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Could HIV-associated nephropathy be associated with Mycoplasma infection?

Sir,

Manhas and colleagues (1) reported genital mycoplasmas in HIV-infected men with urethritis calling attention to the emerging area of genitourinary Mycoplasma infections. Infection with HIV has also been associated with the renal disease termed HIV-associated nephropathy (HIVAN) that we speculated (2) could also be associated with mycoplasma infection. Although the prevalence of HIVAN is not well characterized, especially in the era of highly active antiretroviral therapy (HAART), prevalence has been estimated to be between 3.5 and 10 per cent of people living with HIV infection (3). The prevalence varies predominantly due to the proportion of African Americans in the population and is lower among persons prescribed HAART (4,5).

HIV may directly damage the kidneys (6,7). Because Mycoplasma fermentans has been identified in the renal tissues of AIDS patients with HIVAN at autopsy (8) and in the peripheral blood mononuclear cells, throat swabs, and urine samples from HIV-infected patients (9), we designed a case-control study to compare the prevalence of Mycoplasma infection in HIV-infected patients with and without HIVAN. We tested specimens for M. fermentans, M. penetrans and M. pirum.

From 1998 to 2000 patients were recruited for a case-control study from two sites participating in the Adult/Adolescent Spectrum of HIV Disease Project (ASD) (10) in two cities with dissimilar HIV population demographics (Los Angeles and Seattle). Subjects were excluded if they had diabetes mellitus, essential hypertension, multiple myeloma, or systemic lupus erythematosis.

Cases of HIVAN included HIV-infected patients with renal biopsies consistent with HIVAN and probable cases with (i) enlarged kidneys by ultrasound or radiographic imaging; (ii) nephrotic range proteinuria (>3.5 g per 24 h); and (iii) serum creatinine >2.0 mg/ dl.

One to three HIV-infected controls were matched to each case by facility of medical care and CD4+ cell count per [micro]l ([+ or -] 100 cells/[micro]l) within one year of HIVAN study entry. Controls either had no renal biopsy or a negative renal biopsy, no kidney imaging or no evidence of enlarged kidneys, and did not have evidence in their medical record of nephrotic range proteinuria or serum creatinine elevation >2.0 mg/dl for more than one week duration.

Patients were interviewed and their medical records were abstracted to collect race/ethnicity, clinical laboratory tests, renal imaging studies, renal biopsy results, history of diabetes mellitus, hypertension, hepatitis B and C, syphilis, injection drug use, dialysis, and macrolide antibiotic and tetracycline use prior to the diagnosis of renal disease.

Serum, urine, whole blood (for buffy coat extraction), and throat swab specimens were collected from cases and controls and tested at the Centers for Disease Control and Prevention (CDC), Atlanta. DNA from all specimens was extracted using the Qiagen mini prep kit (Qiagen, Inc., Valencia, CA). Real time polymerase chain reaction (PCR) assays were used to test for the presence of DNA from M. fermentans, M. penetrans and M. pirum (11).

Despite initially matching controls to cases, unmatched analyses were done as the number of matched groups was small and the matching factors, due in part to the broad categories of CD4 counts, were not highly correlated with the outcome (12). Odds ratios, which estimate the relative risk of HIVAN, were calculated to measure associations for the case-control study; 95 per cent CIs were calculated by Newcombe's method (13). Significance of associations was examined by Chi square ([chi square]) tests with Yates correction and [chi square] tests for linear trend. Fishers' exact tests were used for comparisons with small cell sizes. Software used included SAS (SAS v.8.2; SAS Institute, Cary, NC, USA) and Epi Info (v.6.04; CDC, Atlanta, GA, USA).

Two cases, 11 probable cases of HIVAN, and 29 matched controls were enrolled. By study site, five probable cases of HIVAN, and 12 controls were enrolled from Los Angeles; two cases of HIVAN, six probable cases of HIVAN, and 17 matched controls came from Seattle. The median age was 39 yr for cases and 38 yr for controls. Somewhat fewer cases had ever had hepatitis B infection (2 cases vs. 15 controls, P=0.06) (Table).

Infection with M. fermentans was uncommon, but more frequent in cases than controls. M. fermentans was found in two of the cases (15%, 95% CI=3-46%) and in none of the controls (P=0.09). Three (23%) cases had end stage renal disease and were receiving dialysis at the time of interview. The median CD4 cell count was 186 cells/[micro]l for cases and 197 cells/[micro]l for controls. M. fermentans was identified in one throat sample, none of the urine samples, and one serum sample of HIVAN cases. Infection with M. pirum and M. penetrans was identified in one case each and in one control each (Table).

Our study demonstrated that infection with M. fermentans was uncommon among individuals with HIVAN (15%) but more common than among the controls (0%). Although M. fermentans may be a contaminant of cell cultures, studies implicate it as a pathogen in human disease (14-16), and there is some evidence of its potential role in HIVAN. Support for this theory derives from detection of this organism by immunohistochemical methods in the kidneys of HIV-infected persons but not in kidneys of non HIV-infected persons (8,17) and by PCR evidence of M. fermentans nucleic acid in renal tissue of a patient with HIVAN (18). HIVAN has been described in African American children with perinatally acquired HIV and AIDS (19), and M. fermentans, as well as other urogenital species, have been found in endometrial biopsies of HIV-infected women with pelvic inflammatory disease (20), suggesting the possibility of congenital transmission. Also, immune cell infiltrates have been described in the renal tissue of patients with HWAN7. Thus in addition to HIV, HWAN may also be associated with infection with M. fermentans, but a larger study is needed to confirm these observations.

The most important limitation of our study was sample size. Use of HAART precipated a decline in HIV-associated nephropathy at participating sites, making recruitment difficult. In addition, some patients identified for enrollment were end stage renal disease patients who died shortly before enrollment. A few patients had renal biopsy performed. Therefore, while we believe all of the cases had HIVAN, the infrequency of renal biopsy led to a majority of cases with consistent but not confirmatory findings for HIVAN.

We add support to the potential role of M. fermentans in the development of HIVAN but the small number of participants in this study leave this question still without a definitive answer. Theoretically, if M. fermentans is confirmed as an association with HIVAN, it could have been an aetiologic factor for a greater proportion than the 15 per cent of cases found with M. fermentans in this study. The damage it causes to the kidney might not require the organism to persist in the body long after initial infection or treatment with an effective antimicrobia1 (21). A prospective study could help clarify the role of M. fermentans in HIVAN.

Conflict of interest statements: The authors report no conflicts of interest.

Funding: This work was funded in part by a Cooperative Agreement with the U.S. Centers for Disease for Disease Control and Prevention (CDC).

Prior presentations: None.

Disclaimer: The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Acknowledgment

The authors thank Scott McCombs (project management); Michael Adams, and Marta Juhasz; and Leah Haseley (analytical and medical specialty advice).

References

(1.) Manhas A, Sethi S, Sharma M, Wanchu A, Kanwar AJ, Kaur K, et al. Association of genital mycoplasmas including Mycoplasma genitalium in HIV infected men with nongonococcal urethritis attending STD and HIV clinics. Indian J Med Res 2009; 129 : 305-10.

(2.) Dawson MS, Hayes MM, Wang RY, Armstrong D, Kundsin RB, Lo SC. Detection and isolation of Mycoplasma fermentans from urine of human immunodeficiency virus type 1-infected patients. Arch Pathol Lab Med 1993; 117 : 511-4.

(3.) Ahuja TS, Borucki M, Funtanilla M, Shahinian V, Hollander M, Rajaraman S. Is the prevalence of HIV-associated nephropathy decreasing? Am J Nephrol 1999; 19: 655-9.

(4.) Abbott KC, Hypolite I, Welch PG, Agodoa LY. Human immunodeficiency virus/acquired immunodeficiency syndrome-associated nephropathy at end-stage renal disease in the United States: patient characteristics and survival in the pre highly active antiretroviral therapy era. J Nephrol 2001; 14 : 377-83.

(5.) U.S. Renal Data System. USRDS 2003 Annual data report: Atlas of end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2003. p. 47-60.

(6.) D'Agati V, Appel GB. HIV infection and the kidney. J Am Soc Nephrol 1997; 8 : 139-52.

(7.) Kimmel PL, Barisoni L, Kopp JB. Pathogenesis and treatment of HIV-associated renal diseases: Lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigations. Ann Intern Med 2003; 139 : 214-26.

(8.) Bauer FA, Wear J, Angritt P, Lo S. Mycoplasma fermentans (incognitus strain) infection in the kidneys of patients with acquired immunodeficiency syndrome and associated nephropathy. A light microscopic, immunohistochemical, and ultrastructural study. Hum Pathol 1991; 22 : 63-9.

(9.) Katseni VL, Gilroy CB, Ryait BK, Ariyoshi K, Bieniasz PD, Weber JN, et al. Mycoplasma fermentans in individuals seropositive and seronegative for HIV-1. Lancet 1993; 341 : 271-3.

(10.) Farizo KM, Buehler JW, Chamberland ME, Whyte BW, Froelicher ES, Hopkins SG, et al. Spectrum of disease in persons with human immunodeficiency virus infection in the United States. JAMA 1992; 267 : 1798-805.

(11.) Zhang M, Thacker WL, Talkington DF. Construction of internal controls for detecting Mycoplasma pneumoniae, M. fermentans, M. penetrans, and M. pirum in polymerase chain reaction assays. Presentation at 98th Meeting of the American Society for Microbiology, Atlanta, Georgia, May 1998.

(12.) Diehr P, Martin DC, Koepsell T, Cheadle A. Breaking the matches in a paired t-test for community interventions when the number of pairs is small. Star Med 1995; 14 : 1491-504.

(13.) Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med 1998; 17 : 857-72.

(14.) Lo SC, Wear DJ, Green SL, Jones PG, Legier JF. Adult respiratory distress syndrome with or without systemic disease associated with infections due to Mycoplasma fermentans. Clin Infect Dis 1993; 17 (Suppl 1): S259-63.

(15.) Schaeverbeke T, Gilroy CB, Bebear C, Dehais J, Taylor-Robinson D. Mycoplasma fermentans but not M. penetrans, detected by PCR assays in synovium from patients with rheumatoid arthritis and other rheumatic disorders. J Clin Pathol 1996; 49 : 824-8.

(16.) Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with chronic fatigue syndrome. FEMS Immunol Med Microbiol 1998; 22 : 355-65.

(17.) Taylor-Robinson D. Infections due to species of Mycoplasma and Ureaplasma: an update. Clin Infect Dis 1996; 23 : 67184.

(18.) Ainsworth JG, Katseni V, Hourshid S, Waldron S, Ball S, Cattell V, et al. Mycoplasma fermentans and HIV-associated nephropathy. J Infect 1994; 29 : 323-6.

(19.) Strauss J, Abitbol C, Zilleruelo G, Scott G, Paredes A, Malaga S, et al. Renal disease in children with the acquired immunodeficiency syndrome. N Engl J Med 1989; 321 : 625-30.

(20.) Irwin K, Moorman AC, O'Sullivan MJ, Sperling R, Koestler ME, Soto I, et al. Influence of human immunodeficiency virus infection on pelvic inflammatory disease. Obstet Gynecol 2000; 95 : 525-34.

(21.) Poulin SA, Perkins RE, Kundsin RB. Antibiotic susceptibilities of AIDS-associated Mycoplasmas. J Clin Microbiol 1994; 32 : 1101-3.

Mark S. Dworkin (a,b,c), *, Susan E. Buskin (d) Mauro S. Torno (e), Deborah F. Talkington (f,g) Ming Zhang (g,h), Jeffrey L. Jones (a) Jay C. Butler (g,i) & A.D. McNaghten (a)

(a) Behavioral & Clinical Surveillance Branch Division of HIV/AIDS Prevention Centers for Disease Control & Prevention Atlanta, GA

(b) Illinois Department of Public Health Division of Infectious Diseases, Chicago, IL

(c) University of Illinois at Chicago School of Public Health, Chicago, IL

(d) Public Health--Seattle & King County Seattle, WA, University of Washington Seattle WA

(e) David-Geffen School of Medicine at University of California Los Angeles (UCLA), CA & Harbor-UCLA Medical Center, Torrance

(f) Enteric Diseases Laboratory Branch Division of Foodborne, Bacterial & Mycotic Diseases, National Center for Zoonotic Vector-Borne & Enteric Diseases Centers for Disease Control & Prevention Atlanta, GA

(g) (Formerly with the) Respiratory Diseases Branch Division of Bacterial & Mycotic Diseases National Center for Infectious Diseases CDC

(h) Nutritional Biomarkers Branch Division of Laboratory Sciences National Center for Environmental Health Centers for Disease Control & Prevention Atlanta, GA

(i) Alaska Division of Public Health Anchorage, AK, USA

* For correspondence: mdworkin@uic.edu
Table. Characteristics of cases and controls with and without HIV
associated nephropathy (HIVAN) from Los Angeles and Seattle (Adult/
Adolescent Spectrum of HIV Disease Project, United States, 1998-2000)

Characteristic Cases Controls
 (n = 13) (a) (n = 29)

Race/ethnicity
Black 10 14
Other or unknown 3 15
Age (yr)
[less than or equal to] 35 4 8
35 9 20
Sex
Male 10 27
Female 3 1
CD4<200 cells per [micro]l (b) 8 14
CD4 [greater than or equal to] 200 5 14
cells per [micro]l (3)
Ever had hepatitis B 2 15
Never had hepatitis B 11 14
Chronic carrier of hepatitis B 2 5
Not a chronic carrier of hepatitis B 11 24
Ever had hepatitis C 2 4
Never had hepatitis C 11 25
Ever an injection drug user 3 11
Never an injection drug user 10 18
Ever took >7 days of a macrolide 7 19
antibiotic
Never took >7 days of a macrolide 6 10
antibiotic (c)
Ever took >7 days of a tetracycline 4 14
antibiotic
Never took >7 days of a tetracycline 9 15
antibiotic (c)
Ever took >7 days of either a macrolide 7 23
or tetracycline antibiotic
Never took >7 days of either a macrolide 6 6
or tetracycline antibiotic (c)
For cases: took [greater than or equal 7 --
 7 days of either a macrolide or
tetracycline antibiotic in the year
before diagnosis of nephropathy
For controls: took [greater than or -- 18
equal] 7 days of either a macrolide or
tetracycline antibiotic in the year
before enrollment
M. fermentans 2 0
No M. fermentans 11 29
M. pirum 1 1
No M. pirum 12 28
M.penetrans 1 1
No M. penetrans 12 28

Characteristic Odds ratio P value
 (Yates
 corrected)
Race/ethnicity
Black 3.6 0.16
Other or unknown
Age (yr)
[less than or equal to] 35 1.1 0.58 Fisher
35
Sex
Male 0.1 0.086 Fisher
Female
CD4<200 cells per [micro]l (b)
CD4 [greater than or equal to] 200
cells per [micro]l (3)
Ever had hepatitis B 0.2 0.06
Never had hepatitis B
Chronic carrier of hepatitis B 0.9 0.63 Fisher
Not a chronic carrier of hepatitis B
Ever had hepatitis C 1.1 0.62 Fisher
Never had hepatitis C
Ever an injection drug user 0.5 0.28 Fisher
Never an injection drug user
Ever took >7 days of a macrolide 0.6 0.35 Fisher
antibiotic
Never took >7 days of a macrolide
antibiotic (c)
Ever took >7 days of a tetracycline 0.5 0.47
antibiotic
Never took >7 days of a tetracycline
antibiotic (c)
Ever took >7 days of either a macrolide 0.3 0.1 Fisher
or tetracycline antibiotic
Never took >7 days of either a macrolide
or tetracycline antibiotic (c)
For cases: took [greater than or equal -- --
 7 days of either a macrolide or
tetracycline antibiotic in the year
before diagnosis of nephropathy
For controls: took [greater than or -- --
equal] 7 days of either a macrolide or
tetracycline antibiotic in the year
before enrollment
M. fermentans Undefined 0.09 Fisher
No M. fermentans
M. pirum 2.3 0.53 Fisher
No M. pirum
M.penetrans 2.3 0.53 Fisher
No M. penetrans

Characteristic 95%
 confidence
 limits
Race/ethnicity
Black 0.7-23.7
Other or unknown
Age (yr)
[less than or equal to] 35 0.2-5.6
35
Sex
Male 0-1.8
Female
CD4<200 cells per [micro]l (b)
CD4 [greater than or equal to] 200
cells per [micro]l (3)
Ever had hepatitis B 0.0-1.0
Never had hepatitis B
Chronic carrier of hepatitis B 0.1-6.5
Not a chronic carrier of hepatitis B
Ever had hepatitis C 0.1-9.4
Never had hepatitis C
Ever an injection drug user 0.1-2.6
Never an injection drug user
Ever took >7 days of a macrolide 0.1-2.9
antibiotic
Never took >7 days of a macrolide
antibiotic (c)
Ever took >7 days of a tetracycline 0.1-2.2
antibiotic
Never took >7 days of a tetracycline
antibiotic (c)
Ever took >7 days of either a macrolide 0.1-1.6
or tetracycline antibiotic
Never took >7 days of either a macrolide
or tetracycline antibiotic (c)
For cases: took [greater than or equal --
 7 days of either a macrolide or
tetracycline antibiotic in the year
before diagnosis of nephropathy
For controls: took [greater than or --
equal] 7 days of either a macrolide or
tetracycline antibiotic in the year
before enrollment
M. fermentans Undefined
No M. fermentans
M. pirum 0.0-189.6
No M. pirum
M.penetrans 0.0-189.6
No M. penetrans

(a) Chart and demographic data, including age and gender, was not
available for 1 control

(b) Not analyzed as controls were matched to cases by CD4 count (100
cells per [micro]l)

(c) Both the interview and the medical record abstraction form were
checked to determine if the answer was never
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Title Annotation:Correspondence
Author:Dworkin, Mark S.; Buskin, Susan E.; Torno, Mauro S.; Talkington, Deborah F.; Zhang, Ming; Jones, Jef
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2009
Words:2910
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