Acute kidney injury (AKI) and failure can be found in association with swine-associated influenza A (H1N1) virus contributing to increased morbidity and mortality. We present three cases of H1N1 infection with AKI, the first in the background of renal amyloidosis, the second in a kidney transplant recipient, and the third in a patient who presented with renal failure following upper respiratory tract infection. Renal biopsy in all of them revealed mesangial prominence with tubulointerstitial nephritis. All of them recovered following conservative management. H1N1 infection is known to be associated with dismal prognosis and kidney involvement is mainly in the tubulointerstitial compartment. Contrary to the reported literature mentioning poor prognosis, all three patients in our study recovered fully.
Keywords: Acute kidney injury (AKI), H1N1 infection, mesangial prominence, tubulointerstitial
|How to cite this article:
Nigam LS, Vanikar AV, Patel R, Trivedi HL. Spectrum of histopathological findings in patients with acute kidney injury following H1N1 influenza infection: A study of three cases. Ann Trop Med Public Health 2015;8:296-9
|How to cite this URL:
Nigam LS, Vanikar AV, Patel R, Trivedi HL. Spectrum of histopathological findings in patients with acute kidney injury following H1N1 influenza infection: A study of three cases. Ann Trop Med Public Health [serial online] 2015 [cited 2020 Sep 23];8:296-9. Available from: https://www.atmph.org/text.asp?2015/8/6/296/162614
Influenza viruses are members of the Orthomyxoviridae family and continue to cause problems globally in humans and their livestock, particularly pigs and poultry representing a continuous pandemic threat.  Influenza A viruses are subtyped on the basis of surface hemagglutinin (H) and neuraminidase (N) antigens. Individual strains are designated according to the site of origin, isolate number, year of isolation, and subtype.  The pandemic strain represents a quadruple resortment of two swine strains, one human strain, and one avian strain of influenza. Swine influenza virus was first isolated from pigs in 1930 in the US and has been recognized by pork producers and veterinarians to cause infections in pigs worldwide. Direct transmission of a swine flu virus from pigs to humans is occasionally possible. 
The clinical spectrum caused by pandemic H1N1 is similar to seasonal influenza ranging from mild influenza-like sickness to multiorgan failure. Acute lung injury is the commonest manifestation of H1N1 influenza. Renal involvement has also been observed in a good number of patients. A study reports that acute kidney injury (AKI)/acute renal failure (ARF) and the need for dialysis occurred in 66.7%, 66%, and 11% of H1N1 infected patients, respectively. 
Viruses have been implicated as an etiological agent in the development of AKI. AKI secondary to viral infections has several histomorphologic features ranging from glomerular/tubulointerstitial nephritis to acute tubular necrosis (ATN) and vasculitis. 
Kidneys can be involved secondary to rhabdomyolysis caused by influenza viruses producing AKI.  Viruses can have a direct cytopathic effect on epithelial/tubular cells. The commonest cause of AKI was sepsis with ATN reported by O Brien et al. in a retrospective study on 34 patients diagnosed with H1N1 by reverse transcriptase.  Kidney involvement can also result from deposition or in situ formation of immune complexes containing viral antigens causing glomerular injury as in the case of human immunodeficiency virus (HIV) immune complex glomerulonephritis or hepatitis B-associated membranous nephropathy. In cases of viral hemorrhagic fever, AKI is generally caused by fulminant organ failure with different histopathologic features ranging from ATN to acute tubulointerstitial nephritis (ATIN). Indirectly, kidneys can be involved as a consequence of multiorgan failure, hepatorenal syndrome, or as a result of treatment. 
Solid organ transplant recipients are at higher risk of infection and disease due to depression of both cellular and humoral immune responses. On the other hand, there is evidence showing that more severe disease and increased mortality in the pandemic H1N1 season were associated with an increased inflammatory response, with interleukin (IL)-15, IL-12, IL-8, and IL-6 levels being particularly elevated in severe cases. Solid organ transplant recipients are immune-compromised hosts due to the use of drugs that not only impair immune responses to prevent rejection episodes but also impair inflammatory responses. 
The most common histological finding according to postmortem studies conducted on H1N1 influenza patients was ATN with no signs of glomerular lesions. Similar results have also been reported in data collected in living patients with acute respiratory distress syndrome (ARDS) due to H1N1 infection. ,
The localization of viral particles by immunohistochemical analysis identified influenza A (H1N1) viral nucleoprotein antigens in cytoplasm of glomerular macrophages. Therefore, H1N1 present in kidneys is an evidence of circulating virus rather than direct infection of kidney cells. 
We report three cases of severe H1N1 infection, diagnosed by reverse transcriptase polymerase chain reaction, which became oliguric requiring renal replacement therapy. One of the patients was a renal allograft recipient who presented with AKI.
A 52-year-old female was admitted in the intensive care unit (ICU) with history of oliguria and past history of H1N1 pneumonia 1 month back. There was no evidence of bacterial infection or any drug history at the time of admission. Urine examination revealed +1 albumin and occasional pus cells. Her serum creatinine (SCr) was 7.35 mg/dL on admission. Hematological findings revealed mild anemia and other biochemical and radiological investigations were within normal reference range. She was diagnosed with AKI and a renal biopsy was performed; light microscopy on a 3μ-thick section was evaluated after subjecting to hematoxylin and eosin (H&E;), Gömöri’s trichrome, periodic acid-Schiff (PAS), and Jones’ methanamine silver staining. Immunofluorescence staining using antihuman immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin G (IgM), and C3 and C1q antisera (DAKO, North America, Carpenteria, CA 93013, USA) was also performed.
Two cores of renal tissue revealed 11 glomeruli showing uniform mild mesangial prominence [Figure 1]. The tubules showed mild to moderate injury and the interstitium revealed uniform edema with diffuse lymphoplasmacytic infiltration with few admixed neutrophils. The blood vessels were unremarkable. Immunofluorescence was negative for all the markers. A histological diagnosis of idiopathic mesangial proliferative glomerulonephritis (MePGN) with ATIN associated with H1N1 pneumonia was offered. The patient was managed conservatively. Over a follow-up of 4.5 months, she was clinically stable with SCr of 0.91 mg/dL.
|Figure 1: Case 1: Hematoxylin and eosin (H&E;), ×400 — Glomerulus showing mild mesangial prominence, marked tubular injury, and edema with marked mononuclear cellular infi ltration in the interstitium
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A 53-year-old female who was a known case of secondary renal amyloidosis (to tuberculosis) presented with rise in SCr at 5.9 mg/dL and blood urea of 63 mg/dL following upper respiratory tract infection with fever. She was diagnosed as H1N1 positive pneumonia. Urine examination revealed +2 albumin and occasional pus cells on microscopy. Hematological investigations revealed total leucocyte count of 13.2 × 10 3 /μL.
Renal biopsy was performed. A single core biopsy revealed ten glomeruli, all of which showed segmental widening of the mesangial regions with deposition of PAS positive pale pink and Congo red positive material with apple-green birefringence on polarizer, staining positive with amyloid A by immunohistochemistry [Figure 2]. The interstitium showed mild edema with mixed leukocytic infiltration. All arteries showed moderate fibrointimal proliferation with birefringent amyloid fibrils. Diagnosis of secondary renal amyloidosis with ATIN associated with H1N1 pneumonia was offered. The patient was managed conservatively. SCr dropped to 2.98 mg/dL from 5.12 mg/dL and the patient has been on regular follow-up since 7 months.
|Figure 2: Case 2: H&E;, ×200 — Glomerulus showing pale pink amyloid deposits, moderate tubular injury, and mononuclear infl ammatory infiltrate in the interstitium. INSET: Glomeruli showing amyloid deposit, Stain AA positive
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A 37-year-old male who underwent renal transplantation for obstructive uropathy induced chronic kidney disease (CKD) 5 years back, presented with a rise in SCr of 4.5 mg/dL following an episode of H1N1 pneumonia. The hematological and other biochemical investigations were within normal limits. Renal biopsy was performed that revealed two cores of renal tissue with 40 glomeruli. All the glomeruli showed mild mesangial prominence with mild leukocytic infiltration [Figure 3]a and b. Bowman’s capsules showed segmental thickening. Tubules showed focal atrophy and the interstitium showed diffuse infiltration with mononuclear cells. Sixty percent of peritubular capilaries revealed positivity on C4d staining by immunohistochemistry. The features were consistent with the diagnosis of chronic active T + B cell-mediated rejection. He was antirejected with methylprednisolone 250 mg/day for 3 days. On subsequent follow-up after 1 month, SCr reduced to 2.07 mg/ dL; however, he eventually developed chronic graft dysfunction with SCr of 5 mg/dL and has now been enrolled on the waiting list of deceased donor organ transplantation.
|Figure 3: (a) Case 3: PAS, ×200 — Glomeruli showing glomerular basement membrane (GBM) wrinkling, segmental thickening of Bowman’s capsules, tubular atrophy, and mixed cellular infl ammatory infiltrate in the interstitium (b) Case 3: H&E;, ×400 — Glomerulus showing moderate mesangial matrix accentuation with mild hypercellularity and mild leukocytic infi ltration. The interstitium shows heavy mixed cellular infi ltrate and fi brosis
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AKI is a frequent complication of 2009 influenza A (H1N1) viral pneumonia, leading to increased risk of mortality, lengthened ICU and hospital stay, and development of CKD. ,
The pathophysiological mechanism of kidney injury proposed is multifactorial ATN. Hypoperfusion, renal vasoconstriction, and rhabdomyolysis in the setting of a severe systemic inflammatory response with activation of cytokine cascade occur concurrently and in varying degrees. The possible mechanism for kidney injury in H1N1 virus infection appears to be an abnormal expression of cytokine dysregulation associated with severe viral infection induced injury. Increased cytokines together with lymphokines lead to adhesion of inflammatory cells to endothelium and other injury sites. Factors like endothelial dysfunction, intraglomerular thrombosis, and tubular obstruction with necrotic cells and debris have also been attributed in the pathophysiology of AKI. ,
However, the most important factor implicated in renal injury appears to be associated hemodynamic changes: “The Hyperaemic Injury” in kidney is mediated by vasodilatation of afferent and efferent arterioles, accompanied by an increase in renal blood influx but with decreased glomerular capillary pressure and subsequent decrease in filtration with initial normal tubular function. ,
In our cases, patients developed oliguria postH1N1 influenza virus pneumonia. The histological findings corroborating AKI were mild to moderate injury of renal tubular cells with interstitial nephritis. However, glomerular injury/macrophages/xanthogranulomatous changes and endothelial inflammation were not evident in our cases as seen in study by Carmona et al. 
Although majority of the studies show tubules to be involved in both living and postmortem studies, in our case reports we demonstrated tubulointerstitial inflammation in addition, which has not been documented elsewhere. Probably in the third case reported by us, cellular infiltration in the parenchyma could be an indirect effect of H1N1 virus infection in the form of activation of immune repertoire, especially cytotoxic T-cells expediting graft loss. 
In a majority of the studies, the patients were lost; however, all the three patients in our study are alive and on regular follow-up, which emphasizes that early therapeutic intervention significantly improves the prognosis of such patients.
We are thankful to our librarian Jyotsana Suthar for the literature search and submission.
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Conflicts of interest
The authors declared no conflict of interest with respect to the authorship and/or publication of this article.
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Source of Support: None, Conflict of Interest: None
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