Kidney involvement in hantavirus infections

INTRODUCTION — Infection with a hantavirus may lead to life-threatening pulmonary and kidney 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, kidney function impairment, and fever [7].

The members of the Hantavirus genus cause two main types of clinical syndromes in humans. Hemorrhagic fever with renal syndrome (HFRS) is caused by Hantaan, Seoul, Puumala, and Dobrava virus. Hantavirus cardiopulmonary syndrome (HCPS) is caused by Sin Nombre virus in the United States and Andes and related viruses in South America [8].

Kidney disease due to Puumala virus is relatively mild and is associated with a benign long-term prognosis [9,10]. More severe kidney disease can occur with infections by Hantaan and Dobrava virus [6,11]. The kidney disease in patients with HCPS is usually mild [8].

Clinical syndromes caused by hantaviruses have also been known as epidemic hemorrhagic fever, hemorrhagic nephrosonephritis, Songo fever, Korean hemorrhagic fever (Hantaan virus infection), and nephropathia epidemica (Puumala virus infection) [12].

Kidney disease associated with hantavirus infections will be reviewed here. The epidemiology and diagnosis of hantavirus infections and HCPS are discussed separately. (See "Epidemiology and diagnosis of hantavirus infections" and "Hantavirus cardiopulmonary syndrome".)

EPIDEMIOLOGY — Hantavirus infection is acquired by inhalation of aerosolized virus-containing particles or by coming in contact with urine, secretions, or feces of infected rodents. Infection can also be acquired via the gastrointestinal route [13].

Smoking, possibly by altering the conditions of the human airways, is a risk factor for Puumala virus infection [14,15]. 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 [16].

Infection with hantaviruses is associated with significant morbidity and mortality worldwide, although less than one-fourth of cases have a severe course [1,12]. Overall mortality from hemorrhagic fever with renal syndrome (HFRS) varies widely, from 0.5 percent with the milder European forms of the disease to as high as 5 to 10 percent for Korean hemorrhagic fever [1,6,11]. Supportive care has had a substantial positive effect upon mortality in this illness. For patients with severe HFRS, for example, mortality rates have decreased from 10 to 15 percent in the 1960s to rates of less than 5 percent with advanced supportive care. By contrast, the case fatality rate for hantavirus cardiopulmonary syndrome (HCPS) is higher (up to 40 percent) [8].

Approximately 300 to 500 HFRS cases caused by Hantaan and Seoul virus are reported annually in Korea and more than 11,000 cases in China [17]. In European countries, most HFRS cases are caused by Puumala virus, while Dobrava virus infections are rarer. In some countries, such as Finland, Germany, Sweden, and the European part of Russia, thousands of cases can occur in epidemic peak years [17]. The 1999 war in the Balkans, for example, was associated with a resurgence of cases, most of which resulted from the exposure of soldiers to rodents in the field [18].

Multiple areas of the United States may also harbor reservoirs for the Sin Nombre hantavirus. Serologically proven disease due to HFRS strains has been documented in Baltimore due to a heavily infested rodent population, although the attack rate was low [19]. This topic is discussed in detail elsewhere. (See "Epidemiology and diagnosis of hantavirus infections".)

PATHOGENESIS OF KIDNEY DISEASE — Increased vascular permeability appears to play a general role in the pathogenesis of severe hantavirus infection [20]. This is suggested clinically by an increase in hematocrit and a decrease in serum protein levels, and tracer studies have confirmed a generalized vascular leak [1,21]. The increased permeability may be mediated in part by bradykinin [22,23].

The complement system is activated in hantavirus infections both via classical and alternate pathways, and there is a relationship between the complement activation and the clinical presentation [24-26]. Several molecular mechanisms link the coagulation and fibrinolysis cascades with complement components C3 and C5 [27].

Additional findings are similar to those of septic shock, including a decrease in peripheral vascular resistance and an increase in cardiac output. (See "Pathophysiology of sepsis" and "Pathogenesis of hantavirus infections".)

An abrupt decline in glomerular filtration rate (GFR) is often observed among patients with hantavirus infection. Intrarenal events play an important role in the development of kidney failure in hemorrhagic fever with renal syndrome (HFRS) [1]. The following contributing factors have been proposed:

●Damage to vascular endothelium.

●Initiation of tubular and interstitial damage by cytokines and other humoral factors (such as tumor necrosis factor), causing acute tubulointerstitial nephritis. This is corroborated by the increased expression of cytokines in the peritubular areas on histologic specimens [28] and by the correlation of urinary excretion of interleukin-6 (IL-6) with the amount of proteinuria (eg, severity of damage) [29]. Urine-soluble urokinase-type plasminogen activator receptor (suPAR) levels correlate with proteinuria and with the severity of acute kidney injury (AKI), and it is possible that suPAR has a pathogenic role in Puumala hantavirus-induced nephritis [30,31]. Distal tubular or collecting duct injury is also reflected by increased urinary sediment GATA-3 mRNA levels, which are a risk factor for severe AKI [32].

●Genetic factors may predispose some individuals to the development of severe kidney involvement associated with HFRS due to Puumala virus because of an enhanced immune response to the virus [33,34]. As an example, adults with human leukocyte antigen (HLA) B8 and DR3 alleles develop AKI requiring dialysis more often than those without these alleles [34]; in contrast, patients with HLA B27 have milder disease [35]. A similar association between HLA B8 and DR3 and severity of disease has not been noted in children, perhaps because the overall clinical course of Puumala virus infection is milder than in adults [36-38]. Genetic polymorphisms related to platelet activation, blood coagulation, and fibrinolysis have an impact on kidney function and platelet count in HFRS caused by Puumala virus [39,40]. In addition, many other immunity-related genes and haplotypes are associated with the severity of various human hantavirus infections [41]. (See "Pathogenesis of hantavirus infections".)

●During immune response to Puumala virus, nonclassical monocytes are activated, their number is reduced in the blood, and they are recruited to the kidneys, contributing to the pathogenesis of AKI [42]. Acute hantavirus infection increases the level of immunoglobulin free light chains in serum both in Puumala virus-caused HFRS and in Andes virus-caused hantavirus pulmonary syndrome. In the case of Puumala virus infection, the increase in immunoglobulin free light chains correlates with the severity of AKI [43].

The exact role of the viral infection is unclear. The direct infection of mesangial cells may induce a local environment of signal mediators that contributes to AKI in hantavirus infection [44]. However, although hantaviruses have been shown to infect human endothelial cells using beta3 integrins, they are not necessarily cytotoxic, and similar endothelial cell infection has been documented with many viruses that do not cause severe vascular damage (eg, herpes simplex virus, adenovirus, measles virus).

PATHOLOGY — The virus can be demonstrated by polymerase chain reaction (PCR) in kidney biopsy material [45]. The most prominent kidney histopathologic finding of hantavirus infection is an acute tubulointerstitial nephritis with the inflammatory infiltrate composed predominantly of mononuclear cells, CD8 lymphocytes, and neutrophils [46,47]. Other common interstitial changes include congestion and dilatation of the medullary vessels, hemorrhage into the medullary tissues, interstitial edema, tubular cell necrosis and degeneration [3,45,46], and microvascular inflammation [48].

Hantaviruses can infect tubular epithelial cells, glomerular endothelial cells, and podocytes of human kidney and disrupt cell-to-cell contacts in all of these cell types [49,50]. Podocyte injury seems to be the main cause of proteinuria in Puumala hantavirus infection [51]. Hantavirus infection may disrupt podocyte integrity and impair the migration of renal epithelial cells, resulting in severe glomerular proteinuria [52,53]. It is possible that the local activation of heparinase in the kidneys disrupts the endothelial glycocalyx, leading to increased protein leakage through the glomerular filtration barrier, resulting in proteinuria [54].

Despite the often marked proteinuria, histologic changes in the glomeruli are typically mild. Light microscopy may demonstrate slight mononuclear hypercellularity and mesangial proliferation, and immunohistochemistry may reveal occasional immunoglobulin and complement deposits in the glomeruli [3,46,55,56]. However, membranoproliferative glomerulonephritis shortly after Puumala virus infection has also been reported [57,58].

CLINICAL MANIFESTATIONS — Classic hemorrhagic fever with renal syndrome (HFRS) has several prominent features, including [1-6,11,59]:

●Fever

●Hemorrhage

●Hypotension

●Acute kidney injury (AKI)

The clinical course, however, can be extremely variable, and some infected individual are asymptomatic. The severity of illness manifestations tends to vary based upon the strain of infecting hantavirus, as illustrated below.

●Puumala virus infection usually presents with high fever, loin or abdominal pain, nausea and vomiting, malaise, conjunctival hemorrhage, headache, and acute myopia associated with headache [1-3,11]. Some patients develop hypotension and severe oliguric acute kidney injury (AKI). Abnormal laboratory values include a leukocytosis, thrombocytopenia, an elevated lactate dehydrogenase (LDH), and slightly elevated liver function tests. Enhanced thrombin formation and fibrinolysis are also characteristic [60]. An elevated serum creatinine is universal, and proteinuria and microscopic hematuria are very common. Abnormal electro- and echocardiographic findings are common in HFRS patients [61,62]. The clinical picture of Dobrava infection is similar, but the symptoms are somewhat more severe [11,59,63-67].

●Manifestations of HFRS due to Hantaan virus in Asia are more severe [1,5,6]. In addition to the findings noted with Puumala virus infection, over one-third of patients are hypotensive; almost two-thirds develop oliguria, many of whom may require dialysis; laboratory abnormalities are more severe; and disseminated intravascular coagulation (DIC) can be observed. Among the Asian HFRS, disease due to Hantaan virus is more severe than with the Seoul virus, with a greater likelihood of shock and kidney failure requiring dialysis [6].

●The Sin Nombre virus strain in the United States and Andes and related viruses in South America have been mostly associated with respiratory failure; initial cases had no or relatively mild kidney involvement (low-grade proteinuria and hematuria in 50 percent and a modest increase in the serum creatinine to <2.5 mg/dL [220 micromol/L]) [7,68]. However, more substantial kidney disease has since been reported. In Andes virus infection, proteinuria is a frequent finding [69]. Cases with more severe kidney failure, including those requiring dialysis, may also occur [70-74]. (See "Hantavirus cardiopulmonary syndrome".)

Kidney manifestations — Kidney involvement includes proteinuria, hematuria, and reduced glomerular filtration rate (GFR) [20,75].

Transient nonselective proteinuria (glomerular and tubular) is found in almost all patients with HFRS caused by various hantaviruses [1,75-78]. This was best described in a series of 126 hospitalized patients with Puumala virus infection; protein excretion ranged from 0 to 12.3 g/day (mean 2.6 g/day), and 25 percent of patients had nephrotic-range proteinuria [46]. In one study, urine protein excretion peaked five to six days after the onset of Puumala virus infection and rapidly declined thereafter [79]. Concomitant urinary loss of low-molecular-weight proteins such as beta2-microglobulin [1,76] and alpha1-microglobulin [75] suggests that tubular injury also contributes to proteinuria.

Microscopic hematuria is observed in 58 to 85 percent of patients with Puumala virus and in 85 to 100 percent of patients with Hantaan and Dobrava virus infection [6,11]. Hematuria may persist for months or years after infection [80]. Macroscopic hematuria is uncommon.

Glucosuria has also been found in a minority of cases with Puumala virus infection. In one study, the degree of spot albuminuria, hematuria, and glucosuria (by dipstick) at hospital admission was predictive of the severity of subsequent AKI [81].

Most patients hospitalized with HFRS have a transient reduction in GFR [6,59,76]. Dialysis is infrequently required by patients infected with the Puumala virus (5 percent) but may be required by 20 to 40 percent of patients infected with Dobrava or Hantaan virus (most likely due to the greater overall severity of illness) [6,11].

The severity of AKI in Puumala virus infection associates with high plasma or serum levels of interleukin 6 (IL-6), pentraxin 3 (PTX3), indoleamine 2,3-dioxygenase (IDO), soluble urokinase-type plasminogen activator receptor (suPAR), galectin-3-binding protein (Gal-3BP), YKL-40, resistin, and urine GATA-3 mRNA levels (table 1) [31,32,82-88]. High plasma C-reactive protein (CRP) may be associated with less kidney function impairment [82]. The degree of proteinuria is associated with the levels of urinary IL-6 and suPAR (table 1). Some of these biomarkers might have a pathogenic role in the kidney disease of Puumala hantavirus infection [20,89].

In some reports, the severity of thrombocytopenia was associated with the severity of AKI in Puumala [90,91] or Hantaan virus [92] infection, although this association was not found in other studies [32,93-95]. The amount of proteinuria and urine neutrophil gelatinase-associated lipocalin (NGAL) level predicted the severity of AKI in Puumala virus infection in two reports [91,94].

Phases of disease — Patients with severe HFRS typically progress sequentially from fever to abrupt hypotension and clinical shock and then to oliguria. As thrombocytopenia and DIC develop, findings of diffuse hemorrhage may appear, including petechiae, ecchymoses, hematemesis, hemoptysis, and melena. If patients survive this acute period, they subsequently enter a diuretic phase by day 10 to 14 and then a convalescent phase that often lasts many weeks.

Most patients return to baseline GFR following an episode of AKI related to hantavirus infection [1,6,10,96]. Some patients have persistently reduced GFR. (See 'Prognosis' below.)

Respiratory failure — Respiratory failure was a prominent finding in some patients with Korean hemorrhagic fever caused by Hantaan virus and the epidemic in the Southwestern United States caused by Sin Nombre virus [6,7]. Patients presented with a fever, flushing, pharyngeal and conjunctival congestion, myalgias, headache, cough, and then rapid respiratory failure. Respiratory failure was much more significant than hemorrhage or kidney failure and was thought to be due to noncardiogenic pulmonary edema caused by a diffuse capillary leak syndrome. (See "Hantavirus cardiopulmonary syndrome".)

However, patients with HFRS without significant clinical pulmonary symptoms may also have abnormal chest radiographic findings. As an example, among 125 patients hospitalized with Puumala virus infection, 28 percent had abnormal chest radiographs (pleural effusion, atelectasis, and interstitial infiltrates) [97]. Frank pulmonary edema was rare. However, when studied with high-resolution computed tomography (HRCT), almost every patient showed lung parenchymal abnormalities [98].

DIAGNOSIS — The possibility of Hemorrhagic fever with renal syndrome (HFRS) should be considered in patients with high fever, headache, abdominal pain, and back pain; respiratory symptoms need not be present.

A history should elicit whether the patient is at increased risk of exposure to rodents either due to occupation (eg, farming, forestry, animal trapping) or other situations (eg, military activity, crisis conditions, camping) [11]. The majority of the patients are adult males [11]. Hantavirus infections are rare in children [38].

Laboratory findings suggestive of the diagnosis include leukocytosis, elevated C-reactive protein, thrombocytopenia, elevated serum creatinine level, proteinuria, and hematuria [11].

The diagnosis of hantavirus infection can be confirmed with serologic tests. By the time symptoms are evident, patients usually have antiviral antibodies of the immunoglobulin M (IgM) class, and most also have immunoglobulin G (IgG) antibodies. The diagnosis of hantavirus infections is discussed in detail elsewhere. (See "Epidemiology and diagnosis of hantavirus infections".)

The diagnosis of kidney disease in HFRS is based upon the typical clinical and laboratory manifestations (proteinuria, hematuria, elevated serum creatinine), in conjunction with the serological evidence of a recent hantavirus infection. A kidney biopsy is not required, but may be needed if the clinical course of the kidney disease is not typical of HFRS (eg, kidney function usually recovers following clinical recovery) [57,58,99].

Kidney ultrasound may demonstrate an increase in the length of the kidneys and in the resistive indices and perirenal fluid collections (as well as pleural, pericardial, ascitic fluid) [100]. These findings are nonspecific but correlate with the severity of kidney failure and volume overload.

The differential diagnosis includes other infections associated with acute kidney injury (AKI), such as leptospirosis, and noninfectious acute interstitial nephritis caused by drugs (eg, nonsteroidal antiinflammatory drugs [NSAIDs]). Other noninfectious etiologies include diseases associated with pulmonary hemorrhage, such as granulomatosis with polyangiitis and Goodpasture syndrome. (See appropriate topic reviews.)

PREVENTION AND TREATMENT — Since the vector is the rodent, the risk of infection may be minimized by avoiding areas where rodents live in large numbers and by preventing rodent inhabitation near homes and work areas. The risk of transmission is obviously greater indoors (houses, cabins, barns), where rodents may be seeking food or shelter from the cold. (See "Hantavirus cardiopulmonary syndrome", section on 'Prevention'.)

Smoking is a risk factor for Puumala virus infection [14,15,101,102]. In addition, current smokers suffer from more severe acute kidney injury (AKI) than nonsmokers, and smoking cessation decreases the risk of severe AKI to the same level as in never smokers or ex-smokers [103,104].

A vaccine has been developed in Korea, but it is uncertain whether it would be protective: Although high immunoglobulin G (IgG) titers developed in nearly 100 percent of volunteers after a course of three vaccines, titers declined rapidly [12]. Other vaccines are under development. (See "Hantavirus cardiopulmonary syndrome", section on 'Vaccine development'.)

There are no specific antiviral therapies for hantavirus. Although one prospective, double-blinded study of 242 patients with serologically proven infection found that intravenous ribavirin therapy resulted in a reduction in mortality, other studies did not confirm these benefits [105]. (See "Hantavirus cardiopulmonary syndrome", section on 'Antiviral therapy'.)

In a randomized study, high-dose intravenous methylprednisolone did not provide clinical benefit in the treatment of hantavirus cardiopulmonary syndrome (HCPS) [106].

Therapy is therefore restricted to supportive care. Headache and backache may require analgesics, but nonsteroidal antiinflammatory drugs (NSAIDS) should be avoided. Ibuprofen and diclofenac may be associated with more severe AKI in patients with hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus [107].

Thrombocytopenia may require platelet transfusion, and corticosteroids have been tried in a case of protracted thrombocytopenia associated with HFRS [108]. Dialysis should be provided for the usual indications. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)

Many patients fully recover if there is adequate supportive care (which can require the intensive care unit and dialysis) for often life-threatening complications. Patients with AKI, even if dialysis requiring, usually recover if they survive the initial severe illness.

There is an increasing demand to develop therapy for the deadly hantavirus infections, including both HFRS and HCPS. Drugs that are known to influence increased capillary permeability (for example, those that inhibit VEGFR2, SRC family kinases, angiopoietin 1, and sphingosine 1-phosphate) are in clinical trials for other indications and could be potentially be used to treat patients with severe hantavirus infections [8].

Two patients with extremely severe Puumala virus infection were successfully treated with icatibant, a drug licensed for treatment of acute hereditary angioedema [23,109,110]. Icatibant acts as a selective antagonist of the bradykinin type 2 receptor, reverses increased vascular permeability, and inhibits vasodilatation [111].

PROGNOSIS — Most patients generally return to baseline glomerular filtration rate (GFR) following an episode of acute kidney injury (AKI) related to hantavirus infection [1,6,10,96]. However, there are case reports of residual decreased GFR [12,112,113] and of a possible association with subsequent hypertension [10,114-117].

Long-term sequelae were perhaps best illustrated in observational studies 5, 6, and 10 years after Puumala virus-induced nephropathy (data on other viruses are more limited). At five to six years, affected patients had a higher GFR, more glomerular and tubular proteinuria, hematuria, and higher blood pressure compared with healthy controls [9,80,118]; however, hyperfiltration and proteinuria resolved by 10 years [10]. The severity of acute Puumala virus infection does not predict the long-term outcome of patients [119]. Contrary to the worldwide, well-accepted Kidney Disease: Improving Global Outcomes (KDIGO) criteria, even severe AKI in Puumala virus infection has a good prognosis, both in the short and long term [93]. In a German study, a large proportion of patients had traces of blood in the urine after the acute phase of Puumala virus infection, possibly reflecting persisting damage to glomerular cells [80].

There may be a higher incidence of lymphoma among patients who have recovered from hemorrhagic fever with renal syndrome (HFRS). Among 6582 individuals with Puumala virus-associated HFRS who were reported to the Public Health Agency in Sweden between 1997 and 2011, the risk of lymphoma was increased compared with the general population (sex-standardized incidence ratio 1.73, 95% CI 1.13-2.54) [120]. The overall risk of developing cancer was not increased. The lymphatic system is commonly affected in Puumala virus infection as practically all patients have an enlarged spleen at the acute phase of the disease [121].

There may also be an increased risk of cardiovascular diseases [122] and hormonal deficiencies [123] associated with Puumala virus-induced HFRS.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY

●Kidney manifestations vary depending on the type of hantavirus infection, being more severe with Hantaan and Dobrava virus infection and milder with Puumala virus infection. Sin Nombre virus and related hantaviruses in the Americas cause hantavirus cardiopulmonary syndrome (HCPS), although severe disease may lead to acute kidney injury (AKI). (See "Epidemiology and diagnosis of hantavirus infections" and "Hantavirus cardiopulmonary syndrome".)

●Hantavirus infection is acquired by inhalation of aerosolized virus containing particles or other contact with urine, secretions, or feces of infected rodents (eg, mice, voles, shrews, and rats, depending on the hantavirus genus). (See 'Epidemiology' above.)

●Increased vascular permeability appears to play a general role in the pathogenesis of severe hantavirus infection. An abrupt decline in glomerular filtration rate (GFR) is thought to be related in part to damage to the vascular endothelium and cytokine-induced glomerular, tubular, and interstitial damage. (See 'Pathogenesis of kidney disease' above.)

●The virus can be demonstrated by polymerase chain reaction (PCR) in kidney biopsy material. The most prominent kidney histopathologic finding of hantavirus infection is an acute tubulointerstitial nephritis, sometimes with interstitial hemorrhage. (See 'Pathology' above.)

●Patients with severe, classic hemorrhagic fever with renal syndrome (HFRS) progress sequentially from fever with hemorrhage to hypotension and even shock followed by oliguric AKI. The clinical course, however, can be extremely variable, and some infected patients are asymptomatic. Kidney manifestations include proteinuria, hematuria, and reduced GFR. (See 'Phases of disease' above.)

●The diagnosis is based upon a history of potential exposure to rodents and laboratory findings suggestive of the diagnosis (leukocytosis, thrombocytopenia, elevated serum creatinine level, proteinuria, and hematuria) and is confirmed with serologic testing. (See 'Diagnosis' above and "Epidemiology and diagnosis of hantavirus infections".)

●There are no specific antiviral therapies for hantavirus infection; thus, therapy is restricted to supportive care. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided as they can contribute to AKI. (See "NSAIDs: Acute kidney injury".)

●Dialysis should be provided for the appropriate indications. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)

●Patients who survive typically recover kidney function. Some patients may have persistent proteinuria and hypertension. (See 'Prognosis' above.)