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Postinfectious Versus Infection-Related Glomerulonephritis
Correspondence LETTERS TO THE EDITOR Expanding the Domain of Postinfectious Glomerulonephritis To the Editor: The article on infection-related glomerulonephritis (GN) by Glassock et al1 emphasizes the important differences between true “postinfectious GN,” such as poststreptococcal GN, and infectionassociated GN, such as the IgA-dominant lesion associated with ongoing staphylococcal infection. There is another category of GN that we believe should also be included in the domain of “postinfectious GN,” which is defined by the authors as including a latent period following an infection “lasting more than several days and up to a few weeks, during which the patient returns to or toward his or her usual state of health; and.ends with the acute onset of features of glomerulonephritis.and often some decrease in kidney function”.1(p826) Recent studies suggest that infections have a much wider role in GN, not only through the serum sickness–like mechanisms reviewed in the article from Glassock et al, but also because they initiate an autoimmune response. We have recently reviewed the multiple mechanisms by which infections likely initiate many common types of autoimmune GN, including ANCA-associated vasculitis, IgA nephropathy, membranoproliferative GN type 1, and lupus nephritis.2 Thus, the domain of postinfectious GN extends well beyond classical poststreptococcal disease or entities such as IgA-dominant staphylococcus-associated GN. We strongly endorse the goal of better understanding and treating infection-related GN that is stated in the title of the article by Glassock et al,1 but to achieve this, we need to extend our thinking about postinfectious GN beyond the traditional concepts of serum sickness due to bovine serum albumin to include the role of infections initiating GN through autoimmune mechanisms. William G. Couser, MD1 Richard J. Johnson, MD2 1 University of Washington, Woodinville, Washington 2 University of Colorado Denver, Aurora, Colorado
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests.
References 1. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. 2. Couser WG, Johnson RJ. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86(5): 905-914. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.018
Postinfectious Versus Infection-Related Glomerulonephritis To the Editor: Glassock et al1 raise interesting issues regarding the concept of infection-related glomerulonephritis (GN). The classical features Am J Kidney Dis. 2015;66(4):725-730
of postinfectious GN consist of an episode of infection, resolution of the infection, a latency period, then an acute GN. The pathologic picture is one of acute exudative GN, capillary wall immune deposits containing C3 with or without immunoglobulins (IgG, IgA, and IgM), and electron-dense deposits consisting of subepithelial humps (with or without intramembranous, mesangial, and subendothelial deposits).2 Because this picture is classically described in poststreptococcal GN, the pathologic findings have been designated postinfectious GN. In recent studies, a similar pathologic pattern of glomerular disease has been described in association with ongoing unresolved bacterial infections mainly due to staphylococci.3-7 Although there is no latency period, these are immune-mediated processes, as determined by detectable immune deposits in glomeruli and all the features of postinfectious GN. In such instances, the term “bacterial infection–related GN” has been proposed.8 It is of interest that other forms of immune-mediated GN associated with ongoing bacterial infections of skin, cardiac valves, vascular catheters, and visceral abscesses often have immune deposits without subepithelial humps.2 Hence these are not considered postinfectious GNs, either clinically or pathologically. The designation of “postinfectious” therefore requires knowledge of resolution of a recent episode of bacterial infection and cannot be made using pathologic criteria alone. Because the term “infection-related GN” is nonspecific, perhaps a better generic term for these immunemediated processes is “peri-infectious” or “midinfectious” GN, to indicate GN arising during an ongoing process of bacterial infection. Shane M. Meehan, MB, BCh Sharp Memorial Hospital, San Diego, California
Acknowledgements Financial Disclosure: The author reports that he has no relevant financial interests.
References 1. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. 2. Satoskar AA, Nadasdy T, Silva FG. Acute postinfectious glomerulonephritis and glomerulonephritis caused by persistent bacterial infection. In: Jennette JC, Olson JL, Silva FG, D’Agati VD, eds. Heptinstall’s Pathology of the Kidney. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015:367-436. 3. Nasr SH, Markowitz GS, Whelan JD, et al. IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Hum Pathol. 2003;34(12):1235-1241. 4. Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D’Agati VD. Acute postinfectious glomerulonephritis in the modern era. Medicine. 2008;87(1):21-32. 5. Haas M, Racusen LC, Bagnasco SM. IgA dominant postinfectious glomerulonephritis: a report of 13 cases with common ultrastructural features. Hum Pathol. 2008;39(9):1309-1316. 6. Worawichawong S, Girard L, Trpkov K, Gough JC, Gregson DB, Benediktsson H. Immunoglobulin A-dominant postinfectious glomerulonephritis: frequent occurrence in nondiabetic patients with Staphylococcus aureus infection. Hum Pathol. 2011;42(2):279-284. 7. Nasr SH, Fidler ME, Valeri AM, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol. 2011;22(1): 187-195. 725
Correspondence 8. Nasr SH, Radhakrishnan J, D’Agati VD. Bacterial infectionrelated glomerulonephritis in adults. Kidney Int. 2013;83(5): 792-803. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.017
In Reply to ‘Expanding the Domain of Postinfectious Glomerulonephritis’ and ‘Postinfectious Versus Infection-Related Glomerulonephritis’ We thank both letter writers1,2 for their cogent words. Couser and Johnson1 cite their tour de force review of the potential and established molecular mechanisms that link infection to glomerulonephritis (GN).3 However, the review seems to overreach by suggesting that “infections initiate most forms of GN.”3 For example, there is no credible evidence that infection “triggers” lupus nephritis. As evidence, we meticulously followed up 92 patients with systemic lupus erythematosus (SLE) enrolled in the NIH-sponsored Ohio SLE Study. During follow-up, 51 experienced 73 SLE flares, both renal and nonrenal. In no instance did fever or documented infection precede the flare.4 Also, microbial antigens have never been firmly identified in lupus nephritis immune deposits.5 In our experience, infection also does not trigger ANCAassociated vasculitis (AAV). Couser and Johnson3 mention sinusitis and middle-ear effusion at AAV presentation. However, generally these are manifestations of AAV, not infections; antibiotics are ineffective, whereas steroids/immunosuppressants are quickly efficacious. ANCAs are also seen in bacterial endocarditis. However, they are bystander “effects,”3 not evidence of AAV. Generally, these patients recover completely with antibiotics alone.6 Meehan2 suggests the terms “peri-infectious” and “midinfectious” to describe infection-related GN. Couser and Johnson1 suggest “extending” the definition of postinfectious GN. We do not think that these additions would provide greater clarity. We believe that our Perspective7 got it right from both a historical and pathophysiologic viewpoint. Also, we hope our contribution will lay to rest the illogical and potentially dangerous diagnosis of “poststaphylococcal GN,” which provided the inspiration for this work. Lee A. Hebert, MD1 Richard J. Glassock, MD2 1 The Ohio State University Wexner Medical Center, Columbus, Ohio 2 Geffen School of Medicine at UCLA, Los Angeles, California
5. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, and rheumatoid arthritis. In: Jennette JC, Silva FG, Olson JL, D’Agati VD. D’Agati VD, Stokes MB, eds. Hepinstall’s Pathology of the Kidney. 7th ed.: 559-656. 6. Choi HK, Lamprecht P, Niles JL, et al. Subacute bacterial endocarditis with positive cytoplasmic antineutrophil cytoplasmic antibodies and anti-proteinase 3 antibodies. Arthritis Rheum. 2000;43(1):226-231. 7. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.016
RESEARCH LETTERS Parental History of Cardiovascular Disease and Risk of ESRD in Women To the Editor: Cardiac and kidney disease pathogenesis are linked by both genetic1 and common2,3 risk factors. Parental history of CVD is a widely accepted risk factor for cardiovascular events in offspring.4 In addition, in unselected US adults attending health checkups, we recently reported that a positive parental CVD history is associated with lower estimated glomerular filtration rate (eGFR) and a nominally faster rate of eGFR decline in offspring.5 Here, we test the hypothesis that a positive parental CVD history associates with ESRD risk in an independent population-based prospective cohort of middleaged women. Included were 34,468 women from central Sweden aged 62.3 6 9.3 years attending mammography screening in 1997, who did not have a previous known diagnosis of cancer6 (detailed methods in Item S1). Of 36,304 eligible individuals, we excluded those with a history of CKD (n 5 214) and kidney stones (n 5 1,622). The exposure, parental CVD history (defined as heart disease before the age of 60 years in Table 1. Baseline Characteristics of Participants With and Without a History of Parental CVD
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests.
References 1. Couser WG, Johnson RJ. Expanding the domain of postinfectious glomerulonephritis. Am J Kidney Dis. 2015;66(4):725. 2. Meehan SM. Postinfectious versus infection-related glomerulonephritis. Am J Kidney Dis. 2015;66(4):725-726. 3. Couser WG, Johnson RJ. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86: 905-914. 4. Rovin BH, Tang Y, Sun J, et al. Clinical significance of fever in the SLE patient receiving steroid therapy. Kidney Int. 2005;68:747-750. 726
No. Age, y BMI, kg/m2 Smoker University education Ever drinker of alcohol Physical activity, MET h/d CVD Hypertension Diabetes
With Parental CVD History
Without Parental CVD History
P
3,646 60.6 6 8.8 25.4 6 4.2 1,735 (48) 717 (20) 3,065 (85)
30,822 62.4 6 9.3 25.0 6 3.9 16,463 (55) 5,676 (18) 24,936 (82)
,0.001 ,0.001 ,0.001 0.01 ,0.001
42.3 6 4.9
42.5 6 4.8
0.04
335 (9) 225 (6) 181 (5)
1,799 (6) 1,288 (4) 1,204 (4)
,0.001 ,0.001 0.002
Note: Data are expressed as mean 6 standard deviation or number (percentage), as appropriate. Abbreviations: BMI, body mass index; CVD, cardiovascular disease; MET, metabolic equivalent.
Am J Kidney Dis. 2015;66(4):725-730
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests.
References 1. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. 2. Couser WG, Johnson RJ. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86(5): 905-914. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.018
Postinfectious Versus Infection-Related Glomerulonephritis To the Editor: Glassock et al1 raise interesting issues regarding the concept of infection-related glomerulonephritis (GN). The classical features Am J Kidney Dis. 2015;66(4):725-730
of postinfectious GN consist of an episode of infection, resolution of the infection, a latency period, then an acute GN. The pathologic picture is one of acute exudative GN, capillary wall immune deposits containing C3 with or without immunoglobulins (IgG, IgA, and IgM), and electron-dense deposits consisting of subepithelial humps (with or without intramembranous, mesangial, and subendothelial deposits).2 Because this picture is classically described in poststreptococcal GN, the pathologic findings have been designated postinfectious GN. In recent studies, a similar pathologic pattern of glomerular disease has been described in association with ongoing unresolved bacterial infections mainly due to staphylococci.3-7 Although there is no latency period, these are immune-mediated processes, as determined by detectable immune deposits in glomeruli and all the features of postinfectious GN. In such instances, the term “bacterial infection–related GN” has been proposed.8 It is of interest that other forms of immune-mediated GN associated with ongoing bacterial infections of skin, cardiac valves, vascular catheters, and visceral abscesses often have immune deposits without subepithelial humps.2 Hence these are not considered postinfectious GNs, either clinically or pathologically. The designation of “postinfectious” therefore requires knowledge of resolution of a recent episode of bacterial infection and cannot be made using pathologic criteria alone. Because the term “infection-related GN” is nonspecific, perhaps a better generic term for these immunemediated processes is “peri-infectious” or “midinfectious” GN, to indicate GN arising during an ongoing process of bacterial infection. Shane M. Meehan, MB, BCh Sharp Memorial Hospital, San Diego, California
Acknowledgements Financial Disclosure: The author reports that he has no relevant financial interests.
References 1. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. 2. Satoskar AA, Nadasdy T, Silva FG. Acute postinfectious glomerulonephritis and glomerulonephritis caused by persistent bacterial infection. In: Jennette JC, Olson JL, Silva FG, D’Agati VD, eds. Heptinstall’s Pathology of the Kidney. 7th ed. Philadelphia, PA: Wolters Kluwer; 2015:367-436. 3. Nasr SH, Markowitz GS, Whelan JD, et al. IgA-dominant acute poststaphylococcal glomerulonephritis complicating diabetic nephropathy. Hum Pathol. 2003;34(12):1235-1241. 4. Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D’Agati VD. Acute postinfectious glomerulonephritis in the modern era. Medicine. 2008;87(1):21-32. 5. Haas M, Racusen LC, Bagnasco SM. IgA dominant postinfectious glomerulonephritis: a report of 13 cases with common ultrastructural features. Hum Pathol. 2008;39(9):1309-1316. 6. Worawichawong S, Girard L, Trpkov K, Gough JC, Gregson DB, Benediktsson H. Immunoglobulin A-dominant postinfectious glomerulonephritis: frequent occurrence in nondiabetic patients with Staphylococcus aureus infection. Hum Pathol. 2011;42(2):279-284. 7. Nasr SH, Fidler ME, Valeri AM, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol. 2011;22(1): 187-195. 725
Correspondence 8. Nasr SH, Radhakrishnan J, D’Agati VD. Bacterial infectionrelated glomerulonephritis in adults. Kidney Int. 2013;83(5): 792-803. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.017
In Reply to ‘Expanding the Domain of Postinfectious Glomerulonephritis’ and ‘Postinfectious Versus Infection-Related Glomerulonephritis’ We thank both letter writers1,2 for their cogent words. Couser and Johnson1 cite their tour de force review of the potential and established molecular mechanisms that link infection to glomerulonephritis (GN).3 However, the review seems to overreach by suggesting that “infections initiate most forms of GN.”3 For example, there is no credible evidence that infection “triggers” lupus nephritis. As evidence, we meticulously followed up 92 patients with systemic lupus erythematosus (SLE) enrolled in the NIH-sponsored Ohio SLE Study. During follow-up, 51 experienced 73 SLE flares, both renal and nonrenal. In no instance did fever or documented infection precede the flare.4 Also, microbial antigens have never been firmly identified in lupus nephritis immune deposits.5 In our experience, infection also does not trigger ANCAassociated vasculitis (AAV). Couser and Johnson3 mention sinusitis and middle-ear effusion at AAV presentation. However, generally these are manifestations of AAV, not infections; antibiotics are ineffective, whereas steroids/immunosuppressants are quickly efficacious. ANCAs are also seen in bacterial endocarditis. However, they are bystander “effects,”3 not evidence of AAV. Generally, these patients recover completely with antibiotics alone.6 Meehan2 suggests the terms “peri-infectious” and “midinfectious” to describe infection-related GN. Couser and Johnson1 suggest “extending” the definition of postinfectious GN. We do not think that these additions would provide greater clarity. We believe that our Perspective7 got it right from both a historical and pathophysiologic viewpoint. Also, we hope our contribution will lay to rest the illogical and potentially dangerous diagnosis of “poststaphylococcal GN,” which provided the inspiration for this work. Lee A. Hebert, MD1 Richard J. Glassock, MD2 1 The Ohio State University Wexner Medical Center, Columbus, Ohio 2 Geffen School of Medicine at UCLA, Los Angeles, California
5. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjögren syndrome, and rheumatoid arthritis. In: Jennette JC, Silva FG, Olson JL, D’Agati VD. D’Agati VD, Stokes MB, eds. Hepinstall’s Pathology of the Kidney. 7th ed.: 559-656. 6. Choi HK, Lamprecht P, Niles JL, et al. Subacute bacterial endocarditis with positive cytoplasmic antineutrophil cytoplasmic antibodies and anti-proteinase 3 antibodies. Arthritis Rheum. 2000;43(1):226-231. 7. Glassock RJ, Alvarado A, Prosek J, et al. Staphylococcusrelated glomerulonephritis and poststreptococcal glomerulonephritis: why defining “post” is important in understanding and treating infection-related glomerulonephritis. Am J Kidney Dis. 2015;65(6):826-832. Ó 2015 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.07.016
RESEARCH LETTERS Parental History of Cardiovascular Disease and Risk of ESRD in Women To the Editor: Cardiac and kidney disease pathogenesis are linked by both genetic1 and common2,3 risk factors. Parental history of CVD is a widely accepted risk factor for cardiovascular events in offspring.4 In addition, in unselected US adults attending health checkups, we recently reported that a positive parental CVD history is associated with lower estimated glomerular filtration rate (eGFR) and a nominally faster rate of eGFR decline in offspring.5 Here, we test the hypothesis that a positive parental CVD history associates with ESRD risk in an independent population-based prospective cohort of middleaged women. Included were 34,468 women from central Sweden aged 62.3 6 9.3 years attending mammography screening in 1997, who did not have a previous known diagnosis of cancer6 (detailed methods in Item S1). Of 36,304 eligible individuals, we excluded those with a history of CKD (n 5 214) and kidney stones (n 5 1,622). The exposure, parental CVD history (defined as heart disease before the age of 60 years in Table 1. Baseline Characteristics of Participants With and Without a History of Parental CVD
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests.
References 1. Couser WG, Johnson RJ. Expanding the domain of postinfectious glomerulonephritis. Am J Kidney Dis. 2015;66(4):725. 2. Meehan SM. Postinfectious versus infection-related glomerulonephritis. Am J Kidney Dis. 2015;66(4):725-726. 3. Couser WG, Johnson RJ. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86: 905-914. 4. Rovin BH, Tang Y, Sun J, et al. Clinical significance of fever in the SLE patient receiving steroid therapy. Kidney Int. 2005;68:747-750. 726
No. Age, y BMI, kg/m2 Smoker University education Ever drinker of alcohol Physical activity, MET h/d CVD Hypertension Diabetes
With Parental CVD History
Without Parental CVD History
P
3,646 60.6 6 8.8 25.4 6 4.2 1,735 (48) 717 (20) 3,065 (85)
30,822 62.4 6 9.3 25.0 6 3.9 16,463 (55) 5,676 (18) 24,936 (82)
,0.001 ,0.001 ,0.001 0.01 ,0.001
42.3 6 4.9
42.5 6 4.8
0.04
335 (9) 225 (6) 181 (5)
1,799 (6) 1,288 (4) 1,204 (4)
,0.001 ,0.001 0.002
Note: Data are expressed as mean 6 standard deviation or number (percentage), as appropriate. Abbreviations: BMI, body mass index; CVD, cardiovascular disease; MET, metabolic equivalent.
Am J Kidney Dis. 2015;66(4):725-730