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Absence of human herpes virus-8 (HHV8) in nephrogenic systemic fibrosis
BMC Research Notes volume 1, Article number: 82 (2008)
Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that exhibits CD34 expression in the majority of lesional spindle cells. Several features of NSF bear similarity to Kaposi sarcoma.
Skin lesions procured from two male NSF patients were found to be negative for HHV8 (LNA-1) by means of immunohistochemsitry.
This finding negates a role for HHV8 in the pathogenesis of NSF.
Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder seen exclusively in patients with severe impairment of renal function . Originally defined as a dermatologic condition called Nephrogenic Fibrosing Dermopathy (NFD), the process of NSF is now well characterized as a systemic one, with distinct pathologic changes identified throughout the body . The typical dermatologic clinical presentation is characterized by symmetrical papules, nodules and brawny induration of the skin, limited to the extremities and trunk . Debilitating joint contractures can also be seen.
Histopathologic changes include an increased population of mitotically inactive, bland spindle cells in the dermis which often extends into underlying subcutaneous tissue . Thick collagen bundles with surrounding clefts displaying variable amounts of elastic fibers and mucin, set amongst a paucity of chronic inflammatory cells, are frequent findings [4, 5]. Multinucleated cells may also be present. Immunohistochemical analysis (IHC) of tissue from NSF patients shows dual expression of CD34 and procollagen I in the majority of lesional spindle cells. These cells are postulated to represent circulating fibrocytes recruited from the bone marrow, which subsequently mediate their pathologic effects on lesional tissue [6, 7].
The Centers for Disease Control and Prevention published a report in 2002 of a case controlled study of NSF patients that was unable to find any drug, toxin, or infectious agent (not specified) to explain the etiology of NSF . Cowper et al also proved by in situ hybridization that Epstein Barr virus was not present in tissue of NSF patients . However, recent evidence has shown a strong link between the development of NSF in patients with impaired renal function undergoing Magnetic Resonance (MR) studies using gadolinium based contrast media [3, 8]. The exact pathogenesis between gadolinium exposure and circulating fibrocyte recruitment in NSF is currently unknown.
Several features of NSF bear similarity to Kaposi's sarcoma (KS). Lesions from both NSF and KS are comprised of CD34 positive spindled cells  and stroma containing procollagen type I , albeit KS is more vascular. Similar to NSF, the lesional cells of KS are believed to be derived from circulating CD34+ progenitor cells, which serve as reservoirs of Human Herpes Virus-8 (HHV8) [11–13]. It is well established that HHV8 infection plays an essential role in the development of all forms of KS. Moreover, both renal transplant recipients and hemodialysis patients have been shown to be at higher risk for infection with HHV8 and subsequent development of KS [14–19].
Given the aforementioned similarities, we sought to determine if HHV8 might play a role in the pathogenesis of NSF. To the best of our knowledge, there is no published data assessing for the presence of HHV8 in patients with NSF.
We studied tissue from deep punch biopsies of two male NSF patients (73 and 78 years of age), both of whom had a history of chronic renal insufficiency, repeat exposures to gadolinium containing contrast media (Table 1), and recent onset of symmetrical plaques of the distal lower extremities. Certain gadolinium-containing contrast agents, each with a unique chelator molecule non-covalently bound to a Gd3+ ion, are more likely than others to induce NSF . Unfortunately, we were unable to determine the exact dose and type of agent used in these patients, nor the exact time interval between their exposure and onset of NSF. The histologic findings in both individuals were typical of NSF (Figure 1). IHC using a monoclonal antibody to HHV8 (LNA-1, 1:80 dilution, NovoCastra) was negative in both cases (Figure 2), with appropriate positive HHV8 staining in Kaposi sarcoma control cases (Figure 3).
In contrast to KS, we provide evidence that HHV8 appears unlikely to play an etiologic role in the development of NSF. However, this finding is limited to only two patients. Positive immunostaining for HHV8 using LNA-1 exhibits high sensitivity and specificity (close to 100%) for the diagnosis of HHV8-infected tissue, such as Kaposi sarcoma [21, 22]. Several studies have also shown that an absence of LNA-1 immunostaining corresponds well with an absence of HHV8 DNA sequences in tissue using polymerase chain reaction . Finally, although the precise pathogenesis remains undetermined, this study does lend further support to the link between NSF and gadolinium exposure in patients with underlying renal disease.
Cowper SE, Robin HS, Steinberg SM: Scleromyxedema-like Cutaneous Diseases in Renal Dialysis Patients. Lancet. 2000, 356: 1000-1. 10.1016/S0140-6736(00)02694-5.
Galan A, Cowper SE, Bucala R: Nephrogenic Systemic Fibrosis (Nephrogenic Fibrosing Dermopathy). Curr Opin Rheumatol. 2006, 18: 614-17. 10.1097/01.bor.0000245725.94887.8d.
Cowper SE: Nephrogenic Systemic Fibrosis: An Overview. J Am Coll Radiol. 2008, 5: 23-8. 10.1016/j.jacr.2007.08.013.
Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE: Nephrogenic Fibrosing Dermopathy. Amer J Dermatopathology. 2001, 23: 383-93. 10.1097/00000372-200110000-00001.
Kucher C, Xiaowei X, Pasha T, Elenitsas R: Histopathologic Comparison of Nephrogenic Fibrosing Dermopathy and Scleromyxedema. J Cut Pathol. 2005, 32: 484-90. 10.1111/j.0303-6987.2005.00365.x.
Cowper SE, Bucala R: Nephrogenic Fibrosing Dermopathy: Suspect Identified, Motive Unclear. 2003, 2: 358-
Bucala R: Circulating Fibrocytes: Cellular Basis for NSF. J Am Coll Radiol. 2008, 5: 36-9. 10.1016/j.jacr.2007.08.016.
Grobner T: Gadolinuium – A Specific Trigger for the Development of Nephrogenic Fibrosing Dermopathy and Nephrogenic Systemic Fibrosis?. Nephrol Dial Transplant. 2006, 21: 1104-1108. 10.1093/ndt/gfk062.
Nickoloff BJ: The human progenitor cell antigen (CD34) is localized on endothelial cells, dermal dendritic cells, and perifollicular cells in formalin-fixed normal skin, and on proliferating endothelial cells and stromal spindle-shaped cells in Kaposi's sarcoma. Arch Dermatol. 1991, 127: 523-9. 10.1001/archderm.127.4.523.
Becker J, Schuppan D, Reichart P: The extracellular matrix in oral Kaposi sarcoma (AIDS): the immunohistochemical distribution of collagens type IV, V, VI, of procollagens type I and III, of laminin and of undulin. Virchows Arch A Pathol Anat Histopathol. 1987, 412: 161-8. 10.1007/BF00716189.
Henry M, Uthman A, Geusau A, Rieger A, Furci L, Lazzarin A, Lusso P, Tschachler E: Infection of Circulating CD34+ Cells by HHV-8 in Patients with Kaposi's Saroma. J Invest Dermatol. 1999, 113: 613-6. 10.1046/j.1523-1747.1999.00733.x.
Wu W, Viera J, Fiore N, Banerjee P, Sieburg M, Rochford R, Harrington W, Feuer G: KSHV/HHV-8 Infection of Human Hematopoietic Progenitor (CD34+) Cells: Persistence of Infection During Hematopoiesis In Vitro and In Vivo. Blood. 2006, 108: 141-51. 10.1182/blood-2005-04-1697.
Larcher C, Nguyen VA, Furhapter C, Ebner S, Sölder E, Stössel H, Romani N, Sepp N: Human Herpesvirus-8 Infection of Umbilical Cord-blood-derived CD34+ Stem Cells Enhances the Immunostimulatory Function of their Dendritic Cell Progeny. Exp Dermatol. 2005, 14: 41-9. 10.1111/j.0906-6705.2005.00234.x.
Nampoory MR, Johny KV, Sarkar C, Al-Masry I, Al-Hilali N, Anim JT: The Dialised Patient with Castleman Disease and Kaposi's Sarcoma. Nephrol Dial Transplant. 1998, 13: 2373-6. 10.1093/ndt/13.9.2373.
Zavitsanou A, Sypsa V, Petrodaskalaki M, Psichogiou M, Katsoulidou A, Boletis J, Hadjiconstantinou V, Karalis D, Kalapothaki V, Hatzakis A: Human Herpesvirus 8 infection in Hemodialysis Patients. Am J Kidney Dis. 2006, 47: 167-70. 10.1053/j.ajkd.2005.09.019.
Shahbazian H: Kaposi sarcoma in kidney transplanted patients. Urol J. 2004, 1: 111-4.
Hsu YH, Lin DY, Liou HH: Human Herpesvirus-8 Infection in Hemodialysis Patients from Eastern Taiwan-Hualien. Kaohsiung J Med Sci. 2002, 18: 393-6.
Herr H, Kim JU, Kang GH, Moon KC, Koh JK: Kaposi's Sarcoma Occurring During Short-Term Dialysis: Report of Two Cases. J Korean Med Sci. 2001, 16: 130-4.
Metaxa-Mariatou V, Chiras T, Loli A, Gazouli M, Vallis D, Nasioulas G: Molecular Analysis of Kaposi's Sarcoma Occurring During Haemodialysis. Clin Exp Dermatol. 2004, 29: 188-91. 10.1111/j.1365-2230.2004.01469.x.
Cowper SE: Gadolinium – is it to blame?. J Cutan Pathol. 2008, 35: 520-2. 10.1111/j.1600-0560.2008.01027.x.
Robin YM, Guillou L, Michels JJ, Coindre JM: Human herpesvirus 8 immunostaining: a sensitive and specific method for diagnosing Kaposi sarcoma in paraffin-embedded sections. Am J Clin Pathol. 2004, 121: 330-4. 10.1309/96U16LRRAN5HWWVE.
Cheuk W, Wong KO, Wong CS, Dinkel JE, Ben-Dor D, Chan JK: Immunostaining for human herpesvirus 8 latent nuclear antigen-1 helps distinguish Kaposi sarcoma from its mimickers. Am J Clin Pathol. 2004, 121: 335-42. 10.1309/B8TC0LBVH8XY5MFV.
Su CC, Li CF, Liao YL, Lin CN, Lu JJ: Immunohistochemical and molecular assessment of human herpesvirus type 8 in gastrointestinal tumours. J Clin Pathol. 2005, 58: 856-9. 10.1136/jcp.2004.023622.
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O'Donnell, P.J., Duke, W.H. & Pantanowitz, L. Absence of human herpes virus-8 (HHV8) in nephrogenic systemic fibrosis. BMC Res Notes 1, 82 (2008) doi:10.1186/1756-0500-1-82
- Human Herpes
- Nephrogenic Systemic Fibrosis
- HHV8 Infection
- Gadolinium Base Contrast Medium
- Nephrogenic Fibrosing Dermopathy