Renal involvement with hantavirus infection (hemorrhagic fever with renal syndrome)
- Jukka Mustonen, MD, PhD
Jukka Mustonen, MD, PhD
- Emeritus Professor of Internal Medicine
- University of Tampere School of Medicine
- Medical Adviser
- Tampere University Hospital
- Section Editors
- Gerald B Appel, MD
Gerald B Appel, MD
- Section Editor — Glomerular Diseases
- Professor of Medicine
- Columbia University College of Physicians and Surgeons
- Martin S Hirsch, MD
Martin S Hirsch, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — Viral Infections
- Professor of Medicine
- Harvard Medical School
Infection with a hantavirus may lead to life-threatening pulmonary and renal disease [1-6]. In 1993, a highly fatal epidemic due to acute hantavirus infection in the American Southwest was associated with the rapid onset of respiratory failure, renal insufficiency, and fever .
The members of the Hantavirus genus (eg, Hantaan, Puumala, Seoul, Dobrava, Sin Nombre, and Andes virus) each produce different forms of clinical disease in humans. As an example, renal disease due to Puumala virus is relatively mild and is associated with a benign long-term prognosis [8,9]. Sin Nombre virus is the hantavirus found most frequently in the United States, which primarily induces a cardiopulmonary syndrome, as does the Andes virus, found in South America . More severe renal disease can occur with infections by Hantaan and Dobrava virus [6,11].
Clinical syndromes caused by hantaviruses have also been known as epidemic hemorrhagic fever, hemorrhagic nephrosonephritis, Songo fever, Korean hemorrhagic fever, and nephropathia epidemica. In an attempt to avoid confusion, these diseases are now collectively referred to by the World Health Organization as "hemorrhagic fever with renal syndrome" (HFRS) [1,12].
Renal disease associated with hantavirus infection will be reviewed here. The epidemiology and diagnosis of hantavirus infections and hantavirus-associated cardiopulmonary syndrome are discussed elsewhere. (See "Epidemiology and diagnosis of hantavirus infections" and "Hantavirus cardiopulmonary syndrome".)
Hantavirus infection is acquired by inhalation of aerosolized virus containing particles or contact with urine, secretions, or feces of infected rodents. Smoking, possibly by altering the conditions of the human airways, is a risk factor for Puumala virus infection [13,14]. The rodent vectors differ for each viral species but include mice, voles, shrews, and rats. Person-to-person transmission has been reported in Andes virus infection .
- Cosgriff TM, Lewis RM. Mechanisms of disease in hemorrhagic fever with renal syndrome. Kidney Int Suppl 1991; 35:S72.
- Tkachenko EA, Lee HW. Etiology and epidemiology of hemorrhagic fever with renal syndrome. Kidney Int Suppl 1991; 35:S54.
- Collan Y, Mihatsch MJ, Lähdevirta J, et al. Nephropathia epidemica: mild variant of hemorrhagic fever with renal syndrome. Kidney Int Suppl 1991; 35:S62.
- van Ypersele de Strihou C. Clinical features of hemorrhagic fever with renal syndrome in Europe. Kidney Int Suppl 1991; 35:S80.
- Takeuchi T, Yamamoto T, Itoh M, et al. Clinical studies on hemorrhagic fever with renal syndrome found in Nagoya City University Medical School. Kidney Int Suppl 1991; 35:S84.
- Lee JS. Clinical features of hemorrhagic fever with renal syndrome in Korea. Kidney Int Suppl 1991; 35:S88.
- Duchin JS, Koster FT, Peters CJ, et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med 1994; 330:949.
- Mäkelä S, Ala-Houhala I, Mustonen J, et al. Renal function and blood pressure five years after puumala virus-induced nephropathy. Kidney Int 2000; 58:1711.
- Miettinen MH, Mäkelä SM, Ala-Houhala IO, et al. Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int 2006; 69:2043.
- Khaiboullina SF, Morzunov SP, St Jeor SC. Hantaviruses: molecular biology, evolution and pathogenesis. Curr Mol Med 2005; 5:773.
- Vapalahti O, Mustonen J, Lundkvist A, et al. Hantavirus infections in Europe. Lancet Infect Dis 2003; 3:653.
- Muranyi W, Bahr U, Zeier M, van der Woude FJ. Hantavirus infection. J Am Soc Nephrol 2005; 16:3669.
- Van Loock F, Thomas I, Clement J, et al. A case-control study after a hantavirus infection outbreak in the south of Belgium: who is at risk? Clin Infect Dis 1999; 28:834.
- Vapalahti K, Virtala AM, Vaheri A, Vapalahti O. Case-control study on Puumala virus infection: smoking is a risk factor. Epidemiol Infect 2010; 138:576.
- Enría D, Padula P, Segura EL, et al. Hantavirus pulmonary syndrome in Argentina. Possibility of person to person transmission. Medicina (B Aires) 1996; 56:709.
- Bugert JJ, Welzel TM, Zeier M, Darai G. Hantavirus infection--haemorrhagic fever in the Balkans--potential nephrological hazards in the Kosovo war. Nephrol Dial Transplant 1999; 14:1843.
- Glass GE, Watson AJ, LeDuc JW, Childs JE. Domestic cases of hemorrhagic fever with renal syndrome in the United States. Nephron 1994; 68:48.
- Papadimitriou M. Hantavirus nephropathy. Kidney Int 1995; 48:887.
- Taylor SL, Wahl-Jensen V, Copeland AM, et al. Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system. PLoS Pathog 2013; 9:e1003470.
- Antonen J, Leppänen I, Tenhunen J, et al. A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant. Scand J Infect Dis 2013; 45:494.
- Paakkala A, Mustonen J, Viander M, et al. Complement activation in nephropathia epidemica caused by Puumala hantavirus. Clin Nephrol 2000; 53:424.
- Sane J, Laine O, Mäkelä S, et al. Complement activation in Puumala hantavirus infection correlates with disease severity. Ann Med 2012; 44:468.
- Amara U, Flierl MA, Rittirsch D, et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185:5628.
- Temonen M, Mustonen J, Helin H, et al. Cytokines, adhesion molecules, and cellular infiltration in nephropathia epidemica kidneys: an immunohistochemical study. Clin Immunol Immunopathol 1996; 78:47.
- Mäkelä S, Mustonen J, Ala-Houhala I, et al. Urinary excretion of interleukin-6 correlates with proteinuria in acute Puumala hantavirus-induced nephritis. Am J Kidney Dis 2004; 43:809.
- Outinen TK, Mäkelä S, Huttunen R, et al. Urine soluble urokinase-type plasminogen activator receptor levels correlate with proteinuria in Puumala hantavirus infection. J Intern Med 2014; 276:387.
- Outinen TK, Tervo L, Mäkelä S, et al. Plasma levels of soluble urokinase-type plasminogen activator receptor associate with the clinical severity of acute Puumala hantavirus infection. PLoS One 2013; 8:e71335.
- Libraty DH, Mäkelä S, Vlk J, et al. The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica. PLoS One 2012; 7:e35402.
- Mäkelä S, Mustonen J, Ala-Houhala I, et al. Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism. J Infect Dis 2002; 186:843.
- Mustonen J, Partanen J, Kanerva M, et al. Genetic susceptibility to severe course of nephropathia epidemica caused by Puumala hantavirus. Kidney Int 1996; 49:217.
- Mustonen J, Partanen J, Kanerva M, et al. Association of HLA B27 with benign clinical course of nephropathia epidemica caused by Puumala hantavirus. Scand J Immunol 1998; 47:277.
- Ahlm C, Settergren B, Gothefors L, Juto P. Nephropathia epidemica (hemorrhagic fever with renal syndrome) in children: clinical characteristics. Pediatr Infect Dis J 1994; 13:45.
- Mustonen J, Huttunen NP, Partanen J, et al. Human leukocyte antigens B8-DRB1*03 in pediatric patients with nephropathia epidemica caused by Puumala hantavirus. Pediatr Infect Dis J 2004; 23:959.
- Huttunen NP, Mäkelä S, Pokka T, et al. Systematic literature review of symptoms, signs and severity of serologically confirmed nephropathia epidemica in paediatric and adult patients. Scand J Infect Dis 2011; 43:405.
- Laine O, Joutsi-Korhonen L, Mäkelä S, et al. Polymorphisms of PAI-1 and platelet GP Ia may associate with impairment of renal function and thrombocytopenia in Puumala hantavirus infection. Thromb Res 2012; 129:611.
- Charbonnel N, Pagès M, Sironen T, et al. Immunogenetic factors affecting susceptibility of humans and rodents to hantaviruses and the clinical course of hantaviral disease in humans. Viruses 2014; 6:2214.
- Heiske A, Anheier B, Pilaski J, et al. Polymerase chain reaction detection of Puumala virus RNA in formaldehyde-fixed biopsy material. Kidney Int 1999; 55:2062.
- Mustonen J, Helin H, Pietilä K, et al. Renal biopsy findings and clinicopathologic correlations in nephropathia epidemica. Clin Nephrol 1994; 41:121.
- Krautkrämer E, Zeier M, Plyusnin A. Hantavirus infection: an emerging infectious disease causing acute renal failure. Kidney Int 2013; 83:23.
- Krautkrämer E, Grouls S, Stein N, et al. Pathogenic old world hantaviruses infect renal glomerular and tubular cells and induce disassembling of cell-to-cell contacts. J Virol 2011; 85:9811.
- Grcevska L, Polenaković M, Oncevski A, et al. Different pathohistological presentations of acute renal involvement in Hantaan virus infection: report of two cases. Clin Nephrol 1990; 34:197.
- Ferluga D, Vizjak A. Hantavirus nephropathy. J Am Soc Nephrol 2008; 19:1653.
- Mustonen J, Mäkelä S, Helin H, et al. Mesangiocapillary glomerulonephritis caused by Puumala hantavirus infection. Nephron 2001; 89:402.
- Settergren B, Juto P, Trollfors B, et al. Hemorrhagic complications and other clinical findings in nephropathia epidemica in Sweden: a study of 355 serologically verified cases. J Infect Dis 1988; 157:380.
- Laine O, Mäkelä S, Mustonen J, et al. Enhanced thrombin formation and fibrinolysis during acute Puumala hantavirus infection. Thromb Res 2010; 126:154.
- Puljiz I, Kuzman I, Markotić A, et al. Electrocardiographic changes in patients with haemorrhagic fever with renal syndrome. Scand J Infect Dis 2005; 37:594.
- Makela S, Kokkonen L, Ala-Houhala I, et al. More than half of the patients with acute Puumala hantavirus infection have abnormal cardiac findings. Scand J Infect Dis 2009; 41:57.
- Avsic-Zupanc T, Petrovec M, Furlan P, et al. Hemorrhagic fever with renal syndrome in the Dolenjska region of Slovenia--a 10-year survey. Clin Infect Dis 1999; 28:860.
- Papa A, Antoniadis A. Hantavirus infections in Greece--an update. Eur J Epidemiol 2001; 17:189.
- Markotić A, Nichol ST, Kuzman I, et al. Characteristics of Puumala and Dobrava infections in Croatia. J Med Virol 2002; 66:542.
- Hukić M, Valjevac A, Tulumovic D, et al. Pathogenicity and virulence of the present hantaviruses in Bosnia and Herzegovina: the impact on renal function. Eur J Clin Microbiol Infect Dis 2011; 30:381.
- Tulumovic D, Imamovic G, Mesic E, et al. Comparison of the effects of Puumala and Dobrava viruses on early and long-term renal outcomes in patients with haemorrhagic fever with renal syndrome. Nephrology (Carlton) 2010; 15:340.
- Passaro DJ, Shieh WJ, Hacker JK, et al. Predominant kidney involvement in a fatal case of hantavirus pulmonary syndrome caused by Sin Nombre virus. Clin Infect Dis 2001; 33:263.
- Dara SI, Albright RC, Peters SG. Acute sin nombre hantavirus infection complicated by renal failure requiring hemodialysis. Mayo Clin Proc 2005; 80:703.
- Hjelle B, Goade D, Torrez-Martinez N, et al. Hantavirus pulmonary syndrome, renal insufficiency, and myositis associated with infection by Bayou hantavirus. Clin Infect Dis 1996; 23:495.
- Ala-Houhala I, Koskinen M, Ahola T, et al. Increased glomerular permeability in patients with nephropathia epidemica caused by Puumala hantavirus. Nephrol Dial Transplant 2002; 17:246.
- Settergren B, Trollfors B, Fasth A, et al. Glomerular filtration rate and tubular involvement during acute disease and convalescence in patients with nephropathia epidemica. J Infect Dis 1990; 161:716.
- Matthaeus T, Fries J, Weber M, Schulze-Lohoff E. [Glomerular-type proteinuria in hantavirus nephritis]. Med Klin (Munich) 2004; 99:223.
- Outinen TK, Mäkelä SM, Ala-Houhala IO, et al. The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC Infect Dis 2010; 10:132.
- Outinen TK, Mäkelä SM, Ala-Houhala IO, et al. High activity of indoleamine 2,3-dioxygenase is associated with renal insufficiency in Puumala hantavirus induced nephropathia epidemica. J Med Virol 2011; 83:731.
- Lähdevirta J, Collan Y, Jokinen EJ, Hiltunen R. Renal sequelae to nephropathia epidemica. Acta Pathol Microbiol Scand A 1978; 86:265.
- Kanerva M, Paakkala A, Mustonen J, et al. Pulmonary involvement in nephropathia epidemica: radiological findings and their clinical correlations. Clin Nephrol 1996; 46:369.
- Kim S, Sung SH, An HR, et al. A case report of crescentic glomerulonephritis associated with Hantaan virus infection. Nephrol Dial Transplant 2010; 25:2790.
- Miettinen M, Mäkelä S, Haapala M, et al. Glomerulonephritis emerging shortly after Puumala hantavirus infection: a report on 7 patients. Clin Nephrol 2011; 75:550.
- Paakkala A, Kallio T, Huhtala H, et al. Renal ultrasound findings and their clinical associations in nephropathia epidemica. Analysis of quantitative parameters. Acta Radiol 2002; 43:320.
- Huggins JW, Hsiang CM, Cosgriff TM, et al. Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 1991; 164:1119.
- Vial PA, Valdivieso F, Ferres M, et al. High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial. Clin Infect Dis 2013; 57:943.
- Dunst R, Mettang T, Kuhlmann U. Severe thrombocytopenia and response to corticosteroids in a case of nephropathia epidemica. Am J Kidney Dis 1998; 31:116.
- Vaheri A, Strandin T, Hepojoki J, et al. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013; 11:539.
- Vaheri A, Strandin T, Jääskeläinen AJ, et al. Pathophysiology of a severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant. Antiviral Res 2014; 111:23.
- Laine O, Leppänen I, Koskela S, et al. Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant. Infect Dis (Lond) 2015; 47:107.
- Mustonen J, Mäkelä S, Outinen T, et al. The pathogenesis of nephropathia epidemica: new knowledge and unanswered questions. Antiviral Res 2013; 100:589.
- Novo R, Gagnadoux MF, Le Guenno Y, et al. Chronic renal failure after Puumala virus infection. Pediatr Nephrol 1999; 13:934.
- Pergam SA, Schmidt DW, Nofchissey RA, et al. Potential renal sequelae in survivors of hantavirus cardiopulmonary syndrome. Am J Trop Med Hyg 2009; 80:279.
- Kleinknecht D, Rollin PE. Hypertension after hemorrhagic fever with renal syndrome. Nephron 1992; 61:121.
- Glass GE, Watson AJ, LeDuc JW, et al. Infection with a ratborne hantavirus in US residents is consistently associated with hypertensive renal disease. J Infect Dis 1993; 167:614.
- RUBINI ME, JABLON S, McDOWELL ME. Renal residuals of acute epidemic hemorrhagic fever. Arch Intern Med 1960; 106:378.
- Niklasson B, Hellsten G, LeDuc J. Hemorrhagic fever with renal syndrome: a study of sequelae following nephropathia epidemica. Arch Virol 1994; 137:241.
- Miettinen MH, Makela SM, Ala-Houhala IO, et al. Tubular proteinuria and glomerular filtration 6 years after puumala hantavirus-induced acute interstitial nephritis. Nephron Clin Pract 2009; 112:c115.
- Miettinen MH, Mäkelä SM, Ala-Houhala IO, et al. The severity of acute Puumala hantavirus infection does not predict the long-term outcome of patients. Nephron Clin Pract 2010; 116:c89.
- Klingström J, Granath F, Ekbom A, et al. Increased risk for lymphoma following hemorrhagic fever with renal syndrome. Clin Infect Dis 2014; 59:1130.
- Koskela SM, Laine OK, Paakkala AS, et al. Spleen enlargement is a common finding in acute Puumala hantavirus infection and it does not associate with thrombocytopenia. Scand J Infect Dis 2014; 46:723.
- Connolly-Andersen AM, Hammargren E, Whitaker H, et al. Increased risk of acute myocardial infarction and stroke during hemorrhagic fever with renal syndrome: a self-controlled case series study. Circulation 2014; 129:1295.
- Mäkelä S, Jaatinen P, Miettinen M, et al. Hormonal deficiencies during and after Puumala hantavirus infection. Eur J Clin Microbiol Infect Dis 2010; 29:705.