary glomerulonephritis.
      ,
      • Ojogwu LI
      • Ukoli FA.
      A follow up study of adult nephrotic syndrome in Nigerians: outcome and predictors of endstage renal failure.
      Furthermore, male sex was associated with an increased risk of death in a small study in Nigerian patients with FSGS.
      • Ojogwu LI
      • Ukoli FA.
      A follow up study of adult nephrotic syndrome in Nigerians: outcome and predictors of endstage renal failure.
      Recurrence of FSGS in transplants is more common in males,
      • Moroni G
      • Gallelli B
      • Quaglini S
      • et al.
      Long-term outcome of renal transplantation in adults with focal segmental glomerulosclerosis. Transplant international : official journal of the European Society for.
      however, males are also more likely to achieve remission of post-transplant FSGS recurrence when treated with plasma exchange.
      • Kashgary A
      • Sontrop JM
      • Li L
      • et al.
      The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series.
      Given the similar disease mechanisms underpinning adult MCN and FSGS, it is likely that there will be gender differences in outcomes for patients with MCN and this is an area worthy of further exploration.

      Anti–Glomerular Basement Membrane Disease

      Anti–glomerular basement membrane (GBM) disease is a rare autoimmune disease caused by autoantibodies directed against the noncollagenous C-terminal domain of the α3 chain of type IV collagen. It typically presents as a renopulmonary syndrome with rapidly progressive glomerulonephritis and alveolar hemorrhage, but can present with isolated glomerulonephritis.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Historically, anti-GBM disease had a male bias (indeed, the original patient described by Goodpasture
      • Goodpasture EW.
      Landmark publication from The American Journal of the Medical Sciences: The significance of certain pulmonary lesions in relation to the etiology of influenza.
      was a young man), but most recent studies have shown a more equal sex distribution.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      ,
      • van Daalen EE
      • Jennette JC
      • McAdoo SP
      • et al.
      Predicting Outcome in Patients with Anti-GBM Glomerulonephritis.
      Anti-GBM disease has a bimodal age distribution, with peaks in the third decade (slight male preponderance) and in the sixth to seventh decades (no gender difference).
      • KLUTH DC
      • REES AJ
      Anti-Glomerular Basement Membrane Disease.
      Although the exact pathophysiology of the disease is unknown, environmental factors may be important triggers for disease onset. Both cigarette smoking
      • Donaghy M
      • Rees AJ.
      Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane.
      and inhalation of hydrocarbons
      • Bombassei GJ
      • Kaplan AA.
      The association between hydrocarbon exposure and anti-glomerular basement membrane antibody-mediated disease (Goodpasture's syndrome).
      have been implicated, exposures traditionally more common in males. Lithotripsy may be an initiator for anti-GBM disease because extracorporeal shock wave therapy can disrupt the glomerular basement membrane and unmask epitopes,
      • McAdoo SP
      • Pusey CD.
      Anti-Glomerular Basement Membrane Disease.
      and urolithiasis is another male-dominated disease,
      • Johnson CM
      • Wilson DM
      • O'Fallon WM
      • et al.
      Renal stone epidemiology: a 25-year study in Rochester, Minnesota.
      which may influence the incidence of anti-GBM disease developing as a consequence.
      Clinical presentation of anti-GBM disease differs by sex, age, and smoking status: young male smokers are more likely to present with both lung hemorrhage glomerulonephritis, whereas a subset of young female smokers are more likely to present with isolated lung hemorrhage and no renal involvement, which may reflect differences in anti-GBM antibody subclass between the sexes.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      There is no reported difference in clinical features among older patients.
      • KLUTH DC
      • REES AJ
      Anti-Glomerular Basement Membrane Disease.
      Concurrent ANCA positivity is common in anti-GBM disease and dual-positive patients are more often female.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      ,
      • McAdoo SP
      • Tanna A
      • Hrušková Z
      • et al.
      Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
      Anti-GBM disease in the elderly appears to take a milder course,
      • KLUTH DC
      • REES AJ
      Anti-Glomerular Basement Membrane Disease.
      and there appears to be no difference between the genders in long-term renal outcomes.
      • van Daalen EE
      • Jennette JC
      • McAdoo SP
      • et al.
      Predicting Outcome in Patients with Anti-GBM Glomerulonephritis.

      Lupus Nephritis

      SLE has a striking female preponderance.
      • Lim SS
      • Bayakly AR
      • Helmick CG
      • et al.
      The incidence and prevalence of systemic lupus erythematosus, 2002-2004: The Georgia Lupus Registry.
      Lupus nephritis (LN) is clinically evident in up to 75% of patients with SLE, and LN shows a similar marked female bias.
      • O'Shaughnessy MM
      • Hogan SL
      • Thompson BD
      • et al.
      Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
      However, among males diagnosed with SLE, a higher proportion develop LN compared with females,
      • Shaharir SS
      • Kadir WDA
      • Nordin F
      • et al.
      Systemic lupus erythematosus among male patients in Malaysia: how are we different from other geographical regions?.
      ,
      • Riveros Frutos A
      • Casas I
      • Rua-Figueroa I
      • et al.
      Systemic lupus erythematosus in Spanish males: a study of the Spanish Rheumatology Society Lupus Registry (RELESSER) cohort.
      and male gender is associated with the presence of proliferative LN, a more aggressive pattern of immune-complex–mediated injury.
      • Okpechi IG
      • Swanepoel CR
      • Tiffin N
      • et al.
      Clinicopathological insights into lupus nephritis in South Africans: a study of 251 patients.
      Data are conflicting, but there is some suggestion that the clinical presentation of LN differs between males and females: photosensitivity and mouth ulcers are reportedly more common in females, whereas males have more serositis and vasculitis.
      • Peng W
      • Tang Y
      • Tan L
      • et al.
      Clinicopathological study of male and female patients with lupus nephritis: a retrospective study.
      Along with the presence of the more aggressive histologic findings described earlier, a number of studies also have reported increased disease activity in males with LN.
      • Peng W
      • Tang Y
      • Tan L
      • et al.
      Clinicopathological study of male and female patients with lupus nephritis: a retrospective study.
      ,
      • Soni SS
      • Gowrishankar S
      • Adikey GK
      • et al.
      Sex-based differences in lupus nephritis: a study of 235 Indian patients.
      Male gender consistently is associated with failure to reach complete remission in LN,
      • Peng W
      • Tang Y
      • Tan L
      • et al.
      Clinicopathological study of male and female patients with lupus nephritis: a retrospective study.
      ,
      • Ichinose K
      • Kitamura M
      • Sato S
      • et al.
      Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.
      yet despite this, no gender disparities in long-term renal survival
      • Peng W
      • Tang Y
      • Tan L
      • et al.
      Clinicopathological study of male and female patients with lupus nephritis: a retrospective study.
      ,
      • Resende AL
      • Titan SM
      • Barros RT
      • et al.
      Worse renal outcome of lupus nephritis in male patients: a case-control study.
      ,
      • Feldman CH
      • Broder A
      • Guan H
      • et al.
      Sex Differences in Health Care Utilization, End-Stage Renal Disease, and Mortality Among Medicaid Beneficiaries With Incident Lupus Nephritis.
      or overall mortality
      • Feldman CH
      • Broder A
      • Guan H
      • et al.
      Sex Differences in Health Care Utilization, End-Stage Renal Disease, and Mortality Among Medicaid Beneficiaries With Incident Lupus Nephritis.
      are seen. This is surprising because achieving remission is considered integral to achieving good long-term renal outcomes in LN,
      • Houssiau FA
      • Vasconcelos C
      • D'Cruz D
      • et al.
      Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial.
      and, as such, one might have expected a failure to achieve complete remission resulting in worse renal survival for males.

      AAV

      AAV is a multisystem disease characterized by pauci-immune necrotizing inflammation of medium and small blood vessels, commonly involving the kidneys. Although historically AAV GN was thought to have a slight male preponderance,
      • Jennette JC.
      Rapidly progressive crescentic glomerulonephritis.
      it now is thought that older patients (age, >75 y) are more likely to be female,
      • Hoganson DD
      • From AM
      • Michet CJ.
      ANCA vasculitis in the elderly.
      particularly those with myeloperoxidase (MPO)-ANCA vasculitis.
      • Ono N
      • Niiro H
      • Ueda A
      • et al.
      Characteristics of MPO-ANCA-positive granulomatosis with polyangiitis: a retrospective multi-center study in Japan.
      Approximately 20% of AAV risk is thought to be genetic, and gender-specific genotype risks have been identified, particularly in Microscopic polyangiitis (MPA).
      • Bartfai Z
      • Gaede KI
      • Russell KA
      • et al.
      Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis.
      ,
      • Reynolds WF
      • Stegeman CA
      • Cohen Tervaert JW
      −463 G/A Myeloperoxidase Promoter Polymorphism Is Associated with Clinical Manifestations and the Course of Disease in MPO-ANCA-Associated Vasculitis.
      There are limited data exploring differences between the sexes with respect to clinical presentations of AAV. Tampe et al
      • Tampe D
      • Korsten P
      • Ströbel P
      • et al.
      Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis.
      found no sex-specific associations between clinical characteristics or with serum or urinary parameters. They also reported that systemic disease activity does not differ between the sexes. Unfortunately, this study was from a single center, retrospective in nature, with a small number of patients, and only a short follow-up period; larger multicenter studies are needed.
      Gender-related outcomes in AAV have been explored but findings are conflicting. A recent multicenter cohort study from the United Kingdom and Ireland found no gender differences in patient or renal survival, or when combining ESKD and death as a composite outcome.
      • Scott J
      • Canepa C
      • Buettner A
      • et al.
      A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.
      However, this contrasts with previous work by Bjørneklett et al,
      • Bjørneklett R
      • Solbakken V
      • Bostad L
      • et al.
      Exploring sex-specific differences in the presentation and outcomes of ANCA-associated vasculitis: a nationwide registry-based cohort study.
      who found male sex is associated with greater risk of ESKD. Scott et al
      • Scott J
      • Canepa C
      • Buettner A
      • et al.
      A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.
      specifically questioned whether treatment using fixed-dose regimens resulted in females receiving more treatment per kilogram than males, but, interestingly, this hypothesis was not supported. A number of studies have found a higher mortality risk in female patients,
      • Hoganson DD
      • From AM
      • Michet CJ.
      ANCA vasculitis in the elderly.
      ,
      • Takala JH
      • Kautiainen H
      • Leirisalo-Repo M.
      Survival of patients with Wegener's granulomatosis diagnosed in Finland in 1981-2000.
      although this also is controversial, with another study showing higher mortality in males
      • Bakoush O
      • Segelmark M
      • Torffvit O
      • et al.
      Urine IgM excretion predicts outcome in ANCA-associated renal vasculitis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association.
      and the study from the United Kingdom and Ireland showing no difference in mortality between sexes.
      • Scott J
      • Canepa C
      • Buettner A
      • et al.
      A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.

      IMPACT OF SEX AND GENDER ON SOCIOENVIRONMENTAL ASPECTS OF GLOMERULAR DISEASE

      Differences in verbal, cognitive, motor, and spatial abilities have been reported between sexes and this, combined with societal and cultural influences, may affect an individual's behavior, risk taking, and/or occupational choices. Social and environmental factors may impact these further, and combined with biological risk may influence the likelihood of an individual developing glomerular disease or their subsequent disease trajectory once diagnosed (Fig. 2).
      Figure 2
      Figure 2Impact of sex and gender on socioenvironmental aspects of glomerular disease.

      Accessing Information and Health Care

      Gender affects health care behavior across all areas of medicine,

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      with women displaying greater engagement with health care in high-income countries. A study by Carpenter et al
      • Carpenter DM
      • DeVellis RF
      • Hogan SL
      • et al.
      Use and perceived credibility of medication information sources for patients with a rare illness: differences by gender.
      looked at 232 patients with vasculitis, and how they accessed health care information. They found gender differences in medication information sources: male patients primarily asked their spouse/partner for guidance and rated them as a more credible source than female patients did. Although females were more likely to use medication package inserts or the internet, and less likely to use nurses.
      Gender differences in health care utilization also have been reported, with women showing increased health-seeking behavior.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      This also is true within glomerular disease: males with lupus nephritis have fewer outpatient appointments and emergency department attendances compared with females.
      • Feldman CH
      • Broder A
      • Guan H
      • et al.
      Sex Differences in Health Care Utilization, End-Stage Renal Disease, and Mortality Among Medicaid Beneficiaries With Incident Lupus Nephritis.
      Differences in health care utilization in this study had no effect on overall outcomes, making it difficult to delineate if different genders are underusing or overusing services (or, perhaps most likely, if the answer lies in between).
      Gender differences in ability to access health care services also frequently have been reported. Within nephrology, it is well documented that women with kidney failure have reduced access to the transplant waiting list and to deceased donor transplantation.
      • Ahearn P
      • Johansen KL
      • Tan JC
      • et al.
      Sex Disparity in Deceased-Donor Kidney Transplant Access by Cause of Kidney Disease.
      The reasons for this are complex and might reflect disparities between outcome measures discussed earlier.
      • Ricardo AC
      • Yang W
      • Sha D
      • et al.
      Sex-Related Disparities in CKD Progression.
      Serum creatinine is a commonly used indicator of kidney function but is not directly comparable between the sexes. At the same level of serum creatinine, males have better renal function than females, owing to higher average muscle mass and increased endogenous creatinine function, suggesting women might be referred for specialist care at later time points in the disease process.
      • De La Mata NL
      • Rosales B
      • MacLeod G
      • et al.
      Sex differences in mortality among binational cohort of people with chronic kidney disease: population based data linkage study.

      Exposure to Solvents and Other Occupational Hazards

      Exposure to environmental and occupational hazards has long been recognized as important in disease pathogenesis for a number of autoimmune conditions. Several studies have found causal associations between organic solvent exposure and the development of glomerulonephropathies.
      • Bombassei GJ
      • Kaplan AA.
      The association between hydrocarbon exposure and anti-glomerular basement membrane antibody-mediated disease (Goodpasture's syndrome).
      ,
      • Stengel B
      • Cenee S
      • Limasset JC
      • et al.
      Organic solvent exposure may increase the risk of glomerular nephropathies with chronic renal failure.
      ,
      • Ravnskov U.
      Hydrocarbon exposure may cause glomerulonephritis and worsen renal function: evidence based on Hill's criteria for causality.
      Occupations with a particularly high risk of organic solvent exposure include painters and manufacturing and chemical industries. Although men traditionally have had higher occupational exposure to hydrocarbons, a study exploring chemically induced rodent models of lupus showed gender differences in the downstream effects of exposure to organic solvents: female mice who were injected with pristane (hydrocarbon) had higher mortality rates, kidney disease, serum antinuclear and anti–double-stranded DNA antibodies than their male siblings.
      • Smith DL
      • Dong X
      • Du S
      • et al.
      A female preponderance for chemically induced lupus in SJL/J mice.
      Exposure to silicon-containing compounds also has been associated with renal insufficiency, rapidly progressive glomerulonephritis, as well as the development of SLE, AAV, rheumatoid arthritis, and scleroderma.
      • Chen M
      • Kallenberg CG.
      The environment, geoepidemiology and ANCA-associated vasculitides.
      Occupations that have a high exposure to silica dusts also often are male-predominant and include farming, mill or textile work, sandblasting, lumbar work, and drilling. Over time, occupational exposure in high-income countries appears to be improving, with a move away from manufacturing industries to service provision, and mandated improvements to health and safety legislation.

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Working conditions for many in low- and middle-income countries remain hazardous.

      Smoking

      Smoking has been implicated in both the development of glomerular disease, particularly AAV,
      • McDermott G
      • Fu X
      • Stone JH
      • et al.
      Association of Cigarette Smoking With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
      but also in potentiating disease (eg, young male and female smokers have more aggressive anti-GBM disease, with marked pulmonary involvement).

      Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

      Cigarette consumption in most countries has decreased over the past 3 decades, but despite this the absolute number of smokers has increased from 720 million people in 1980, to almost 1 billion in 2012.
      • Beaglehole R
      • Bonita R
      • Yach D
      • et al.
      A tobacco-free world: a call to action to phase out the sale of tobacco products by 2040.
      Smoking also is associated with increased progression of CKD, so also might contribute to the excess of males with poor outcomes in glomerulonephritis.

      Drugs

      Many drugs are implicated in the development of AAV.
      • Chen M
      • Kallenberg CG.
      The environment, geoepidemiology and ANCA-associated vasculitides.
      ,
      • Weng CH
      • Liu ZC.
      Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.
      Propylthiouracil (a commonly used antithyroid medication) is well recognized, as are levamisole (often used to adulterate cocaine), hydralazine, sulfasalazine, D-penicillamine, minocycline, and anti–tumor necrosis factor α agents. Drug-induced AAV has a more positive prognosis than primary AAV, with most patients with drug-induced AAV achieving complete remission after cessation of the disease-causing medication.
      • Weng CH
      • Liu ZC.
      Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.
      More females are thought to develop drug-induced AAV, largely as a result of the prevalence of thyroid disease in young women, but, interestingly, cocaine/levamisole-associated AAV also shows a female bias
      • McGrath MM
      • Isakova T
      • Rennke HG
      • et al.
      Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease.
      despite cocaine use being more prevalent in males.
      • Requena-Ocaña N
      • Flores-Lopez M
      • Martín AS
      • et al.
      Influence of gender and education on cocaine users in an outpatient cohort in Spain.
      Gender differences also have been seen with medications prescribed for glomerular disease. More females than males are prescribed medication across all illnesses, and adherence to medication is lower in women.
      • Manteuffel M
      • Williams S
      • Chen W
      • et al.
      Influence of patient sex and gender on medication use, adherence, and prescribing alignment with guidelines.
      In addition, women are less likely to receive medication treatment and monitoring as recommended by clinical guidelines.
      • Manteuffel M
      • Williams S
      • Chen W
      • et al.
      Influence of patient sex and gender on medication use, adherence, and prescribing alignment with guidelines.
      Although not a finding specific to nephrology, this is a particular concern in glomerular disease, given the marked toxicity of many therapeutic agents used. In addition, because of the teratogenicity of some standard treatments, females may be offered or may choose less effective treatments for their glomerulonephritis to avoid medications that impair fertility or that are contraindicated in pregnancy. The prime example of this would be the use of azathioprine for maintenance treatment of lupus nephritis instead of mycophenolate mofetil—the latter is superior in preventing relapses and improving kidney outcomes in all but Northern European White patients, but is teratogenic so females planning a pregnancy will be switched to azathioprine. Undertaking a gender-focused audit of local treatment and monitoring compliance would be an achievable goal for most renal units: using a multicenter collaborative approach would benefit the wider nephrology community.

      SUMMARY AND CONCLUSIONS

      The majority of glomerular diseases show a male bias, with the exception of LN, which is strongly female-predominant. Regional and ethnic variations in glomerular disease incidence make delineating effects of sex and gender on disease pathophysiology complex, but there is a marked paucity of research in this area, which needs urgent action from the nephrology community. Clinical trials must ensure adequate representation of both genders when recruiting participants, and document and acknowledge potential effects of sex or sex-specific treatments when assessing outcomes. In vivo and in vitro studies must ensure data are replicated in both male and female animals, organisms, or cells, and that appropriate reporting guidelines [eg, Animal Research: Reporting of In Vivo Experiments (ARRIVE)] are adhered to. The development of both sex-specific biomarkers and sex-specific therapeutics represent opportunities to improve and ensure equity of health care provision. However, gender differences in access to health care should be recognized, and sex and gender, as well as physician biases regarding sex and gender, must be specifically considered when presenting and analyzing clinical and scientific research in glomerular disease. There is much work to be undertaken exploring the roles of sex and gender in individual glomerular diseases, which may benefit patients and their children for generations to come.

      References

        • Darwin C.
        The Descent of Man, and Selection in Relation to Sex.
        Murray, London1871
        • Bairey Merz CN
        • Dember LM
        • Ingelfinger JR
        • et al.
        Sex and the kidneys: current understanding and research opportunities.
        Nat Rev Nephrol. 2019; 15: 776-783https://doi.org/10.1038/s41581-019-0208-6
      1. Organisation WH. Gender and Health, https://www.who.int/health-topics/gender#tab=tab_1 (accessed 22/12/2021 2021).

      2. Oxford Textbook of Medicine. 6 ed: Oxford University Press, 2020.

        • O'Shaughnessy MM
        • Hogan SL
        • Thompson BD
        • et al.
        Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
        European Renal Association. 2018; 33 (2017/11/07): 661-669https://doi.org/10.1093/ndt/gfx189
        • Anonymous
        The New Zealand Glomerulonephritis Study: introductory report.
        Clinical nephrology. 1989; 31: 239-246
      3. Cattran DC, Reich HN, Beanlands HJ, et al. The impact of sex in primary glomerulonephritis. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 2008;23:2247-2253. 2008/01/10. https://doi.org/10.1093/ndt/gfm919.

        • Deng W
        • Tan X
        • Zhou Q
        • et al.
        Gender-related differences in clinicopathological characteristics and renal outcomes of Chinese patients with IgA nephropathy.
        BMC Nephrol. 2018; 19 (2018/02/09): 31https://doi.org/10.1186/s12882-018-0829-1
        • Sandberg K
        • Pai AV
        • Maddox T.
        Sex and rigor: the TGF-β blood pressure affair.
        Am J Physiol Renal Physiol. 2017; 313 (2017/08/11): F1087-f1088https://doi.org/10.1152/ajprenal.00381.2017
        • Ricardo AC
        • Yang W
        • Sha D
        • et al.
        Sex-Related Disparities in CKD Progression.
        Journal of the American Society of Nephrology: JASN. 2019; 30 (2018/12/05): 137-146https://doi.org/10.1681/asn.2018030296
        • Whitacre CC.
        Sex differences in autoimmune disease.
        Nat Immunol. 2001; 2 (2001/08/30): 777-780https://doi.org/10.1038/ni0901-777
        • Billi AC
        • Kahlenberg JM
        • Gudjonsson JE.
        Sex bias in autoimmunity.
        Curr Opin Rheumatol. 2019; 31 (2018/11/06): 53-61https://doi.org/10.1097/bor.0000000000000564
        • Lim SS
        • Bayakly AR
        • Helmick CG
        • et al.
        The incidence and prevalence of systemic lupus erythematosus, 2002-2004: The Georgia Lupus Registry.
        Arthritis & rheumatology (Hoboken, NJ). 2014; 66 (2014/02/08): 357-368https://doi.org/10.1002/art.38239
        • Batocchi AP
        • Majolini L
        • Evoli A
        • et al.
        Course and treatment of myasthenia gravis during pregnancy.
        Neurology. 1999; 52 (1999/02/20): 447-452https://doi.org/10.1212/wnl.52.3.447
        • Lateef A
        • Petri M.
        Management of pregnancy in systemic lupus erythematosus.
        Nat Rev Rheumatol. 2012; 8 (2012/08/22): 710-718https://doi.org/10.1038/nrrheum.2012.133
        • Billip-Tomecka Z
        • Gellert R
        • Zaleska M
        • et al.
        [Renal biopsy in the aged].
        Biopsja nerki u osob w wieku podeszlym. 1993; 89: 335-341
        • Coppo R.
        The Gut-Renal Connection in IgA Nephropathy.
        Semin Nephrol. 2018; 38 (2018/09/05): 504-512https://doi.org/10.1016/j.semnephrol.2018.05.020
        • Klein SL
        • Flanagan KL.
        Sex differences in immune responses.
        Nat Rev Immunol. 2016; 16 (2016/08/23): 626-638https://doi.org/10.1038/nri.2016.90
        • Lissauer D
        • Eldershaw SA
        • Inman CF
        • et al.
        Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.
        Eur J Immunol. 2015; 45 (2015/08/08): 2858-2872https://doi.org/10.1002/eji.201445404
        • Dragin N
        • Bismuth J
        • Cizeron-Clairac G
        • et al.
        Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.
        J Clin Invest. 2016; 126 (2016/03/22): 1525-1537https://doi.org/10.1172/jci81894
        • Kovats S.
        Estrogen receptors regulate innate immune cells and signaling pathways.
        Cell Immunol. 2015; 294 (2015/02/16): 63-69https://doi.org/10.1016/j.cellimm.2015.01.018
        • Bereshchenko O
        • Bruscoli S
        • Glucocorticoids Riccardi C.
        Sex Hormones, and Immunity. Front Immunol. 2018; 9 (2018/06/28): 1332https://doi.org/10.3389/fimmu.2018.01332
        • Hao S
        • Zhao J
        • Zhou J
        • et al.
        Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors.
        Int Immunopharmacol. 2007; 7 (2007/11/13): 1765-1775https://doi.org/10.1016/j.intimp.2007.09.017
        • Karpuzoglu E
        • Phillips RA
        • Gogal Jr, RM
        • et al.
        IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12.
        Mol Immunol. 2007; 44 (2006/10/19. doi:10.1016/j.molimm.2006.08.005): 1808-1814
        • Cunningham MA
        • Wirth JR
        • Scott JL
        • et al.
        Early Ovariectomy Results in Reduced Numbers of CD11c+/CD11b+ Spleen Cells and Impacts Disease Expression in Murine Lupus.
        Front Immunol. 2016; 7 (2016/02/26): 31https://doi.org/10.3389/fimmu.2016.00031
        • Trigunaite A
        • Dimo J
        • Jørgensen TN.
        Suppressive effects of androgens on the immune system.
        Cell Immunol. 2015; 294 (2015/02/25): 87-94https://doi.org/10.1016/j.cellimm.2015.02.004
        • Zhu ML
        • Bakhru P
        • Conley B
        • et al.
        Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.
        Nat Commun. 2016; 7 (2016/04/14): 11350https://doi.org/10.1038/ncomms11350
        • Borba VV
        • Zandman-Goddard G
        • Shoenfeld Y.
        Prolactin and Autoimmunity. Front Immunol. 2018; 9 (2018/02/28): 73https://doi.org/10.3389/fimmu.2018.00073
        • Song GG
        • Lee YH.
        Circulating prolactin level in systemic lupus erythematosus and its correlation with disease activity: a meta-analysis.
        Lupus. 2017; 26 (2017/04/20): 1260-1268https://doi.org/10.1177/0961203317693094
        • Scofield RH
        • Bruner GR
        • Namjou B
        • et al.
        Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome.
        Arthritis and rheumatism. 2008; 58 (2008/08/01): 2511-2517https://doi.org/10.1002/art.23701
        • Lam IKY
        • Chow JX
        • Lau CS
        • et al.
        MicroRNA-mediated immune regulation in rheumatic diseases.
        Cancer Lett. 2018; 431 (2018/06/04): 201-212https://doi.org/10.1016/j.canlet.2018.05.044
        • Hewagama A
        • Gorelik G
        • Patel D
        • et al.
        Overexpression of X-linked genes in T cells from women with lupus.
        J Autoimmun. 2013; 41 (2013/02/26): 60-71https://doi.org/10.1016/j.jaut.2012.12.006
        • Pickard JM
        • Zeng MY
        • Caruso R
        • et al.
        Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease.
        Immunol Rev. 2017; 279 (2017/09/01): 70-89https://doi.org/10.1111/imr.12567
        • Markle JG
        • Frank DN
        • Mortin-Toth S
        • et al.
        Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.
        Science. 2013; 339 (2013/01/19): 1084-1088https://doi.org/10.1126/science.1233521
        • Tanaka R
        • Tsutsui H
        • Kobuchi S
        • et al.
        Protective effect of 17β-estradiol on ischemic acute kidney injury through the renal sympathetic nervous system.
        Eur J Pharmacol. 2012; 683 (2012/03/20): 270-275https://doi.org/10.1016/j.ejphar.2012.02.044
        • Mankhey RW
        • Bhatti F
        • Maric C.
        17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy.
        Am J Physiol Renal Physiol. 2005; 288 (2004/09/30. DOI: 10.1152/ajprenal.00195.2004): F399-F405
        • Sakemi T
        • Toyoshima H
        • Shouno Y
        • et al.
        Estrogen attenuates progressive glomerular injury in hypercholesterolemic male Imai rats.
        Nephron. 1995; 69 (1995/01/01): 159-165https://doi.org/10.1159/000188433
        • Corradetti C
        • Jog NR
        • Cesaroni M
        • et al.
        Estrogen Receptor alpha Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity.
        Journal of immunology (Baltimore, Md : 1950). 2018; 200: 512-522https://doi.org/10.4049/jimmunol.1700770
        • Fortepiani LA
        • Yanes L
        • Zhang H
        • et al.
        Role of androgens in mediating renal injury in aging SHR.
        Hypertension. 2003; 42 (2003/10/22): 952-955https://doi.org/10.1161/01.Hyp.0000099241.53121.7f
        • Ji H
        • Zheng W
        • Wu X
        • et al.
        Sex chromosome effects unmasked in angiotensin II-induced hypertension.
        Hypertension. 2010; 55 (2010/03/17): 1275-1282https://doi.org/10.1161/hypertensionaha.109.144949
        • De La Mata NL
        • Rosales B
        • MacLeod G
        • et al.
        Sex differences in mortality among binational cohort of people with chronic kidney disease: population based data linkage study.
        BMJ. 2021; 375e068247https://doi.org/10.1136/BMJ-2021-068247
        • Canetta PA
        • Troost JP
        • Mahoney S
        • et al.
        Health-related quality of life in glomerular disease.
        Kidney international. 2019; 95 (2019/03/23): 1209-1224https://doi.org/10.1016/j.kint.2018.12.018
        • Phyo AZZ
        • Freak-Poli R
        • Craig H
        • et al.
        Quality of life and mortality in the general population: a systematic review and meta-analysis.
        BMC Public Health. 2020; 20: 1596https://doi.org/10.1186/s12889-020-09639-9
        • Mahr N
        • Neyer U
        • Prischl F
        • et al.
        Proteinuria and hemoglobin levels in patients with primary glomerular disease.
        American journal of kidney diseases: the official journal of the National Kidney Foundation. 2005; 46: 424-431
      4. Coggins CH, Breyer Lewis J, Caggiula AW, et al. Differences between women and men with chronic renal disease. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association 1998;13:1430-1437. 1998/06/26. https://doi.org/10.1093/ndt/13.6.1430.

        • Reckelhoff JF.
        Gender differences in the regulation of blood pressure.
        Hypertension. 2001; 37 (2001/05/23): 1199-1208https://doi.org/10.1161/01.hyp.37.5.1199
        • Ronkainen J
        • Nuutinen M
        • Koskimies O.
        The adult kidney 24 years after childhood Henoch-Schönlein purpura: a retrospective cohort study.
        Lancet (London, England). 2002; 360 (2002/09/21): 666-670https://doi.org/10.1016/s0140-6736(02)09835-5
        • Nakamura I
        • Iwase H
        • Arai K
        • et al.
        Detection of gender difference and epitope specificity of IgG antibody activity against IgA1 hinge portion in IgA nephropathy patients by using synthetic hinge peptide and glycopeptide probes.
        Nephrology (Carlton, Vic). 2004; 9 (2004/03/05): 26-30https://doi.org/10.1111/j.1440-1797.2003.00225.x
        • Magistroni R
        • D’Agati VD
        • Appel GB
        • Kiryluk K
        New developments in the genetics, pathogenesis, and therapy of IgA nephropathy.
        Kidney Int. 2015; 88: 974-989
        • Feng Y
        • Su Y
        • Ma C
        • et al.
        3′UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.
        International immunopharmacology. 2019; 71: 295-300https://doi.org/10.1016/j.intimp.2019.03.041
        • Cattran DC
        • Reich HN
        • Beanlands HJ
        • et al.
        The impact of sex in primary glomerulonephritis.
        Nephrology Dialysis Transplantation. 2008; 23: 2247-2253https://doi.org/10.1093/ndt/gfm919
        • Goto M
        • Wakai K
        • Kawamura T
        • et al.
        A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
        European Renal Association. 2009; 24 (2009/06/12): 3068-3074https://doi.org/10.1093/ndt/gfp273
        • Moriyama T
        • Tanaka K
        • Iwasaki C
        • et al.
        Prognosis in IgA nephropathy: 30-year analysis of 1,012 patients at a single center in Japan.
        PLoS One. 2014; 9 (2014/03/25): e91756https://doi.org/10.1371/journal.pone.0091756
        • Donadio JV
        • Bergstralh EJ
        • Grande JP
        • et al.
        Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association.
        European Renal Association. 2002; 17 (2002/07/10): 1197-1203https://doi.org/10.1093/ndt/17.7.1197
        • Ronco P
        • Beck L
        • Debiec H
        • et al.
        Membranous nephropathy.
        Nature Reviews Disease Primers. 2021; 7: 69https://doi.org/10.1038/s41572-021-00303-z
        • Hogan SL
        • Muller KE
        • Jennette JC
        • et al.
        A review of therapeutic studies of idiopathic membranous glomerulopathy.
        Am J Kidney Dis. 1995; 25 (1995/06/01): 862-875https://doi.org/10.1016/0272-6386(95)90568-5
        • Lee H
        • Yoo KD
        • Oh YK
        • et al.
        Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease.
        Medicine. 2016; 95 (2016/03/26): e3179https://doi.org/10.1097/md.0000000000003179
        • Fenton A
        • Smith SW
        • Hewins P.
        Adult minimal-change disease: observational data from a UK centre on patient characteristics, therapies, and outcomes.
        BMC Nephrol. 2018; 19 (2018/08/18): 207https://doi.org/10.1186/s12882-018-0999-x
        • Troyanov S
        • Wall CA
        • Miller JA
        • et al.
        Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.
        Journal of the American Society of Nephrology. 2005; 16 (JASN2005/02/18): 1061-1068https://doi.org/10.1681/asn.2004070593
        • Ojogwu LI
        • Ukoli FA.
        A follow up study of adult nephrotic syndrome in Nigerians: outcome and predictors of endstage renal failure.
        African journal of medicine and medical sciences. 1993; 22: 43-50
        • Moroni G
        • Gallelli B
        • Quaglini S
        • et al.
        Long-term outcome of renal transplantation in adults with focal segmental glomerulosclerosis. Transplant international : official journal of the European Society for.
        Organ Transplantation. 2010; 23: 208-216https://doi.org/10.1111/j.1432-2277.2009.00977.x
        • Kashgary A
        • Sontrop JM
        • Li L
        • et al.
        The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: A systematic review and meta-analysis of 77 case-reports and case-series.
        BMC nephrology. 2016; 17: 104https://doi.org/10.1186/s12882-016-0322-7
        • Goodpasture EW.
        Landmark publication from The American Journal of the Medical Sciences: The significance of certain pulmonary lesions in relation to the etiology of influenza.
        Am J Med Sci. 2009; 338 (2009/08/15): 148-151https://doi.org/10.1097/MAJ.0b013e31818fff94
        • van Daalen EE
        • Jennette JC
        • McAdoo SP
        • et al.
        Predicting Outcome in Patients with Anti-GBM Glomerulonephritis.
        Clinical Journal of the American Society of Nephrology. 2018; 13: 63https://doi.org/10.2215/CJN.04290417
        • KLUTH DC
        • REES AJ
        Anti-Glomerular Basement Membrane Disease.
        Journal of the American Society of Nephrology. 1999; 10: 2446-2453https://doi.org/10.1681/asn.V10112446
        • Donaghy M
        • Rees AJ.
        Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane.
        Lancet (London, England). 1983; 2 (1983/12/17): 1390-1393https://doi.org/10.1016/s0140-6736(83)90923-6
        • Bombassei GJ
        • Kaplan AA.
        The association between hydrocarbon exposure and anti-glomerular basement membrane antibody-mediated disease (Goodpasture's syndrome).
        Am J Ind Med. 1992; 21 (1992/01/01): 141-153https://doi.org/10.1002/ajim.4700210204
        • McAdoo SP
        • Pusey CD.
        Anti-Glomerular Basement Membrane Disease.
        Clinical journal of the American Society of Nephrology. 2017; 12 (CJASN2017/05/19): 1162-1172https://doi.org/10.2215/cjn.01380217
        • Johnson CM
        • Wilson DM
        • O'Fallon WM
        • et al.
        Renal stone epidemiology: a 25-year study in Rochester, Minnesota.
        Kidney international. 1979; 16 (1979/11/01): 624-631https://doi.org/10.1038/ki.1979.173
        • McAdoo SP
        • Tanna A
        • Hrušková Z
        • et al.
        Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
        Kidney international. 2017; 92 (2017/05/17): 693-702https://doi.org/10.1016/j.kint.2017.03.014
        • Shaharir SS
        • Kadir WDA
        • Nordin F
        • et al.
        Systemic lupus erythematosus among male patients in Malaysia: how are we different from other geographical regions?.
        Lupus. 2019; 28: 137-144https://doi.org/10.1177/0961203318812676
        • Riveros Frutos A
        • Casas I
        • Rua-Figueroa I
        • et al.
        Systemic lupus erythematosus in Spanish males: a study of the Spanish Rheumatology Society Lupus Registry (RELESSER) cohort.
        Lupus. 2017; 26: 698-706https://doi.org/10.1177/0961203316673728
        • Okpechi IG
        • Swanepoel CR
        • Tiffin N
        • et al.
        Clinicopathological insights into lupus nephritis in South Africans: a study of 251 patients.
        Lupus. 2012; 21: 1017-1024https://doi.org/10.1177/0961203312441981
        • Peng W
        • Tang Y
        • Tan L
        • et al.
        Clinicopathological study of male and female patients with lupus nephritis: a retrospective study.
        International urology and nephrology. 2018; 50: 313-320https://doi.org/10.1007/s11255-017-1780-y
        • Soni SS
        • Gowrishankar S
        • Adikey GK
        • et al.
        Sex-based differences in lupus nephritis: a study of 235 Indian patients.
        J Nephrol. 2008; 21 (2008/07/25): 570-575
        • Ichinose K
        • Kitamura M
        • Sato S
        • et al.
        Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort.
        Lupus. 2019; 28: 295-303https://doi.org/10.1177/0961203319826690
        • Resende AL
        • Titan SM
        • Barros RT
        • et al.
        Worse renal outcome of lupus nephritis in male patients: a case-control study.
        Lupus. 2011; 20: 561-567https://doi.org/10.1177/0961203310392422
        • Feldman CH
        • Broder A
        • Guan H
        • et al.
        Sex Differences in Health Care Utilization, End-Stage Renal Disease, and Mortality Among Medicaid Beneficiaries With Incident Lupus Nephritis.
        Arthritis & rheumatology (Hoboken, NJ). 2018; 70: 417-426https://doi.org/10.1002/art.40392
        • Houssiau FA
        • Vasconcelos C
        • D'Cruz D
        • et al.
        Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial.
        Arthritis and rheumatism. 2004; 50 (2004/12/14): 3934-3940https://doi.org/10.1002/art.20666
        • Jennette JC.
        Rapidly progressive crescentic glomerulonephritis.
        Kidney international. 2003; 63 (2003/03/13): 1164-1177https://doi.org/10.1046/j.1523-1755.2003.00843.x
        • Hoganson DD
        • From AM
        • Michet CJ.
        ANCA vasculitis in the elderly.
        Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2008; 14: 78-81https://doi.org/10.1097/RHU.0b013e31816b2fbd
        • Ono N
        • Niiro H
        • Ueda A
        • et al.
        Characteristics of MPO-ANCA-positive granulomatosis with polyangiitis: a retrospective multi-center study in Japan.
        Rheumatology international. 2015; 35: 555-559https://doi.org/10.1007/s00296-014-3106-z
        • Bartfai Z
        • Gaede KI
        • Russell KA
        • et al.
        Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis.
        Clinical immunology (Orlando, Fla). 2003; 109: 330-337
        • Reynolds WF
        • Stegeman CA
        • Cohen Tervaert JW
        −463 G/A Myeloperoxidase Promoter Polymorphism Is Associated with Clinical Manifestations and the Course of Disease in MPO-ANCA-Associated Vasculitis.
        Clinical Immunology. 2002; 103: 154-160https://doi.org/10.1006/clim.2002.5206
        • Tampe D
        • Korsten P
        • Ströbel P
        • et al.
        Comprehensive Analysis of Sex Differences at Disease Manifestation in ANCA-Associated Glomerulonephritis.
        Front Immunol. 2021; 12 (2021/10/12)736638https://doi.org/10.3389/fimmu.2021.736638
        • Scott J
        • Canepa C
        • Buettner A
        • et al.
        A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.
        Sci Rep. 2021; 11 (2021/06/24): 13080https://doi.org/10.1038/s41598-021-92629-7
        • Bjørneklett R
        • Solbakken V
        • Bostad L
        • et al.
        Exploring sex-specific differences in the presentation and outcomes of ANCA-associated vasculitis: a nationwide registry-based cohort study.
        International urology and nephrology. 2018; 50 (2018/05/24): 1311-1318https://doi.org/10.1007/s11255-018-1888-8
        • Takala JH
        • Kautiainen H
        • Leirisalo-Repo M.
        Survival of patients with Wegener's granulomatosis diagnosed in Finland in 1981-2000.
        Scandinavian journal of rheumatology. 2010; 39: 71-76https://doi.org/10.3109/03009740903140701
        • Bakoush O
        • Segelmark M
        • Torffvit O
        • et al.
        Urine IgM excretion predicts outcome in ANCA-associated renal vasculitis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association.
        European Renal Association. 2006; 21: 1263-1269
        • Carpenter DM
        • DeVellis RF
        • Hogan SL
        • et al.
        Use and perceived credibility of medication information sources for patients with a rare illness: differences by gender.
        Journal of health communication. 2011; 16: 629-642https://doi.org/10.1080/10810730.2011.551995
        • Ahearn P
        • Johansen KL
        • Tan JC
        • et al.
        Sex Disparity in Deceased-Donor Kidney Transplant Access by Cause of Kidney Disease.
        Clinical journal of the American Society of Nephrology: CJASN. 2021; 16 (2021/01/28): 241-250https://doi.org/10.2215/cjn.09140620
        • Stengel B
        • Cenee S
        • Limasset JC
        • et al.
        Organic solvent exposure may increase the risk of glomerular nephropathies with chronic renal failure.
        International journal of epidemiology. 1995; 24: 427-434
        • Ravnskov U.
        Hydrocarbon exposure may cause glomerulonephritis and worsen renal function: evidence based on Hill's criteria for causality.
        QJM : monthly journal of the Association of Physicians. 2000; 93: 551-556
        • Smith DL
        • Dong X
        • Du S
        • et al.
        A female preponderance for chemically induced lupus in SJL/J mice.
        Clinical immunology (Orlando, Fla). 2007; 122: 101-107
        • Chen M
        • Kallenberg CG.
        The environment, geoepidemiology and ANCA-associated vasculitides.
        Autoimmunity reviews. 2010; 9 (2009/11/0710.1016/j.autrev.2009.10.008): A293-A298
        • McDermott G
        • Fu X
        • Stone JH
        • et al.
        Association of Cigarette Smoking With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
        JAMA Intern Med. 2020; 180 (2020/04/14): 870-876https://doi.org/10.1001/jamainternmed.2020.0675
        • Beaglehole R
        • Bonita R
        • Yach D
        • et al.
        A tobacco-free world: a call to action to phase out the sale of tobacco products by 2040.
        Lancet (London, England). 2015; 385 (2015/03/19): 1011-1018https://doi.org/10.1016/s0140-6736(15)60133-7
        • Weng CH
        • Liu ZC.
        Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis.
        Chin Med J (Engl). 2019; 132 (2019/12/20): 2848-2855https://doi.org/10.1097/cm9.0000000000000539
        • McGrath MM
        • Isakova T
        • Rennke HG
        • et al.
        Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease.
        Clinical journal of the American Society of Nephrology: CJASN. 2011; 6 (2011/10/08): 2799-2805https://doi.org/10.2215/cjn.03440411
        • Requena-Ocaña N
        • Flores-Lopez M
        • Martín AS
        • et al.
        Influence of gender and education on cocaine users in an outpatient cohort in Spain.
        Sci Rep. 2021; 11 (2021/10/24): 20928https://doi.org/10.1038/s41598-021-00472-7
        • Manteuffel M
        • Williams S
        • Chen W
        • et al.
        Influence of patient sex and gender on medication use, adherence, and prescribing alignment with guidelines.
        J Womens Health (Larchmt). 2014; 23 (2013/11/12): 112-119https://doi.org/10.1089/jwh.2012.3972