Introduction

Influenza is an acute respiratory disease of global importance that has caused epidemics and pandemics of human disease [24]. Although most influenza infections are self-limited, infants, young children, elderly adults, and people with underlying pulmonary and cardiac diseases are at increased risk for hospitalization for illnesses attributable to influenza, and some die from their complications [24, 41]. Various complications of seasonal influenza virus infection have been reported in the pulmonary, neurological, cardiac, and muscular systems [24, 73].

Renal complications of seasonal influenza A virus are uncommon and have been reported primarily as single cases or small series of patients, which include rhabdomyolysis [2, 4, 14, 25, 27, 32, 35, 40, 52, 70, 78, 79, 87, 96, 98, 99, 105], hemolytic uremic syndrome (HUS) [5, 26, 68, 97], disseminated intravascular coagulation (DIC) [26, 78, 102], acute renal failure (ARF) in critically ill patients [60, 78, 100, 101], and Goodpasture’s syndrome [37, 103] (Table 1).

Table 1 Renal complications of influenza A virus infections
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Human infection of a novel influenza A (H1N1) virus of swine origin was first reported in Mexico during the spring of 2009 [31, 67]. Thereafter, the pandemic influenza A (H1N1) 2009 virus (A(H1N1)pdm09) spread rapidly and globally, resulting in the worldwide influenza pandemic [86, 104]. The clinical manifestations of A(H1N1)pdm09 and seasonal influenza are similar, and most illnesses associated with A(H1N1)pdm09 are mild with an overall case fatality rate of ≤0.5 % [86, 104]. However, in contrast to seasonal influenza, most of the serious illnesses caused by A(H1N1)pdm09 have occurred among children and non-elderly adults [104].

The complications of A(H1N1)pdm09 are similar to the complications of the seasonal influenza A virus, and include an exacerbation of underlying chronic illnesses, respiratory tract, neurologic, cardiac, and musculoskeletal complications, and secondary bacterial infections [74, 86]. Unlike seasonal influenza A infections, renal complications of A(H1N1)pdm09 have been increasingly reported, and include acute kidney injury (AKI) in critically ill patients, rhabdomyolysis, HUS, acute postinfectious glomerulonephritis (AGN), DIC, and acute tubulointerstitial nephritis (TIN) (Table 1).

Herein, we review the renal complications of influenza A virus infections, especially of A(H1N1)pdm09 infections, as have been described to date.

AKI in critically ill patients

AKI is the new consensus term for ARF [80] and has replaced ARF to emphasize that a continuum of kidney injury exists that begins long before sufficient loss of excretory kidney function can be measured with standard laboratory tests [10]. The Acute Dialysis Quality Initiative proposed the risk, injury, failure, loss, and end-stage (RIFLE) criteria as a definition for AKI [12]. The AKI network subsequently proposed the AKIN criteria with some minor modifications to the RIFLE criteria [57]. Both definitions have now been validated in thousands of patients and seemed to be similar [10].

AKI has emerged as a major public health problem and is common in critically ill patients [10, 80]. The occurrence of AKI is ≥36 % on the day after admission to an intensive care unit (ICU) [8], and the prevalence is ≥60 % during the ICU admission [39]. Moreover, critically ill patients with AKI incur an increased risk of hospital mortality [39].

AKI and ARF have rarely been reported in patients with seasonal influenza A virus infections as single case reports [60, 78, 101]. Watanabe et al. studied 45 hospitalized children with seasonal influenza A virus infection and reported that 24.4 % of the patients had renal involvement, of which 11 % exhibited ARF; all of the patients with renal involvement had sepsis and multiple organ dysfunction syndrome (MODS) [100].

AKI occurs in approximately one third of all hospitalized patients with A(H1N1)pdm09 [17, 28, 67]. Perez-Padilla et al. studied hospitalized patients with A(H1N1)pdm09 pneumonia in Mexico and reported that 6 of 18 patients developed AKI, and 5 patients died [67]. Demirjian et al. reported that 37 of 89 adult patients hospitalized with A (H1N1) pdm09 in the USA developed AKI; the majority of the patients were critically ill; 12 of 89 patients required renal replacement therapy (RRT); and 24 % of the patients with AKI died [28]. Brien et al. reported that 11 of 34 patients hospitalized with A(H1N1)pmd09 in Ireland developed AKI; 4 of 34 patients required RRT; and the most common cause of AKI was sepsis with acute tubular necrosis (ATN) [17].

AKI has been reported to occur in 7–66.7 % of critically ill patients with A(H1N1)pdm09 [1, 11, 21, 43, 47, 48, 54, 62, 69, 84, 90, 91, 95]. This diversity in the incidence of AKI results from different severities of infections and/or distinct definitions in AKI among studies. In patients with A(H1N1)pdm09 who are admitted to the ICU for mechanical ventilator support, the incidence of AKI, as defined by RIFLE or AKIN criteria, is 51–66.7 % [47, 62, 84]. Of the critically ill patients with A(H1N1)pdm09 and AKI, 15.6–51.6 % required RRT [1, 11, 21, 43, 47, 54, 62, 69, 90, 91]. The mortality rate of patients with A(H1N1)pdm09 and AKI is 25–92.3 % [1, 11, 21, 43, 47, 54, 62, 69, 90, 91], and AKI is associated with an increase in mortality [1, 28, 43, 54, 62, 69, 90, 91]. These clinical characteristics of AKI in critically ill patients with A(H1N1)pdm09 virus infections are similar to the characteristics of AKI in critically ill patients without A(H1N1)pdm09 infections [8, 39].

Underlying conditions, organ dysfunctions, and laboratory data have been reported as the risk factors for AKI (Table 2). Underlying conditions associated with AKI included older age [43, 84], diabetes mellitus [28, 69], obesity or elevated body mass index [28, 84], pregnancy [90], a history of asthma [84], and chronic kidney disease (CKD) [28, 43, 69]. Patients with organ dysfunction and AKI had the following characteristics: required ventilator support or had respiratory dysfunction [1, 54, 62, 69]; used vasopressor or had cardiovascular dysfunction [1, 69, 90]; had hematological dysfunction [28, 62, 90]; and had high Acute Physiology and Chronic Health Evaluation II [1, 54, 62, 84], Sequential Organ Failure Assessment [43, 54, 90], and Murray scores [90]. Patients with elevated creatine kinase (CK) levels [28, 69], severe acidosis, elevated C-reactive protein concentrations, or lactate dehydrogenase levels [1] were more likely to develop AKI.

Table 2 Risk factors for acute kidney injury in critically ill patients with A(H1N1)pdm09
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The precise pathogenic mechanisms underlying the development of AKI in patients with influenza A remain unclear; however, the following hypotheses have been postulated: ATN due to renal hypoperfusion or rhabdomyolysis, DIC, and direct viral injury to the kidney (although not proven) [84, 90, 99]. Based on histologic studies, Soto-Abraham et al. reported that one of five patients who died of A(H1N1)pdm09 had ATN [85]. Mauad et al. analyzed the autopsy findings of 21 patients who died of A(H1N1)pdm09 and showed that all patients exhibited mild-to-moderate forms of ATN; myoglobin pigment in the tubules existed in four patients and thrombotic angiopathy existed in another patient [55]. Bal et al. reported two patients with ATN and another patient with pathologic findings in the kidney consistent with DIC among nine patients who died of A(H1N1)pdm09 [9]. Nin et al. studied renal biopsies of four patients who died of A(H1N1)pdm09 and showed that two patients exhibited ATN with an increase in immunoreactivity for A(H1N1)pdm09 viral nucleoprotein in the distal tubules and in Bowman’s capsule epithelia [61]. Carmona et al. examined the autopsy specimens of five patients who died of A(H1N1)pdm09 and showed the following: ATN was present in all of the patients; there was no evidence of direct virus-induced kidney injury; and A(H1N1)pdm09 were in the cytoplasma of glomerular macrophages in the kidneys of four patients [20]. These studies indicate that ATN frequently occurs in patients who die of A(H1N1)pdm09, myoglobin pigments and glomerular microthrombosis due to DIC are present in some patients, and A(H1N1)pdm09 is present in the kidneys of some patients, although there is no evidence of direct viral injury to the kidney.

Rhabdomyolysis

Rhabdomyolysis is a potentially life-threatening syndrome characterized by the leak of muscle contents, including electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation [16, 46]. AKI is a potential complication of severe rhabdomyolysis, regardless of etiology, that develops in 33 % of patients [16, 46].

There are multiple potential causes of rhabdomyolysis, which are divided into the following eight categories: trauma, exertion, muscle hypoxia, genetic defects, body-temperature changes, metabolic and electrolyte disorders, drugs and toxins, and infections [16]. Viral infections as a cause of rhabdomyolysis have been described in a number of reports worldwide, of which influenza A and B viruses are the most common [46]. Although the pathogenesis underlying the development of rhabdomyolysis in influenza A virus infection has not been completely determined, it is presumed that direct viral invasion, viral toxins, or cytokines may induce myonecrosis causing rhabdomyolysis [46, 81].

Rhabdomyolysis in seasonal influenza A infection has been reported in 31 patients [2, 4, 14, 23, 25, 27, 29, 32, 33, 35, 40, 52, 58, 59, 70, 78, 79, 81, 87, 96, 98, 99, 105]. The clinical characteristics of the 31 patients included a relatively young age (median age, 28 years; range, 3–83 years), male predominance (18 of 31), and frequent occurrence of muscle symptoms (muscle pain, 24 of 31; muscle weakness, 18 of 31). Peak concentrations of CK ranged from 1,263 to 1,150,000 U/l (mean, 103,412 U/l). ARF occurred in 24 patients (77.4 %), and 21 patients with ARF underwent RRT. Although most patients recovered completely without any sequelae, three patients died secondary to MODS [25, 81, 105] and one patient with diabetes mellitus developed CKD [81]. Muscle biopsies showed a focal necrosis of muscle fibers without inflammation [4, 29, 58, 105] or degeneration of muscle fibers with an infiltration of inflammatory cells [4, 33, 40, 87]. These results suggest that rhabdomyolysis in patients with influenza A infections might result from muscle necrosis due to cytokines or viral myositis.

Although the true incidence of rhabdomyolysis in A(H1N1)pdm09 infections is unknown, a recent report showed that CK levels were elevated in 13.9 % of hospitalized patients with A(H1N1)pdm09 infections [19]. Another report demonstrated mild to moderate elevation of CK levels in 62 % of patients with A(H1N1)pdm09 pneumonia and respiratory failure [67]. Eleven patients with A(H1N1)pmd09 infections have been reported to develop rhabdomyolysis, and their clinical characteristics were similar to the patients with seasonal influenza A [7, 22, 30, 38, 50, 65, 75, 82, 88, 93]. The median age was 28 years (range, 8–59 years) and 6 of the 11 patients were males. The peak concentrations of CK were 1,371–1,127,000 U/l (mean, 206,355 U/l). AKI occurred in seven patients (63.6 %), and five patients with AKI underwent RRT. Nine patients recovered, but two patients died secondary to MODS [88, 93].

HUS

HUS is a disease characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment [64, 94]. Microvascular injury with endothelial cell damage is a pathologic characteristic of all forms of HUS [94]. The various etiologies of HUS allow classification into infection induced (Shiga- and verotoxin-producing bacteria, neuraminidase-producing Streptococcus pneumoniae, and human immunodeficiency virus), genetic (complement dysregulation and defective cobalamine metabolism), medication induced (calcineurin inhibitors, cytotoxic, chemotherapy agents, and quinine), and HUS associated with systemic diseases characterized by microvascular injury [15, 94]. The most common form of HUS is caused by verotoxin-producing Escherichia coli that cause prodromal acute enteritis and is termed diarrhea associated, typical HUS [64, 94].

Approximately 10 % of cases of HUS are classified as atypical when not caused by verotoxin-producing bacteria [63]. The primary causes of atypical HUS are defects in the regulation of the alternative complement pathway on vascular endothelial cells, including complement factor H (CFH), factor I, factor B, thrombomodulin, C3, membrane cofactor protein (MCP), and autoantibodies against factor H with or without CFH-related protein 1 and 3 deficiency [15].

HUS associated with seasonal influenza A virus is extremely rare; only four patients have been reported [5, 26, 68, 97], in whom two were postrenal transplant patients. Peterson and Olsen reported a 20-year-old female with posttransplant HUS related to influenza A virus infection [68]. The patient did not take calcineurin inhibitors, and refractory thrombocytopenia and hemolysis of the patient promptly subsided after removal of the graft kidney. Asaka et al. also described a 35-year-old male with posttransplant HUS following influenza A infection [5]. The patient recovered from HUS, despite continuing cyclosporine treatment without a dose reduction. Davison et al. reported a previously healthy, 14-year-old girl with HUS following influenza A infection [26]. The patient recovered from HUS with hemodialysis therapy alone. Watanabe reported a previously healthy, 3-year-old girl who presented HUS following influenza A infection. The girl had significant elevations in serum tumor necrosis factor-α and soluble interleukin-2 receptor levels [97].

HUS associated with A(H1N1)pdm09 has been reported in eight patients [3, 13, 18, 36, 51, 71, 72, 89] and can be classified into three categories: S. pneumoniae-associated HUS following A(H1N1)pdm09 infection; HUS triggered by A(H1N1)pdm09 in patients with genetic complement dysregulation; and HUS associated with A(H1N1)pdm09 without any known underlying disorders.

Lei et al. reported a 3-year-old girl with S. pneumoniae-associated HUS following A(H1N1)pdm09 infection in whom the erythrocyte cryptic Thomsen–Friedenreich (TF) antigen activation was positive [51]. S. pneumoniae is well-known as a causative pathogen of secondary bacterial pneumonia following influenza virus infection [51, 56]. Influenza virus alters the lungs of the host in a way that predisposes to adherence, invasion, and induction of disease by pneumococcus [56]. Access to receptors is a key factor and may be facilitated by the virus through epithelial damage, exposure or upregulation of existing receptors, or provoking damage. Alteration of the immune response by diminishing the ability of the host to clear pneumococcus or amplification of the inflammatory cascade likely contributes to the severity of the resulting infection [56]. Therefore, co-infection of S. pneumoniae should be sought in patients with HUS following influenza A virus infection.

Atypical HUS associated with complement dysregulation following A(H1N1)pdm09 has been reported in three patients. Bento et al. reported atypical HUS triggered by A(H1N1)pdm09 in a 17-year-old boy with a mutation in the gene (CD46) encoding MCP [13]. Rhee et al. described a 27-year-old male with atypical HUS, diffuse alveolar hemorrhage, and decreased complement factor C3 level following A(H1N1)pdm09 infection [72]. Al-Akash et al. reported recurrent posttransplant HUS triggered by A(H1N1)pdm09 in a 15-year-old male with a C3 gene mutation [3]. In addition, Çaltik et al. reported atypical HUS following A(H1N1) infection in a 15-year-old male with normal C3, CFH, and CHI levels who had experienced recurrent attacks of HUS four times with recovery of renal function [18]. The authors suggested the patient might have a CD46 gene mutation [18].

HUS associated with A(H1N1)pdm09 without any known underlying disorders has been reported in three patients. Printza et al. reported a case of A(H1N1)pdm09 that triggered atypical HUS in a 7-year-old boy with posterior reversible encephalopathy syndrome who had normal immune status findings, including C3, MCP, and ADAMTS-13, and did not have pneumonia [71]. Trachtman et al. described atypical HUS associated with A(H1N1)pdm09 in a 5-year-old girl [89]. Her blood and endotracheal tube cultures were negative for bacteria; the complement system was not studied. Golubovic et al. reported an 11-year-old boy with an A(H1N1)pdm09 virus infection complicated by atypical HUS [36]. The serum C3 and C4 levels were normal, and the blood, sputum, and throat swab cultures for bacteria did not reveal bacterial super-infection. Although the mechanisms of influenza A virus-associated HUS without complement dysregulation or S. pneumoniae co-infection have not been elucidated, an altered immune system such as systemic mononuclear cell activation following influenza A viral infection [5, 97], and unmasking of cryptic TF antigen caused by viral neuraminidase of influenza A [36] have been postulated.

AGN

AGN is an immunologic response of the kidney to infection that is commonly triggered by group A streptococci [45]. The typical clinical features of AGN include acute onset with gross hematuria, edema, hypertension and moderate proteinuria (acute nephritic syndrome) [45]. AGN can be caused by organisms other than group A streptococci including other strains of streptococci (group C and G), Gram-negative bacilli, mycobacteria, and viruses (influenza) [77]. Viruses have been incriminated in the evolution of acute immune complex-mediated glomerulonephritis [77].

Smith et al. prospectively studied 240 previously healthy personnel with non-streptococcal upper respiratory infections to define the incidence and clinicopathologic characteristics of virus-associated glomerulonephritis [83]. Among the 240 personnel, 9 had biopsy-proven, asymptomatic glomerulonephritis and 4 had serologic evidence of infection with seasonal influenza A [83].

AGN associated with A(H1N1)pdm09 has been reported in two publications. Jain et al. reported a 14-year-old boy who developed hypertension with macroscopic hematuria and marked proteinuria following A(H1N1)pdm09 [42]. The boy’s condition improved rapidly, with the exception of persistent microscopic hematuria. Kupferman et al. also described a 5-month-old girl who had generalized edema and hypertension with AKI, hematuria, proteinuria in the nephrotic range, and hypocomplementemia following A(H1N1)pdm09 infection [49]. His condition also improved rapidly. Although neither patient had a renal biopsy, the clinical and laboratory findings were strongly suggestive of AGN.

DIC

DIC is characterized by the widespread activation of tissue factor-dependent coagulation, insufficient control of coagulation by physiologic anticoagulation pathways, and plasminogen activator inhibitor-1-mediated attenuation of fibrinolysis and is most commonly precipitated by sepsis or trauma [34]. Histologic evidence of microvascular thrombosis and tissue injury in DIC has been reported in clinical, experimental, and autopsy findings [34]. DIC has also been associated with glomerular microthrombosis and acute renal failure [34]. Pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1 and interleukin-6) released early in the course of sepsis stimulate a procoagulant state that causes development of intravascular fibrin deposition, which results in DIC and organ dysfunction, including kidney dysfunction [34, 53, 100].

ARF due to DIC has been reported in patients with seasonal influenza A virus infection. Davison et al. reported the necropsy findings of 14-year-old boy with DIC and ARF who died from seasonal influenza A virus infection [26]. The histologic findings of the kidney showed fibrin deposition within glomerular capillaries and denuded endothelial cells nuclei of glomerular capillaries. Shenouda and Hatch reported a case of a 33-year-old female with DIC and ARF who died from influenza A viral pneumonia [78]. Whitaker et al. described six patients who developed ARF and DIC following seasonal influenza A virus infection [102]. Watanabe et al. studied 45 children hospitalized with seasonal influenza A virus infection and reported that five patients developed ARF, four of whom had DIC [100]. Bal et al. found DIC pathologic findings in the kidneys of a deceased 25-year-old pregnant woman who had A(H1N1)pdm09 [9].

Goodpasture’s syndrome

Goodpasture’s syndrome is an autoimmune disease that is frequently characterized by rapidly progressive glomerulonephritis, occasional pulmonary hemorrhage, and the presence of autoantibodies to the glomerular and alveolar basement membranes [44]. The target antigen is the α3NC1 domain of type IV collagen, which is expressed in target organs as an α345 network [66].

Influenza virus infection has been associated with Goodpasture’s syndrome. In 1919, Goodpasture described an 18-year-old male who died of pulmonary hemorrhage and a proliferative glomerulonephritis 6 weeks after influenza virus infection [37]; however, this patient with pulmonary-renal vasculitis syndrome likely had anti-neutrophil cytoplasmic antibody disease rather than true Goodpasture’s syndrome because there was a necrotizing small vessel vasculitis in the spleen and gut, which are unlikely in a case of Goodpasture’s syndrome [76]. Wilson et al. reported that a 43-year-old female developed pulmonary hemorrhage and a proliferative glomerulonephritis following influenza A virus infection [103]. The proliferative glomerular lesion of the patient contained immunofluorescent deposits of immunoglobulin G and complement in a linear pattern along the glomerular basement membrane [103].

Acute TIN

Acute TIN is a frequent cause of ARF and is characterized by the presence of an inflammatory call infiltrate in the interstitium of the kidney [92]. Although immune-allergic reactions to certain drugs are the most frequent etiology for acute TIN, viral infections are known to induce TIN [92]. Some viruses have been reported to cause TIN, including cytomegalovirus, hepatitis virus, human immunodeficiency virus, Epstein–Barr virus, and hantavirus [92]; however, acute TIN associated with influenza A virus infection has never been reported.

Ashtiani et al. recently described a case of acute TIN and incomplete renal Fanconi syndrome in a 4-year-old boy with A(H1N1)pdm09 infection who made a full recovery with supportive therapy alone [6]. The pathogenesis underlying the development of TIN in patients with virus infection is unknown; however, infection-related acute TIN usually leads to a sterile infiltrate, suggesting that immunologic disturbances might be responsible for TIN [6].

Conclusions

Renal complications of influenza A virus infection are uncommon but can lead to deterioration of the patient’s condition, including AKI in critically ill patients, rhabdomyolysis, HUS, AGN, DIC, Goodpasture’s syndrome, and acute TIN. Although the pathogenesis of renal injuries due to influenza A virus is incompletely described, some hypotheses have been postulated, including ATN due to renal hypoperfusion or rhabdomyolysis, glomerular microthrombosis due to DIC, direct viral injury to the kidney, and an altered immune system, such as systemic mononuclear cell activation following influenza A virus infection.