Leptospirosis NephropathyLeptospirosis Nephropathy

LeptospirosisLeptospirosis

Leptospirosis is a bacterial zoonotic Leptospirosis is a bacterial zoonotic infection caused by a spirochete, infection caused by a spirochete, L.interrogansL.interrogans

Synonyms for the disease include Weil's Synonyms for the disease include Weil's disease, Swineherd's disease, rice-field disease, Swineherd's disease, rice-field fever, cane-cutter fever, swamp fever, fever, cane-cutter fever, swamp fever, mud fever, hemorrhagic jaundice, mud fever, hemorrhagic jaundice, Stuttgart disease, and Canicola feverStuttgart disease, and Canicola fever

A tropical environment with a heavy rainfall, A tropical environment with a heavy rainfall, high humidity and wet soil are good media high humidity and wet soil are good media for growthfor growth

Although Leptospirosis is usually Although Leptospirosis is usually encountered in warm-climate and developing encountered in warm-climate and developing regions but is also reported in European regions but is also reported in European countries and in the USAcountries and in the USA

Grows well in neutral or alkaline environmentGrows well in neutral or alkaline environment Rodent (or rats) with their alkaline urine are Rodent (or rats) with their alkaline urine are

rich reservoirs rich reservoirs

Renal involvement is a prominent feature of Renal involvement is a prominent feature of both mild and severe forms of this re-both mild and severe forms of this re-emerging but frequently ignored infectious emerging but frequently ignored infectious disease disease

Subclinical infection, and even the anicteric Subclinical infection, and even the anicteric febrile disease, are self-limiting forms and febrile disease, are self-limiting forms and thus carry an excellent prognosisthus carry an excellent prognosis

However, 10-60% of leptospirosis infections However, 10-60% of leptospirosis infections may induce acute renal failure (ARF) and are may induce acute renal failure (ARF) and are associated with significant morbidity and associated with significant morbidity and mortalitymortality

Risk factors for infection include Risk factors for infection include Occupational exposure Occupational exposure Recreational activities Recreational activities Household exposure Household exposure OtherOther

PresentationsPresentations

HypotensionHypotension (MAP<70 mmHg), representing moderate (MAP<70 mmHg), representing moderate to severe disease, is noted in 60% of people with to severe disease, is noted in 60% of people with leptospirosisleptospirosis

A patient with leptospirosis can be fully conscious A patient with leptospirosis can be fully conscious despite the presence of hypotension, but can rapidly despite the presence of hypotension, but can rapidly develop ARF and lung complications, and die within 5–6 develop ARF and lung complications, and die within 5–6 h of admission to the hospitalh of admission to the hospital

‘‘leptospirosis triad’ was coined to describe a syndrome leptospirosis triad’ was coined to describe a syndrome of hypotension, ARF and pulmonary complications that of hypotension, ARF and pulmonary complications that occurs in 20% of patients with this disease. Pulmonary occurs in 20% of patients with this disease. Pulmonary complications, which include pulmonary edema, acute complications, which include pulmonary edema, acute respiratory distress syndrome, pulmonary hemorrhage respiratory distress syndrome, pulmonary hemorrhage and pneumonitis, are less common in normotensive and pneumonitis, are less common in normotensive patients than in hypotensive patients (Niwattayakul K patients than in hypotensive patients (Niwattayakul K et et al. al. (2002) (2002) Ren Fail Ren Fail 24: 24: 297–305)297–305)

Lancet Infectious Disease Vol 3,Dec 2003

A retrospective 5-year study in Moldova of acute renal failure due toleptospirosis: 58 cases and a review of the literature Nephrol Dial Transplant (2003) 18: 1128–1134

Severity of disease related to Severity of disease related to platelets?platelets?

Peces R, Escalada P, Gorostidi M, Alvarez J. Fracaso renal agudo en la leptospirosis. Nefrologı´a 1992; 12 [Suppl 4]: 182–187

Incidences of ARF varies between 10-60% in Incidences of ARF varies between 10-60% in case series reportscase series reports

Renal failure is hypercatabolic a/w Renal failure is hypercatabolic a/w cholestatic jaundicecholestatic jaundice

Hyperbilirubinamic renal failure represents a Hyperbilirubinamic renal failure represents a severe form of renal failure often with oliga-severe form of renal failure often with oliga-anuricanuric

Neurological symptoms are related with Neurological symptoms are related with uremiauremia

(Nephropathy in Leptospirosis, Visith S., J Postgrad Med (Nephropathy in Leptospirosis, Visith S., J Postgrad Med 2005;51;184-188)2005;51;184-188)

PathologyPathology

Broad spectrum of renal pathology changesBroad spectrum of renal pathology changes Interstitial nephritis is the first to occur and Interstitial nephritis is the first to occur and

is present even in patients with normal is present even in patients with normal renal functionrenal function

The pathogenesis of renal lesions includes The pathogenesis of renal lesions includes bacterial invasion, toxicity of bacterial bacterial invasion, toxicity of bacterial products, effects of proinflammatory products, effects of proinflammatory cytokines and mediators, and cytokines and mediators, and hemodynamic alterationshemodynamic alterations

Tubulointerstitial nephritis is the main Tubulointerstitial nephritis is the main manifestation of acute renal failuremanifestation of acute renal failure

Interstitial odema and cellular infiltrates in Interstitial odema and cellular infiltrates in the tubulo interstitial areathe tubulo interstitial area

Changes can be reversible if treatment is Changes can be reversible if treatment is instituted earlyinstituted early

Leptospiral renal dysfunction is thought to Leptospiral renal dysfunction is thought to originate from leptospiral endotoxinoriginate from leptospiral endotoxin

Leptospiral endotoxin induces an increase Leptospiral endotoxin induces an increase in TNF in TNF αα

Leptospirosis Renal Disease, Yang et al, NDT 2001; 16 (S5), 73-77

Glomerular changes are not Glomerular changes are not significantsignificant

Mesangial proliferative GN seen Mesangial proliferative GN seen (Sitprija V, (Sitprija V,

Evans H. The kidney in human leptospirosis. Am J Med 1970;49:780-8. )Evans H. The kidney in human leptospirosis. Am J Med 1970;49:780-8. )

Vasculitis with focal haemorrhages Vasculitis with focal haemorrhages seen early. Tubular atrophy and seen early. Tubular atrophy and necrosis may also be seen in necrosis may also be seen in leptospirosis renal failure leptospirosis renal failure

(Arean VM. The pathologic anatomy and pathogenesis of fatal human leptospirosis (Arean VM. The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). Am J Pathol 1962;40:393-423. )(Weil's disease). Am J Pathol 1962;40:393-423. )

DiagnosisDiagnosis

High index of suspicionHigh index of suspicion The definitive diagnostic test is the The definitive diagnostic test is the

recovery of leptospires from clinical recovery of leptospires from clinical specimens, either by culture, which specimens, either by culture, which is insensitive and slow, by is insensitive and slow, by immunohistochemical staining, or by immunohistochemical staining, or by showing the presence of leptospiral showing the presence of leptospiral DNA by PCR.DNA by PCR.

Leptospires can be isolated from Leptospires can be isolated from blood and CSF samples during the blood and CSF samples during the first 7–10 days of illnessfirst 7–10 days of illness

Urine during the 2nd and 3rd week of Urine during the 2nd and 3rd week of illnessillness

Slow growth and only can be Slow growth and only can be reported as negative after 6-8 weeksreported as negative after 6-8 weeks

(Levett PN. Usefulness of serologic analysis as a predictor of the infecting serovar in (Levett PN. Usefulness of serologic analysis as a predictor of the infecting serovar in patients with severe leptospirosis. Clin Infect Dis 2003; patients with severe leptospirosis. Clin Infect Dis 2003; 36: 36: 447–52)447–52)

SerologySerology

Gold standard is MAT (microscopic Gold standard is MAT (microscopic agglutination test)agglutination test)

The standard criterion for a positive MAT The standard criterion for a positive MAT are a fourfold increase in antibody titre, or are a fourfold increase in antibody titre, or a conversion from seronegativity to a titre a conversion from seronegativity to a titre of 1/100 or aboveof 1/100 or above

Requires certain expertiseRequires certain expertise ELISA is then used as preliminary ELISA is then used as preliminary

screeningscreening

Fluid administrationFluid administration

Decreased response to fluids similar Decreased response to fluids similar to sepsis patientsto sepsis patients

Systemic vasodilation is seen with Systemic vasodilation is seen with elevated plasma aldosterone and elevated plasma aldosterone and ADH ADH (Barsoum et Tropical Nephrology In Diseases of Kidney (Barsoum et Tropical Nephrology In Diseases of Kidney

and Urinary Tract. Lippincott Williams and Wilkins 2001, pg 2301)and Urinary Tract. Lippincott Williams and Wilkins 2001, pg 2301) Cautious treatment with fluid to Cautious treatment with fluid to

avoid iatrogenic pulmonary odema. avoid iatrogenic pulmonary odema. Small dose of dopamine may Small dose of dopamine may improve hypotension and increase improve hypotension and increase urine outputurine output(Losuwanrak K, Potential use of dopamine in (Losuwanrak K, Potential use of dopamine in leptospirosis, Int Med of Thailand 2003:19:180-184)leptospirosis, Int Med of Thailand 2003:19:180-184)

TreatmentTreatment

In the case series reported from Hawaii In the case series reported from Hawaii from 1974–1998, no significant difference from 1974–1998, no significant difference was seen between use and non-use of was seen between use and non-use of antibiotics and duration of illness antibiotics and duration of illness (Vinetz JM. A Mountain (Vinetz JM. A Mountain out of a molehill: do we treat acute leptospirosis, and if so, with what? out of a molehill: do we treat acute leptospirosis, and if so, with what? Clin Infect Dis Clin Infect Dis 2003; 2003; 36: 36: 1514–1514–15.)15.)

Edwards et all Penicillin therapy in icteric Edwards et all Penicillin therapy in icteric leptospirosis. leptospirosis. Am J Trop Med Hyg Am J Trop Med Hyg 1988; 1988; 39: 39: 388–90 reported no difference in treated 388–90 reported no difference in treated and untreated patients in regards to and untreated patients in regards to normalization of biochemical parameters, normalization of biochemical parameters, fever or mortalityfever or mortality

Reports favouring treatmentReports favouring treatment

RCT showed treatment with RCT showed treatment with doxycylline and penicillin shortened doxycylline and penicillin shortened duration of fever and prevented duration of fever and prevented leptospiral shedding in urine leptospiral shedding in urine (McClain et al,Ann (McClain et al,Ann

Intern Med 1984 May;100(5):696-8 Watt G et,Lancet 1988 Feb 27;1(8583):433-5)Intern Med 1984 May;100(5):696-8 Watt G et,Lancet 1988 Feb 27;1(8583):433-5)

Ceftriaxone, cefotaxime were also Ceftriaxone, cefotaxime were also shown to be effective in Thailand shown to be effective in Thailand (Panaphut T, Clin Infect Dis 2003 Jun 15;36(12):1507-13;Suputtamongkol Y,Clin Infect (Panaphut T, Clin Infect Dis 2003 Jun 15;36(12):1507-13;Suputtamongkol Y,Clin Infect Dis 2004 Nov 15;39(10):1417-24.Dis 2004 Nov 15;39(10):1417-24.

Treatment of renal failureTreatment of renal failure

PD is still done in rural places and is PD is still done in rural places and is seldom complicated with bleeding seldom complicated with bleeding (Sitprija (Sitprija V, Leptospiral nephropathy. Semin Nephrol 2003;23:42-8)V, Leptospiral nephropathy. Semin Nephrol 2003;23:42-8)

Plasmapheresis or blood exchange Plasmapheresis or blood exchange offers good results in patients with offers good results in patients with hyperbilirubinaemic renal failure with a hyperbilirubinaemic renal failure with a total serum bilirubin above 425 total serum bilirubin above 425 mmol/L mmol/L (Sitprija V, Renal failure and hyperbilirubinaemia in (Sitprija V, Renal failure and hyperbilirubinaemia in leptospirosis: Treatment with exchange transfusion. Med J Aust 1973;1:171-2. leptospirosis: Treatment with exchange transfusion. Med J Aust 1973;1:171-2.  Pecchini F, Borghi M,  Pecchini F, Borghi M, et alet al . Acute renal failure from leptospirosis: New trends . Acute renal failure from leptospirosis: New trends of treatmentof treatment . . Clin Nephrol 1982;18:164. Pochanugool C, Hyperbilirubinemic Clin Nephrol 1982;18:164. Pochanugool C, Hyperbilirubinemic renal failure in tropical disease: Treatment with exchange transfusion. J Med renal failure in tropical disease: Treatment with exchange transfusion. J Med Assoc Thai 1978;61:75-7.Tse KC, Assoc Thai 1978;61:75-7.Tse KC, et alet al . Potential benefit of plasma exchange . Potential benefit of plasma exchange in treatment of severe icteric leptospirosis complicated by acute renal failure. in treatment of severe icteric leptospirosis complicated by acute renal failure. Clin Diagn Lab Immunol 2002;9:482-4.)Clin Diagn Lab Immunol 2002;9:482-4.)

In patients with severe leptospirosis In patients with severe leptospirosis with multiple organ failure, continuous with multiple organ failure, continuous venovenous haemofiltration (CVVH) or venovenous haemofiltration (CVVH) or plasmapheresis has been shown to plasmapheresis has been shown to improve systemic and renal improve systemic and renal haemodynamics and clinical condition haemodynamics and clinical condition (Siriwanij T, Haemodynamics in leptospirosis: Effects of plasmapheresis and continuous (Siriwanij T, Haemodynamics in leptospirosis: Effects of plasmapheresis and continuous venovenous haemofiltration. Nephrology 2005;10:1-6 )venovenous haemofiltration. Nephrology 2005;10:1-6 )

Copyright ©2007 American Society of Nephrology

Andrade, L. et al. Clin J Am Soc Nephrol 2007;2:739-744

Figure 1. (A) Door-to-dialysis time (from intensive care unit admission to the initiation of dialysis); (B) mean serum urea during the dialysis treatment period

739-744, 2007

Copyright ©2007 American Society of Nephrology

Andrade, L. et al. Clin J Am Soc Nephrol 2007;2:739-744

Figure 2. Mortality according to treatment group

739-744, 2007

Prognosis Prognosis Prognosis of renal failure in leptospirosis is Prognosis of renal failure in leptospirosis is

usually favourable unless complicated by usually favourable unless complicated by multiple organ involvementmultiple organ involvement

Pulmonary complications, Pulmonary complications, hyperbilirubinaemia, oligo-anuria, diarrhoea, hyperbilirubinaemia, oligo-anuria, diarrhoea, hyperkalaemia, old age and associated hyperkalaemia, old age and associated infection or underlying diseases carry bad infection or underlying diseases carry bad prognosis with mortality ranging from 12% prognosis with mortality ranging from 12% to 36%to 36% (Leptospirosis in northeastern Thailand : Hypotens Comp Pub Health 2002;33:155-(Leptospirosis in northeastern Thailand : Hypotens Comp Pub Health 2002;33:155-60Risk factors for death and changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg 60Risk factors for death and changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg 1999;61:630-4. . Acute lung injury in leptospirosis: Clinical and laboratory features outcome, and 1999;61:630-4. . Acute lung injury in leptospirosis: Clinical and laboratory features outcome, and factors associated with mortality. Clin Infect Dis 1999;29:1561-3. Epidemiology of leptospirosis in New factors associated with mortality. Clin Infect Dis 1999;29:1561-3. Epidemiology of leptospirosis in New Caledonia (South Pacific): A one-year survey. Eur J Epidemiol 1997;13:161-7. Epidemic leptospirosis Caledonia (South Pacific): A one-year survey. Eur J Epidemiol 1997;13:161-7. Epidemic leptospirosis associated with pulmonary hemorrhage-Nicaragua. 1995. J Infect Dis 1998;178:1457-63 associated with pulmonary hemorrhage-Nicaragua. 1995. J Infect Dis 1998;178:1457-63

ARF in presence of failure of two or more ARF in presence of failure of two or more organ-systems carries an unfavourable organ-systems carries an unfavourable prognosis.prognosis. (A retrospective 5 - year study in Moldova of acute renal failure due to (A retrospective 5 - year study in Moldova of acute renal failure due to leptospirosis: 58 cases and a review of the literature. Nephrol Dial Transplant 2003;18:1128-34 )leptospirosis: 58 cases and a review of the literature. Nephrol Dial Transplant 2003;18:1128-34 )

A retrospective 5-year study in Moldova of acute renal failure due toleptospirosis: 58 cases and a review of the literature Nephrol Dial Transplant (2003) 18: 1128–1134

HantavirusHantavirus

Historical PerspectiveHistorical Perspective

Korean War – 3000 UN soldiers approaching Korean War – 3000 UN soldiers approaching mortality of 10% (“Korean Hemorrhagic mortality of 10% (“Korean Hemorrhagic Fever”)Fever”)

Thought to be a new diseaseThought to be a new disease Only in 1978, was this group of virus known Only in 1978, was this group of virus known

as hantavirus identified as hantavirus identified (Lee HW, Lee PW, Johnson KM: (Lee HW, Lee PW, Johnson KM: Isolation of the etiologic agent of Korean hemorrhagic fever. Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect DisJ Infect Dis 137: 137: 298–308, 1978 )298–308, 1978 )

Old disease re-emergedOld disease re-emerged American civil war in 1862 and 1863American civil war in 1862 and 1863 World War IWorld War I Known as ‘trench’ nephritisKnown as ‘trench’ nephritis

The genus comprises a few types of virus with The genus comprises a few types of virus with each giving rise to different presentationseach giving rise to different presentations

Clinical syndromes caused by hantaviruses Clinical syndromes caused by hantaviruses have also been known as epidemic have also been known as epidemic hemorrhagic fever, hemorrhagic hemorrhagic fever, hemorrhagic nephrosonephritis, Songo fever, Korean nephrosonephritis, Songo fever, Korean hemorrhagic fever, and nephropathia hemorrhagic fever, and nephropathia epidemica epidemica

Now collectively referred to by the World Now collectively referred to by the World Health Organization as "hemorrhagic fever Health Organization as "hemorrhagic fever with renal syndrome" (HFRS)with renal syndrome" (HFRS)

EpidemiologyEpidemiology

Hantavirus infection is acquired by inhalation Hantavirus infection is acquired by inhalation of aerosolized virus containing particles, or of aerosolized virus containing particles, or contact with urine, secretions or feces of contact with urine, secretions or feces of infected rodents infected rodents

The rodent vectors differ for each viral The rodent vectors differ for each viral species but include mice, voles, shrews, and species but include mice, voles, shrews, and ratsrats

Many cases have been reported in Europe Many cases have been reported in Europe and Asia, including Scandinavia, the Balkans, and Asia, including Scandinavia, the Balkans, and Korea. In addition, the 1999 war in the and Korea. In addition, the 1999 war in the Balkans was associated with a resurgence of Balkans was associated with a resurgence of cases, most of which resulted from the cases, most of which resulted from the exposure of soldiers to rodents in the field exposure of soldiers to rodents in the field

BiologyBiology The genus The genus Hantavirus Hantavirus is roughly composed is roughly composed

of two main groups: Old World and New of two main groups: Old World and New World hantaviruses. World hantaviruses.

HFRS in humans is caused by pathogenic HFRS in humans is caused by pathogenic Old World hantaviruses that include Amur Old World hantaviruses that include Amur virus, Seoul virus, and HTNVvirus, Seoul virus, and HTNV

Mortality can be up till 15%Mortality can be up till 15% Puumala virus (PUUV) is the main Puumala virus (PUUV) is the main

hantavirus species in Europe and induces hantavirus species in Europe and induces Nephropathia epidemica (NE), a milder Nephropathia epidemica (NE), a milder variant of HFRS, with mortality rates of variant of HFRS, with mortality rates of 0.1% 0.1% (Hantaviruses: Immunology, treatment, and prevention. (Hantaviruses: Immunology, treatment, and prevention. Viral Immunol Viral Immunol 17: 17: 481–497, 2004Hantavirus infections in Europe. 481–497, 2004Hantavirus infections in Europe. Lancet Infect Dis Lancet Infect Dis 3: 653–661, 2003)3: 653–661, 2003)

Nephropathia Epidemica Nephropathia Epidemica (NE)(NE)

a sudden onset with high fever, headache, a sudden onset with high fever, headache, backache, and abdominal pain backache, and abdominal pain

Transient thrombocytopenia Transient thrombocytopenia conjunctival hemorrhages, palatine petechiae, conjunctival hemorrhages, palatine petechiae,

and a truncal petechial rash after 3 or 4 d is and a truncal petechial rash after 3 or 4 d is possible possible

Hemorrhages are accompanied by oliguria, Hemorrhages are accompanied by oliguria, azotemia, proteinuria, and hematuria azotemia, proteinuria, and hematuria

Within 3 d, the rash disappears and the patients Within 3 d, the rash disappears and the patients develop polyuria. The convalescent phase extends develop polyuria. The convalescent phase extends over several weeks, and sequelae are rare. over several weeks, and sequelae are rare.

Severe courses of NE with acute renal failure and Severe courses of NE with acute renal failure and lethal outcome range between 0.1 and 1% lethal outcome range between 0.1 and 1% (Infectious (Infectious diseases; Viral diseases. In: diseases; Viral diseases. In: The Merck Manual of Diagnosis and TherapyThe Merck Manual of Diagnosis and Therapy, 17th Ed., Indianapolis, , 17th Ed., Indianapolis, Wiley Publishers, 2005 )Wiley Publishers, 2005 )

HFRSHFRS Incubation period of HFRS is 7 to 36 dIncubation period of HFRS is 7 to 36 d Only 10 to 15% of cases have a severe Only 10 to 15% of cases have a severe

course, with lethality rates between 6 to course, with lethality rates between 6 to 15%. 15%.

Characterized by systemic involvement of Characterized by systemic involvement of capillaries and venules. It induces various capillaries and venules. It induces various hemorrhagic manifestations and circulation hemorrhagic manifestations and circulation disorders. disorders.

Renal involvement is characterized by acute Renal involvement is characterized by acute renal failure as a result of interstitial renal failure as a result of interstitial hemorrhage and interstitial infiltrates hemorrhage and interstitial infiltrates

5 clinical phases of HFRS5 clinical phases of HFRS Febrile, hypotensive, oliguric, diuretic, and convalescent Febrile, hypotensive, oliguric, diuretic, and convalescent Initial onset resembles NEInitial onset resembles NE Visual symptoms may be prominent (photophobia, Visual symptoms may be prominent (photophobia,

visual impairment, conjunctival haemorrhages)visual impairment, conjunctival haemorrhages) The urinary sediment reveals hematuria and atypical The urinary sediment reveals hematuria and atypical

gross proteinuria (in some cases >3 g/24 h) gross proteinuria (in some cases >3 g/24 h) Hypotensive phase ranges 3 to 6 d after onset of fever Hypotensive phase ranges 3 to 6 d after onset of fever A wide range of renal conditions, including acute A wide range of renal conditions, including acute

tubulointerstitial nephritis, necrotizing tubulointerstitial nephritis, necrotizing glomerulonephritis, and IgA nephropathy. glomerulonephritis, and IgA nephropathy.

The oliguric phase starts at approximately day 8, and The oliguric phase starts at approximately day 8, and hemorrhagic manifestations become more prominent. hemorrhagic manifestations become more prominent. The diuretic phase starts at approximately day 11, and The diuretic phase starts at approximately day 11, and the convalescent phase lasts approximately 3 wk to 6 the convalescent phase lasts approximately 3 wk to 6 mo. mo.

Hantavirus Pulmonary Hantavirus Pulmonary SyndromeSyndrome

Flu-like symptomsFlu-like symptoms Acute non cardiac pulmonary oedema and Acute non cardiac pulmonary oedema and

hypotension within 2-15dhypotension within 2-15d Bilateral infiltrates develop rapidly,

sometimes associated with pleural effusions. Neutrophilic leukocytosis, hemoconcentration, hrombocytopenia, and circulating immunoblasts are observed

ARF is a result of shock and respiratory failure

Renal prognosisRenal prognosis Most patients generally return to baseline Most patients generally return to baseline

glomerular filtration rate (GFR) following an glomerular filtration rate (GFR) following an episode of acute renal failure related to episode of acute renal failure related to hantavirus infection hantavirus infection

Long-term sequelae were perhaps best Long-term sequelae were perhaps best illustrated in observational studies five and illustrated in observational studies five and ten years after Puumala virus-induced ten years after Puumala virus-induced nephropathy. At five years, affected nephropathy. At five years, affected patients had a higher GFR, more patients had a higher GFR, more proteinuria, and higher blood pressure proteinuria, and higher blood pressure compared with healthy controls; however, compared with healthy controls; however, hyperfiltration and proteinuria resolved by hyperfiltration and proteinuria resolved by ten years.ten years. (Ten-year prognosis of Puumala hantavirus-induced acute (Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Miettinen MH et alKidney Int. 2006 Jun;69(11):2043-8 interstitial nephritis. Miettinen MH et alKidney Int. 2006 Jun;69(11):2043-8 Renal function and blood pressure five years after puumala virus-induced Renal function and blood pressure five years after puumala virus-induced nephropathy. - Makela S, et alKidney Int 2000 Oct;58(4):1711-8)nephropathy. - Makela S, et alKidney Int 2000 Oct;58(4):1711-8)

PathologyPathology

Immunohistology analysis of hantavirus-infected Immunohistology analysis of hantavirus-infected renal tissue reveals interstitial infiltrates with renal tissue reveals interstitial infiltrates with immune cells and interstitial hemorrhageimmune cells and interstitial hemorrhage

The most common histopathologic lesion are acute The most common histopathologic lesion are acute tubulointerstitial nephritis tubulointerstitial nephritis

Intertubular capillaries are congested, and the Intertubular capillaries are congested, and the interstitium is broadened by edema, indicative of a interstitium is broadened by edema, indicative of a generalized capillary damage. generalized capillary damage.

Occasionally, glomerular pathology, Occasionally, glomerular pathology, e.g.e.g., , hypercellularity and expansion of the mesangium, hypercellularity and expansion of the mesangium, are observed, and this is probably the underlying are observed, and this is probably the underlying cause of gross proteinuria. Tubular, interstitial, and cause of gross proteinuria. Tubular, interstitial, and glomerular histologic damage are associated with glomerular histologic damage are associated with the clinical severity of renal failure the clinical severity of renal failure

A) Focal mononuclear interstitial infiltration, capillary congestion, and interstitial hemorrhage at the corticomedullary junction.

B) Normal glomeruli. Focal interstitial edema with a mild mononuclear infiltrate and prominent endothelial cells of peritubular capillaries. Magnification, x100 in A, Masson trichrome stain; x160 in B, PAS stain.

Kidney International, Vol. 48 (1995), Pp. 887—902

Kidney International, Vol. 48 (1995), Pp. 887—902

DiagnosisDiagnosis

Diagnosis is made on a basis of clinical and Diagnosis is made on a basis of clinical and laboratory findingslaboratory findings

The diagnosis of hantavirus infection can be The diagnosis of hantavirus infection can be confirmed with serologic tests. By the time confirmed with serologic tests. By the time symptoms are evident, patients usually have symptoms are evident, patients usually have antiviral antibodies of the IgM class, and most also antiviral antibodies of the IgM class, and most also have IgG antibodieshave IgG antibodies

The diagnosis of kidney disease in HFRS is based The diagnosis of kidney disease in HFRS is based upon the typical clinical and laboratory upon the typical clinical and laboratory manifestations (proteinuria, hematuria, elevated manifestations (proteinuria, hematuria, elevated serum creatinine), in conjunction with the serum creatinine), in conjunction with the serological evidence of a recent hantavirus infectionserological evidence of a recent hantavirus infection

TherapyTherapy There are no specific antiviral therapies for There are no specific antiviral therapies for

hantavirushantavirus The treatment of patients with HFRS or The treatment of patients with HFRS or

HPS is restricted to supportive procedures HPS is restricted to supportive procedures to keep under control the symptoms, to keep under control the symptoms, which may be life-threateningwhich may be life-threatening

One prospective double-blinded study of One prospective double-blinded study of 242 patients with serologically proven 242 patients with serologically proven infection found that intravenous ribavirin infection found that intravenous ribavirin therapy resulted in a reduction in therapy resulted in a reduction in mortality, other studies did not confirm mortality, other studies did not confirm these benefitsthese benefits (Huggins JW, (Huggins JW, et al.et al.: Prospective, double-blind, : Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. hemorrhagic fever with renal syndrome. J Infect DisJ Infect Dis 164: 1119–1127, 1991 ) 164: 1119–1127, 1991 )

Supportive therapy on ARF as indicatedSupportive therapy on ARF as indicated

PreventionPrevention

Vaccine has been developed in Korea Vaccine has been developed in Korea and has shown high titers of IgG in and has shown high titers of IgG in the initial few months. However, the the initial few months. However, the antibodies reduce rapidly after that antibodies reduce rapidly after that (Cho HW, Howard CR: Antibody responses in humans to an (Cho HW, Howard CR: Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax). inactivated hantavirus vaccine (Hantavax). VaccineVaccine 17: 2569– 17: 2569–2575, 1999 Cho HW, Howard CR, Lee HW: Review of an 2575, 1999 Cho HW, Howard CR, Lee HW: Review of an inactivated vaccine against inactivated vaccine against hantavirushantaviruses. es. IntervirologyIntervirology 45: 328– 45: 328–333, 2002 Hjelle B: Vaccines against 333, 2002 Hjelle B: Vaccines against hantavirushantaviruses. es. Expert Rev Expert Rev VaccinesVaccines 1: 373–384, 2002 Park K, Kim CS, Moon KT: Protective 1: 373–384, 2002 Park K, Kim CS, Moon KT: Protective effectiveness of effectiveness of hantavirushantavirus vaccine. vaccine. Emerg Infect DisEmerg Infect Dis 10: 2218– 10: 2218–2220, 2004)2220, 2004)

LS vs HVLS vs HV

Acute renal failure caused by leptospirosis and Hantavirus infection in an urban hospital European Journal of Internal Medicine 13 (2002) 264–268

LS vs HVLS vs HV

Acute renal failure caused by leptospirosis and Hantavirus infection in an urban hospital European Journal of Internal Medicine 13 (2002) 264–268

Mis-diagnosis of HantavirusMis-diagnosis of Hantavirus

Clement J, Hinrichsen S, Crescente J Clement J, Hinrichsen S, Crescente J et et al.al. HantavirusHantavirus-induced hemorrhagic -induced hemorrhagic fever with renal syndrome (HFRS) has fever with renal syndrome (HFRS) has to be considered in the differential to be considered in the differential diagnosis of leptospirosis-suspected diagnosis of leptospirosis-suspected cases in the New and the Old World. cases in the New and the Old World. Am J Trop Med HygAm J Trop Med Hyg 1999; 61: 316–317 1999; 61: 316–317