NDT Advance Access originally published online on May 3, 2005
Nephrology Dialysis Transplantation 2005 20(6):1029-1031; doi:10.1093/ndt/gfh792
© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Editorial Comment
Did syphilis truly strike the kidneys this time?
S. van Assen1,2 and
S. J. L. Bakker1
1 Department of Internal Medicine and 2 Division of Infectious Diseases, University Medical Center Groningen, The Netherlands
Correspondence and offprint requests to: S. van Assen, Department of Internal Medicine, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. Email: s.van.assen{at}int.umcg.nl
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Introduction
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The causative agents of sexually transmitted diseases are seldom
involved in kidney disease. Only a handful of cases have been
described of pyelonephritis or immune complex-mediated glomerulonephritis
in patients with gonococcal infections [
1,
2]. The most important
association is present in human immunodeficiency virus (HIV)-infected
patients: HIV-associated nephropathy was diagnosed at autopsy
in 12% of HIV-infected black people and in 1% of HIV-infected
non-black people [
3]. A clear relationship between hepatitis
C virus infection and glomerulonephritis has been demonstrated.
Cryoglobulinaemic membranoproliferative glomerulonephritis and
membranous nephropathy occur in 2.6 and 1.8% of cases, respectively
[
4]. Hepatitis B virus infection is also associated with glomerulonephritis,
but the prevalence is not known. However, it is estimated to
be low because of the low endemicity in most Western countries.
Nephropathy associated with syphilis seems to have been more common in the past, presenting as nephrotic syndrome caused by immune complex-mediated membranous or mesangial glomerulonephritis. Nowadays, the possibility of renal involvement in syphilis is no longer even mentioned in textbooks of infectious diseases [5].
Interstitial syphilitic nephritis has been described in the literature only once, by Docolomansky et al., in the Slovakian language, without an abstract in Medline [6]. In this issue of Nephrology Dialysis Transplantation, Chen et al. present a case of salt-losing nephropathy as the only symptom of interstitial nephritis, and they suggest a causative role for syphilis [7]. Let us therefore take a closer look at syphilis and Treponema pallidum, the organism causing it, in the light of this particular case.
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Clinical features
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The manifestations of syphilis can be split up into three different
stages. Primary syphilis is characterized by a painless, indurated,
clear-based ulcer, accompanied by locoregional lymph node swelling.
About 25% of cases progress to secondary syphilis, in several
weeks to months, as a consequence of extensive dissemination
of the spirochete [
8]. The typical presentation of secondary
syphilis is a symmetric papular rash on the entire trunk and
extremities, including the palms and soles. The latter localization
is highly suggestive of secondary syphilis. In moist areas,
syphilitic papules can coalesce and lead to painless erosions,
condylomata lata. Other possible symptoms of secondary syphilis
are described in
Table 1. Without treatment, 20–40% of
patients will develop tertiary syphilis, independent of former
manifestations of primary or secondary syphilis [
8,
9]. Tertiary
syphilis is usually localised in the brain (meningovascular
syphilis or parenchymatous syphilis), but the cardiovascular
system can also be affected (cardiovascular syphilis). Gummata
(late benign syphilis) are another manifestation of tertiary
syphilis. These granulomatous-like lesions can most commonly
be found in the skeletal system, skin and mucocutaneous tissues,
but are not confined to these locations.
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Diagnostic pitfalls and solutions
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The patient in the presented case developed erosions in the
genital region that were not specified further. These could
have been condylomata lata, a manifestation of secondary syphilis.
Dark-field microscopy can reveal spirochetes in scrapings of
such lesions, which are loaded with spirochetes [
10]. Unfortunately,
this technique is not broadly used and
T. pallidum cannot be
cultivated
in vitro. Therefore, the diagnosis is based mainly
on serology, although polymerase chain reaction (PCR) is very
promising when performed on swabs of ulcerative lesions [
11].
A combination of treponema-specific (
T. pallidum haemagglutination
assay, TPHA) and non-specific tests (Venereal Disease Research
Laboratory, VDRL or rapid-plasma-reagin) are necessary to reach
the diagnosis. However, there remain many pitfalls. False-positive
tests can be found in many patients, either because of cross-reactivity
with other members of the family of Spirochaetaceae, because
of situations that lead to mono- or polyclonal B-cell stimulation
(e.g. multiple myeloma, Epstein–Barr virus or auto-immune
disease), or because of other acute infections and immunizations
(
Table 2). Serological tests of the described patient were positive
for both treponema-specific and non-specific tests, but with
the lowest possible titre that can be classified positive for
both VDRL and TPHA. In particular, during the secondary stage
of syphilis, when dissemination occurs, VDRL titres are high,
and almost always exceed 1:8. A VDRL titre below 1:8 in the
presence of lesions suggestive of secondary syphilis for >1
month virtually excludes this diagnosis [
12]. Very low titres,
as were found in the patient under discussion, could fit serological
testing that is performed too early in the course of the disease.
Other possible explanations could be the presence of late latent
syphilis or infection with cross-reacting antibodies [
10]. For
TPHA, a titre of 1:80 is the cut-off value, and any lower titre
should be considered negative. Since hyponatraemia was present
for at least 6 months, the low titres cannot be explained by
short duration of illness, and should be interpreted cautiously.
Based on the histopathological findings, mononuclear cell infiltration
instead of the characteristic granulomatous reaction, renal
gummata are also unlikely in this case. Causes of false-positive
tests or (treated) syphilis in the past should be sought, knowing
that serology (in particular treponema-specific tests) can remain
positive for the rest of life. Altogether, the serological results
do not unconditionally support the diagnosis of secondary syphilis.
Another diagnostic opportunity in this patient, besides serology,
would have been to search for spirochetes in a swab taken from
the genital erosions and in the renal biopsy specimen. In secondary
syphilis, a high burden of spirochetes is present, whereas in
tertiary syphilis it is mainly the immunological reaction that
causes disease. Also, PCR could have been performed, and would
have been interesting, in particular on the kidney tissue. PCR
is not yet widely used in the clinical setting. However, when
the test is applied to genital ulcers, both sensitivity and
specificity exceed 95% [
13].
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Alternative diagnoses
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A striking phenomenon remains the salt-losing response to treatment
with penicillin. Despite the former remarks concerning the validity
of the proposed diagnosis, this response supports an infectious
disease as the underlying cause. What penicillin-reactive (four
consecutive low doses of benzyl benzithine penicillin) diseases
can both cause the clinical manifestations that were described,
and might provoke a serological cross-reaction? Leptospirosis
can indeed cause interstitial nephritis and can be contracted
in Taiwan [
14], but is not known to present in a chronic fashion.
Borrelia burgdorferii can induce interstitial nephritis in animals,
but there is only one case report on this manifestation in humans
[
15]. No cases of nephritis have been described in relation
to ‘Relapsing fever’ (
Borrelia recurrentis), and
‘Ratbite fever’ (
Spirillium minus). The characteristic
clinical picture of these diseases, with recurrent periods of
high fever (in combination with local skin lesions at the site
of the bite in the latter disease), is also absent in the patient
under discussion. Other treponema species, the non-venereal
treponemata (Yaws, Pinta and Bejel), are not endemic in Taiwan,
nor are they associated with renal disease [
5].
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Conclusion
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One can doubt whether the diagnosis of interstitial nephritis
caused by secondary syphilis is correct. On the other hand,
after treatment with benzathine penicillin in a schedule that
is used for late latent syphilis, complete resolution of hyponatraemia
and salt losing occurred. Syphilis is called ‘the great
imitator’ and keeps surprising us time after time. Because
of the better treatment options for HIV, making this a chronic
instead of fatal infection, safe sex is practised less. As a
consequence, the incidence of syphilis is rising rapidly now
[
16]. Therefore, we can expect rare and unlikely manifestations
of syphilis to occur more often in the near future.
Conflict of interest statement. None declared.
[See related Case Report by Chen et al., doi:10.1093/ndt/gfh778]
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References
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- Panwalker AP. Gonococcal epididymitis and pyelonephritis in a male. Urology 1985; 25: 630–631[Medline]
- Ebright JR, Komorowski R. Gonococcal endocarditis associated with immune complex glomerulonephritis. Am J Med 1980; 68: 793–796[Medline]
- Shahinian V, Rajaraman S, Borucki et al. Prevalence of HIV-associated nephropathy in autopsies of HIV-infected patients. Am J Kidney Dis 2000; 35: 884–888[Medline]
- Gopalani A, Ahuja TS. Prevalence of glomerulopathies in autopsies of patients infected with the hepatitis C virus. Am J Med Sci 2001; 322: 57–60[CrossRef][Medline]
- Mandell GL, Bennett JE, Dolin R. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases, 6th edn. http://www.ppidonline.com
- Docolomansky A, L'angos J, Slugen I et al. Syphilis secundaria recens with interstitial nephritis and hypertension. Bratisl Lek Lisry 1973; 60: 615–621
- Chen Y-C, Lee N, Chang CT, Wu M-S. Salt loss and hyponatraemia in a patient with syphilitic nephritis. Nephrol Dial Transplant 2005; (in press)
- Gjestland T. The Oslo study of untreated syphilis; an epidemiologic investigation of the natural course of the syphilitic infection based upon a re-study of the Boeck–Bruusgaard material. Acta Derm Venereol 1955; 35: 3–368
- Rosahn PD. Autopsy studies in syphilis. J Vener Disease 1947; 649 Information supplement 21, US Public Health Service Venereal Disease Division, Washington, DC
- Hook EW 3rd, Marra CM. Acquired syphilis in adults. N Engl J Med 1992; 326: 1060–1069[ISI][Medline]
- Palmer HM, Higgins SP, Herring AJ, Kingston MA. Use of PCR in the diagnosis of early syphilis in the United Kingdom. Sex Transm Infect 2003; 79: 479–483[Abstract/Free Full Text]
- Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med 1986; 104: 368–376[ISI][Medline]
- Liu H, Rodes B, Chen CY, Steiner B. New tests for syphilis: rational design of a PCR method for detection of Treponema pallidum in clinical specimens using unique regions of the DNA polymerase I gene. J Clin Microbiol 2001; 39: 1941–1946[Abstract/Free Full Text]
- Yang CW, Wu MS, Pan MJ. Leptospirosis renal disease. Nephrol Dial Transplant 2001; 16 [Suppl 5]: 73–77[Medline]
- Aberer E, Neumann R, Lubec G. Acrodermatitis chronica atrophicans in association with lichen sclerosus et atrophicans: tubulo-interstitial nephritis and urinary excretion of spirochete-like organisms. Acta Dermatol Venereol 1987; 67: 62–65[Medline]
- Trends in primary and secondary syphilis and HIV infections in men who have sex with men—San Francisco and Los Angeles, California, 1998–2002. MMWR Morb Mortal Wkly Rep 2004; 53: 575–578[Medline]
- van Assen S, van Kasteren ME. Perianal ulcer and rash. Secondary syphilis. Neth J Med 2003; 61: 82, 98[Medline]
Received for publication: 17. 2.05
Accepted in revised form: 21. 2.05
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Introduction
Clinical features