INTRODUCTION

Hantavirus infection occupies a distinctive position in clinical nephrology. Whereas acute kidney injury (AKI) in most viral diseases occurs as a downstream consequence of sepsis, systemic hemodynamic compromise, or nephrotoxin exposure, in hemorrhagic fever with renal syndrome (HFRS)—and in nephropathia epidemica (NE), its milder European expression—kidney injury constitutes a defining, central feature of the pathogenesis 1,2. Patients typically present with abrupt onset of fever, flank or abdominal pain, thrombocytopenia, capillary leak, urinary abnormalities, and rapidly deteriorating kidney function. Globally, hantavirus causes an estimated 150,000–200,000 cases of HFRS annually. China and Korea account for the largest documented burden, driven predominantly by Hantaan and Seoul viruses, whereas Puumala virus is responsible for NE across Northern and Central Europe, and Dobrava-Belgrade virus drives more severe disease in the Balkans 3,4,5.

Viral species, geographical distribution, and host factors collectively dictate clinical severity. Hantaan and Dobrava-Belgrade viruses are associated with severe HFRS; Puumala virus with NE; and Seoul virus with a globally distributed, generally milder renal syndrome 2,4,6. For the consulting nephrologist, the diagnosis of HFRS must be translated into phase-specific risk stratification: oliguria, dialysis necessity, bleeding diathesis, electrolyte derangement, and recovery trajectory (Table 1). The differential diagnosis of febrile AKI accompanied by thrombocytopenia and hematuria is broad, encompassing sepsis-associated AKI, leptospirosis, severe fever with thrombocytopenia syndrome, thrombotic microangiopathy, acute glomerulonephritis, systemic vasculitis, and drug-induced acute interstitial nephritis 1,2. Hantavirus infection should be prioritized when a compatible exposure history is present, proteinuria is disproportionate to the initial serum creatinine elevation, thrombocytopenia occurs in the absence of overt disseminated intravascular coagulation, and the clinical course transitions characteristically from oliguria toward polyuria 7. Hantavirus-associated nephropathy is increasingly recognized in core nephrology curricula as a unique infectious cause of AKI requiring tailored diagnostic and management considerations 8.

A foundational nephrology-focused framework was established by Koehler et al. 1. The present narrative review expands upon that work by synthesizing literature published through May 2026, with focused emphasis on integrin receptor tropism, endothelial glycocalyx degradation, interleukin-6 (IL-6) trans-signaling, immune checkpoint dynamics, coagulation monitoring, structured biomarker risk stratification, and long-term renal sequelae. Our primary objective is to provide a comprehensive clinicopathologic model to guide bedside nephrology assessment, renal replacement therapy (RRT) decision-making, and long-term post-discharge follow-up.

Relevant literature was identified through systematic searches of PubMed, Scopus, and Google Scholar utilizing search terms including hantavirus, hemorrhagic fever with renal syndrome, nephropathia epidemica, acute kidney injury, proteinuria, and renal outcomes. Priority was given to clinical cohort studies, renal pathology reports, mechanistic translational studies, and long-term renal outcome evaluations; review articles were cited selectively for context and synthesis. All primary human studies cited were conducted in accordance with the Declaration of Helsinki and received appropriate institutional ethical approvals.

CLINICAL SPECTRUM OF KIDNEY INJURY

The renal presentation in hantavirus infection is often abrupt. In European Puumala virus cohorts, elevated serum creatinine and Kidney Disease: Improving Global Outcomes (KDIGO) stage 2–3 AKI are frequent among hospitalized patients, though mortality and irreversible kidney failure are rare when supportive care is accessible 9,10,11,12. Long-term cohort evaluations reveal a nuanced clinical picture: although most patients achieve complete normalization of serum creatinine, a distinct subset exhibits persistent microscopic hematuria, proteinuria, hypertension, or tubular proteinuria years after the acute illness 13,14,15. Dobrava-Belgrade virus infection induces a significantly more severe AKI phenotype than Puumala virus, characterized by higher rates of anuria and RRT in comparative studies 16,17. In East Asian HFRS caused by Hantaan virus genetic variants, severe AKI develops in approximately one in seven hospitalized cases, accompanied by universal thrombocytopenia and prominent hepatic transaminase elevations that can complicate initial diagnostic triage 18. Seoul virus continues to cause sporadic renal disease via contact with pet or laboratory rats in urban settings, with recent cases from Korea and Germany illustrating the expanding geographic reach of Seoul virus-associated AKI 7,19.

The clinical distinction between Puumala-driven NE and Hantaan-driven HFRS carries direct bedside relevance (Figure 1). European NE cohorts document dialysis requirements ranging from 1% to 15% among hospitalized patients, minimal case fatality (<1%), and near-universal creatinine recovery 9,10,11,12. In contrast, hospitalized patients with Hantaan virus HFRS exhibit a markedly higher risk profile: shock, anuria, severe coagulopathy, and multiorgan failure are substantially more common; RRT is required in approximately 20–40% of severe East Asian cases 4,18; and historical case fatality reached 5–15% in resource-limited settings 4,6. Dobrava-Belgrade virus occupies an intermediate-to-high severity tier in European comparative cohorts, causing more frequent anuria and dialysis dependency than Puumala virus within the same geographic regions 16. These species-specific gradients should directly inform clinical triage: a patient returning from a Hantaan-endemic region in East Asia or the Balkans with febrile AKI and thrombocytopenia has a substantially higher a priori risk of severe oliguria and dialysis than a patient presenting similarly in a Puumala-endemic European setting. Nevertheless, viral species should serve as a prior probability guide rather than a substitute for individualized bedside assessment, given the broad clinical variability within each viral phenotype.

Serum creatinine elevation alone inadequately captures the full spectrum of the syndrome. Staging of AKI must be integrated with serial monitoring of urine output, fluid balance, body weight, blood pressure, oxygenation requirements, and urine chemistry. A patient with a stable serum creatinine plateau but escalating pulmonary edema presents greater immediate clinical risk than one with a rising creatinine whose urine output is recovering 20,21.

Proteinuria warrants meticulous clinical appraisal due to its characteristically dramatic yet transient nature. Studies of acute Puumala virus infection describe a "flash-like" albuminuric surge that frequently precedes peak serum creatinine and rapidly resolves as the polyuric phase commences 22,23. Microscopic hematuria and leukocyturia routinely accompany acute disease (Table 2). Identified host risk factors—including active smoking, lymphopenia, dyspnea at presentation, and an elevated neutrophil-to-lymphocyte ratio—identify patients at elevated risk for a complicated clinical course 24,25,26,27.

A frequent diagnostic pitfall is misinterpreting heavy acute proteinuria as primary nephrotic syndrome; during active hantavirus infection, proteinuria reflects reversible disruption of the glomerular and tubular filtration barriers 1. Persistent proteinuria following the acute phase, active urine sediment that fails to clear, or a progressive decline in estimated glomerular filtration rate (eGFR) should prompt investigation for superimposed or infection-triggered glomerular pathology 9. The clinical course is best interpreted across defined clinical phases (Figure 1), recognizing that fluid balance requirements change rapidly: an edematous, oliguric patient with severe capillary leak and thrombocytopenia requires fundamentally different management than a volume-depleted patient with uncomplicated prerenal azotemia. Hyponatremia, hyperkalemia, and metabolic acidosis during the oliguric phase frequently give way to solute wasting, hypokalemia, and intravascular depletion during the polyuric recovery phase 1,9,11.

RENAL PATHOLOGY AND MECHANISTIC INTERPRETATION

The predominant histopathologic pattern in hantavirus nephropathy is tubulointerstitial injury accompanied by microvascular inflammation, rather than immune-complex glomerulonephritis. Contemporary renal pathology series describe acute tubular injury/necrosis, marked interstitial edema, medullary hemorrhage, and prominent cortical peritubular capillaritis 28. These structural lesions account for the clinical presentation of sudden AKI, impaired tubular concentration ability, and subsequent polyuria during recovery 15,29. In severe cases, microvascular congestion and endothelial activation exacerbate hypoxic tubular stress beyond what would occur from systemic hemodynamic instability alone 28,30.

Glomerular involvement is increasingly supported by translational research (Figure 2). Pathogenic Old World hantaviruses directly infect human glomerular endothelial cells, tubular epithelial cells, and podocytes, leading to the disassembly of intercellular tight junction and adherens junction proteins, including zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) 31. Elevated urinary excretion of nephrin, immunoglobulin G (IgG), and other markers of glomerular filtration barrier breakdown are detectable during severe acute disease 32. Furthermore, biopsy-confirmed reports demonstrating podocyte foot-process effacement in patients with massive proteinuria provide ultrastructural confirmation of a reversible viral glomerulopathy 33. Hantaviruses replicate within human mesangial cells without inducing immediate cytolysis, reinforcing the concept that functional filtration barrier failure—rather than direct parenchymal cell death—drives the proteinuric phenotype 34. Glycocalyx shedding, tight-junction disassembly, cytokine exposure, and complement activation collectively impair vascular and podocyte permeability in a self-limiting manner that aligns with the rapid onset and clearance of albuminuria seen clinically 35,36,37,38.

A critical molecular determinant of pathogenic hantaviruses is their selective utilization of β3 integrins for cell entry. Pathogenic Old World and New World strains enter endothelial cells and platelets via αvβ3 and αIIbβ3 integrins, whereas non-pathogenic strains (such as Prospect Hill and Tula viruses) utilize β1 integrins (α5β1) 39. This receptor preference is mechanistically crucial: endothelial β3 integrins modulate vascular permeability downstream of vascular endothelial growth factor (VEGF) signaling. Co-option of β3 integrins by pathogenic hantaviruses hyper-sensitizes endothelial cells to VEGF-mediated capillary leak—an effect absent in cells infected by β1 integrin-binding non-pathogenic strains 40. Pathogenic hantaviruses selectively dysregulate β3 integrin-dependent endothelial barrier function without altering β1 integrin pathways, directly linking viral entry receptor choice to the systemic vascular permeability phenotypes of both HFRS and hantavirus cardiopulmonary syndrome 39,40. Furthermore, because αIIbβ3 is the primary fibrinogen receptor on platelets, this integrin tropism links vascular hyperpermeability directly to the thrombocytopenia and platelet dysfunction characteristic of severe HFRS.

Endothelial pathology extends beyond integrin signaling. Elevated levels of urinary heparanase and matrix metalloproteinase-9 (MMP-9)—key enzymes responsible for endothelial glycocalyx degradation—are measurable in HFRS patients and correlate directly with disease severity 35,36. IL-6 trans-signaling mediates proinflammatory cytokine secretion and endothelial barrier breakdown in infected tissues, independently predicting AKI severity and proteinuria magnitude in clinical cohorts 37,41,42. Complement system activation, evidenced by elevated terminal complement complex (SC5b-9) and reduced C3 levels, correlates strongly with disease severity metrics during acute Puumala virus infection 38. Neutrophil activation triggered by infected microvascular endothelial cells—with elevated plasma myeloperoxidase, elastase, and IL-8—amplifies inflammatory tissue damage without requiring widespread viral cytolysis 30. Furthermore, elevated serum concentrations of soluble immune checkpoint molecules (TIM-3, LAG-3, and PD-1) indicate that an exhaustion-like immune state coexists with systemic inflammation, potentially modulating individual clinical trajectories 43.

Biomarkers of hantavirus nephropathy can be stratified into two clinical tiers based on diagnostic readiness. At the established tier, serum/plasma cystatin C and urinary α1-microglobulin reliably detect tubular and filtration impairment prior to peak serum creatinine, while plasma or urinary IL-6 correlates strongly with AKI severity 41,42,44. At the investigational tier, urinary nephrin 27,32, soluble urokinase plasminogen activator receptor (suPAR) 45, plasma thrombomodulin 46,47, coagulation indices (such as fibrinogen and prothrombin time) 48, and soluble immune checkpoint proteins 43 offer mechanistic insight and cohort-level prognostic value, though external validation is required before routine clinical implementation.

MANAGEMENT FROM A NEPHROLOGY PERSPECTIVE

Management of hantavirus-associated AKI remains primarily supportive, but supportive care must be proactive and highly structured (Table 3). Initial clinical evaluation should document exposure history, day of illness, blood pressure trends, body weight changes, urine output, urinalysis with microscopy, serum creatinine trajectory, serum potassium, bicarbonate, sodium, albumin, platelet count, coagulation profile, and evidence of cardiopulmonary involvement. Standard AKI principles—avoidance of nephrotoxic medications, maintenance of renal perfusion, and timely application of RRT—are paramount. However, HFRS introduces two unique management challenges: systemic capillary leak renders intravascular volume status difficult to assess using single static parameters, and profound thrombocytopenia increases the risk of vascular access procedures 20,21.

Early nephrology consultation is most effective prior to crossing the dialysis threshold to determine whether AKI represents an isolated renal insult or part of a systemic capillary leak syndrome, verify that urinary findings align with hantavirus nephropathy, and establish an appropriate monitoring plan 1,2. In healthcare facilities lacking on-site hemodialysis capabilities, patient transfer should be arranged before severe hyperkalemia, refractory pulmonary edema, or progressive coagulopathy render transport hazardous.

A structured monitoring protocol updated at each phase transition should incorporate: urine output recorded hourly in critically ill patients or per shift in stable ward patients; daily serum creatinine, electrolytes (potassium, sodium, bicarbonate, phosphate), and fluid balance; serial blood pressure and body weight measurements; complete blood count and coagulation profile; and serial pulse oximetry accompanied by careful pulmonary examination 20,21. Indications for clinical escalation include KDIGO stage 2 or higher AKI, oliguria (<0.5 mL/kg/h for >6 hours), serum potassium >5.5 mmol/L, serum bicarbonate <18 mmol/L with clinical deterioration, or new pulmonary infiltrates in a fluid-overloaded oliguric patient 20,21.

Fluid administration represents the most delicate bedside decision. Judicious crystalloid resuscitation may be required during the early vascular leak phase to maintain systemic organ perfusion; however, aggressive fluid boluses accelerate pulmonary edema once oliguria and capillary leak predominate 1,2. Dynamic monitoring—including serial oxygenation requirements, chest imaging or point-of-care lung ultrasound, hematocrit trends, and small fluid challenge responsiveness—is substantially more reliable than static volume assessments.

Initiation of RRT should follow standard clinical indications: refractory hyperkalemia, severe metabolic acidosis, medically refractory volume overload/pulmonary edema, uremic complications, or progressive oligoanuria with severe biochemical derangement 20,21. RRT requirement is almost universally temporary among survivors 9,10,12. Coagulopathy and thrombocytopenia necessitate individualized anticoagulation strategies: intermittent hemodialysis without systemic anticoagulation is suitable for hemodynamically stable patients, whereas continuous renal replacement therapy (CRRT) is preferred when shock, severe fluid overload, or high bleeding risk complicates management 1,20,21. Coagulation abnormalities require vigilant parallel monitoring: in a retrospective cohort of 395 HFRS patients, disseminated intravascular coagulation (DIC) was documented in 27.3% of cases, and prolonged prothrombin time, reduced fibrinogen, and elevated serum bilirubin were independent predictors of in-hospital mortality 48. Consequently, coagulation parameters should be routinely integrated into monitoring bundles alongside renal and hematologic tests, particularly in Hantaan or Dobrava-Belgrade virus cases with stage 3 AKI.

Evidence regarding specific antiviral therapy remains limited and species-dependent. A double-blind, placebo-controlled randomized trial of intravenous ribavirin in 242 Chinese patients with Hantaan virus-associated HFRS demonstrated significant reductions in mortality and risk of oliguria when treatment was initiated within seven days of fever onset 49. Conversely, a subsequent randomized trial involving 73 patients with Puumala virus HFRS in Russia showed no significant effect on viral load kinetics, alongside higher rates of adverse events including hemolysis, hyperbilirubinemia, and bradycardia in the ribavirin arm 50. This discrepancy highlights key biological differences: Hantaan virus replicates to significantly higher viremic titers during the early febrile phase than Puumala virus, creating a broader therapeutic window for a nucleoside analogue; differences in patient acuity, sample size, and timing of intervention further preclude direct comparison. Therefore, ribavirin efficacy in Hantaan virus HFRS cannot be extrapolated to Puumala-dominated NE. Currently, no specific antiviral agent is approved for hantavirus treatment by major regulatory authorities 51.

From a pathophysiological standpoint, complement activation in HFRS provides a rationale for complement-targeted therapies (such as eculizumab), familiar to nephrologists from atypical hemolytic uremic syndrome 38; however, clinical trial data in HFRS are lacking. Endothelial barrier-stabilizing agents, including the fibrin-derived peptide FX06 (which preserves VE-cadherin integrity via Fyn kinase-mediated RhoA inhibition), have shown promise in reducing capillary leak in animal models of dengue hemorrhagic fever and endotoxemia 52, but remain unstudied in human HFRS. Bradykinin receptor blockade with icatibant remains speculative based on isolated case reports 53. This review focuses on supportive nephrology management; detailed appraisals of experimental antiviral and immunomodulatory agents are available in specialized infectious disease literature 2,51.

RENAL OUTCOMES AND FOLLOW-UP

The short-term renal prognosis of hantavirus-associated AKI is highly favorable among patients who survive the acute phase. Serum creatinine typically recovers over days to weeks, proteinuria resolves during the polyuric phase, and RRT can almost always be successfully discontinued. The Acute Disease Quality Initiative (ADQI) framework distinguishes acute kidney disease (AKD) from complete recovery, emphasizing the necessity of structured post-episode monitoring 21. In the 556-patient Tampere Puumala virus cohort, KDIGO stage 3 AKI was associated with higher serum creatinine at one month, but no significant difference in median creatinine was observed at one year; after five years, all but one patient had returned to baseline renal function 10.

Long-term outcome studies present a more nuanced perspective. Progression to end-stage kidney disease following a single episode of Puumala virus infection is rare 11,12. However, elevated blood pressure 14, persistent urinary sediment abnormalities 15, subtle tubular protein wasting 17, and circulating endothelial dysfunction markers detectable up to 14 years post-infection have been reported in survivor subsets 54. In a 20-year follow-up cohort of 156 NE survivors, chronic kidney disease (CKD) was identified in 8%, persistent hematuria in 6%, and hypertension in 78%; however, the authors concluded that these rates did not support an increased risk of incident CKD attributable to prior hantavirus infection 12. These observations suggest that prior hantavirus AKI represents a renal risk state warranting structured long-term health surveillance, rather than a cause of progressive nephropathy 21.

Post-AKI follow-up should be risk-stratified. Patients with a history of severe AKI, RRT requirement, prolonged oliguria, persistent proteinuria or hematuria, uncontrolled hypertension, advanced age, diabetes mellitus, pre-existing CKD, or infection with Hantaan or Dobrava-Belgrade viruses should undergo structured nephrology follow-up 11. A practical follow-up schedule includes evaluation at 4–12 weeks post-discharge, followed by repeat assessment at 6–12 months if abnormalities persist. Evaluation should include blood pressure measurement, serum creatinine/eGFR, urine albumin-to-creatinine ratio (UACR), and urine sediment microscopy, with formal nephrology referral indicated for unresolving proteinuria, hematuria accompanied by declining eGFR, or persistent tubular dysfunction 11,15,21. Survivors of New World hantavirus infections who experience documented AKI or proteinuria during their acute illness should also be included in renal follow-up programs, regardless of their primary cardiopulmonary presentation 55.

KNOWLEDGE GAPS AND FUTURE DIRECTIONS

Significant knowledge gaps remain in hantavirus nephropathy. The field lacks prospective, biopsy-correlated longitudinal cohorts that simultaneously evaluate viral species, urine sediment kinetics, novel glomerular and tubular biomarkers, endothelial shed markers, and long-term renal outcomes 28,29. Most mechanistic studies to date are limited by small sample sizes and single-center designs. The most immediate priority is the establishment of integrated nephrology registries to determine whether early measurement of proteinuria 22,23, cystatin C and α1-microglobulin 44, urinary nephrin 27,32, suPAR 45, thrombomodulin 46,47, or IL-6 trans-signaling markers 37,41 improves prediction of RRT requirement and non-recovery beyond standard clinical variables.

Comparative research spanning the full geographic and viral spectrum—including East Asian Hantaan and Seoul viruses, Balkan Dobrava-Belgrade strains, and American New World hantaviruses—is essential. Standardized renal phenotyping across endemic regions will help differentiate universal pathophysiological mechanisms from species-specific features and health-system variables, establishing a necessary foundation for validating novel prognostic biomarkers and targeted therapeutic interventions 1,2.

CONCLUSIONS

Hantavirus-associated kidney injury is a complex, dynamic renal syndrome resulting from the interplay of systemic capillary leak, integrin-mediated endothelial permeability signaling, tubulointerstitial inflammation, tubular epithelial stress, glomerular barrier breakdown, and cytokine-mediated inflammatory amplification. Its clinical signature comprises febrile AKI, severe thrombocytopenia, marked transient proteinuria, hematuria, an oliguric-to-polyuric transition, and generally favorable—though occasionally incomplete—long-term functional recovery. A dedicated nephrology-focused management approach optimizes diagnostic accuracy, ensures safe fluid and electrolyte management, guides RRT timing, and structures long-term post-discharge surveillance. Future clinical research must advance from descriptive biomarker studies toward validated renal risk-prediction models and mechanism-targeted therapeutic trials.

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