|Year : 2013 | Volume
| Issue : 3 | Page : 527-533
|Dialysis for acute kidney injury associated with influenza a (H1N1) infection
Augusto Vallejos1, Marcelo Arias2, Ana Cusumano3, Eduardo Coste4, Miguel Simon5, Ricardo Martinez6, Sandra Mendez7, Miguel Raño8, Luis Sintado9, Bruno Lococo10, Carlos Blanco11, Jorge Cestari12
1 Nephrology and Kidney Transplant Unit, Argerich Hospital, Buenos Aires City; Nephrology Unit, Sanatorio Junín, Junín City, Buenos Aires Province, Argentina
2 Nephrology Unit, Abete Hospital, Malvinas Argentinas District, Buenos Aires Province, Argentina
3 Instituto de Nefrología Pergamino, Pergamino City, Buenos Aires Province, Argentina
4 Nephrology Unit, Alende Hospital, Mar del Plata City, Buenos Aires Province, Argentina
5 Nephrology Unit, Oñativia Hospital, Rafael Calzada District, Buenos Aires Province, Argentina
6 Nephrology Unit, Churruca Visca Hospital, Buenos Aires City, Argentina
7 Ministry of Health, Buenos Aires City, Argentina
8 Nephrology and Kidney Transplant Unit, Argerich Hospital, Buenos Aires City, Argentina
9 Nephrology Unit, Durand Hospital, Buenos Aires City, Argentina
10 Nephrology Unit, Fernandez Hospital, Buenos Aires City, Argentina
11 Nephrology Unit, Naval Hospital, Buenos Aires City, Argentina
12 Nephrology Unit, Austral Hospital, Pilar District, Buenos Aires Province; AKI-SOIV Working Group, Critical Care Nephrology Council, Buenos Aires Nephrology Association, Buenos Aires City, Argentina
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|Date of Web Publication||24-Apr-2013|
| Abstract|| |
In June 2009, the World Health Organization declared a novel influenza A, S-OIV (H1N1), pandemic. We observed 44 consecutive patients during the "first wave" of the pandemic. 70.5% of them showed co-morbidities (hypertension, obesity, chronic respiratory diseases, chronic renal disease, diabetes, pregnancy). Serious cases were admitted to the intensive care unit (ICU), particularly those with severe acute respiratory failure. Some of them developed acute kidney injury (AKI) and required renal replacement therapy (RRT). The average time between admission to the ICU and initiation of RRT was 3.16 ± 2.6 days. At initiation of RRT, most patients required mechanical ventilation. No relationship was found with creatinine-kinase levels. Seventy-five percent of the cases were observed during a 3-week period and mortality, related to respiratory failure, doubling of alanine amino transferase and use of inotropics was 81.8%. In conclusion, the H1N1-infected patients who developed RRT-requiring AKI, in the context of multi-organ failure, showed a high mortality rate. Thus, it is mandatory that elaborate strategies aimed at anticipating potential renal complications associated to future pandemics are implemented.
|How to cite this article:|
Vallejos A, Arias M, Cusumano A, Coste E, Simon M, Martinez R, Mendez S, Raño M, Sintado L, Lococo B, Blanco C, Cestari J. Dialysis for acute kidney injury associated with influenza a (H1N1) infection. Saudi J Kidney Dis Transpl 2013;24:527-33
|How to cite this URL:|
Vallejos A, Arias M, Cusumano A, Coste E, Simon M, Martinez R, Mendez S, Raño M, Sintado L, Lococo B, Blanco C, Cestari J. Dialysis for acute kidney injury associated with influenza a (H1N1) infection. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Oct 20];24:527-33. Available from: http://www.sjkdt.org/text.asp?2013/24/3/527/111045
| Introduction|| |
A novel type-1 hemaglutinine, type-1 neuraminidase, Influenza A virus (H1N1), was identified in April 2009. Significant changes in both the proteins distinguish it from the 2008 strain. This feature explains the lack of immunity among people  and its high person-to-person transmissibility. , The virus is widely disseminated in both hemispheres and, on 10 June 2009, a level-six pandemic alert due to infection with this micro-organism was issued by the World Health Organization (WHO). According to recent estimates, 30% of the population worldwide could get infected with this virus. 
This novel virus of swine origin (S-OIV) manifests clinically as a mild to severe flu or influenza-like febrile upper respiratory tract infection that affects both genders similarly; 80% of the cases comprise patients younger than 30 years. , Therapy with the neuraminidase inhibitors oseltamivir and zanamivir was effective. 
The first cases detected in Argentina were reported from individuals returning to the country from Mexico and Southern United States around the 18 th epidemiological week (EW).  This was immediately followed by new cases of severe adult respiratory distress syndrome (ARDS) and renal failure, mainly reported in Buenos Aires and other surrounding cities with a high demographic density. By 16 June 2009, the local health authority declared the area as one of "extended transmissibility" and shifted the action from the contention to the mitigation phase. A significant increase in the circulation of H1N1 and the non-typified influenza A virus was observed starting from EW 21 (May 24-30). By EW 29 (July 19-25), they roughly represented 95% of the circulating respiratory viruses among adults. This feature forced the decision to administer empiric oseltamivir treatment to all patients presenting with influenza-like illness (ILI).
The peak hospital admission due to severe acute respiratory failure (SARF) was observed around EW 25, reaching 1700 cases.  In an estimated population of 14.1 million people by the metropolitan area and other cities considered in this study, there were 198,440 cases of ILI (1406 per 100,000), 2501 of who were hospitalized and 559 patients were in the intensive care unit (ICU). In this evaluation period, 151 patients died of H1N1 influenza infection. Some of those patients developed acute kidney injury (AKI) and required renal replacement therapy (RRT).
The aim of this study is to report the clinical outcome in patients with H1N1 infection who required acute dialysis during the 2009 pandemic.
| Patients and Methods|| |
Data were retrospectively obtained from a voluntary registry elaborated by the ANBA Critical Care Nephrology Council, sent to public and private health institutions located in the Buenos Aires Metropolitan Area and properly equipped to deal with the pandemic, once the first cases of H1N1-associated AKI were recognized. Data were collected from 24 May 2009 to 8 August 2009 (EW 21 through EW 31). This study was revised by the ethical board of Argerich Hospital, Buenos Aires City. Patient identification remained anonymous and informed consent was waived due to the observational nature of the study.
Patients older than 18 years with ILI, which was confirmed as H1N1 with positive realtime transcriptase reverse protein chain reaction (RT-PCR) test, who developed RRT-requiring AKI, were included. The material for testing was collected by tracheal aspirate or nasopharynx brushing. The RT-PCR tests were carried out in reference laboratories and the microbiologic procedures were performed according to the US Center for Diseases Control and Prevention guidelines.
- Influenza-like illness: Acute febrile respiratory disease (>38°C) with respiratory symptoms including odinophagia, cough and dyspnea.
- SARF: Patients with ILI developing hypoxemia and lung infiltrates.
- Oliguria: Urine output≤15 mL per hour.
- Metropolitan Area of Buenos Aires City. Cities of Mar del Plata, Pergamino and Junín. Malvinas Argentinas, Rafael Calzada and Pilar Districts.
The admission criteria to the ICU and the decision to treat all potentially affected individuals with oseltamivir, as well as the provision of respiratory and hemodynamic support and the determination of the RRT type and dose, had not been defined beforehand. Patients suffering from end-stage renal disease (ESRD) and those without serologic confirmation of H 1N1 infection were excluded from the analysis. The following data were evaluated: Demographic information, dates of hospital and/or ICU admission, date of inclusion for RRT, laboratory results at the time of RRT initiation, clinical status, presence of comorbidities, H 1N1 diagnosis and therapy, and outcome.
| Statistical Analysis|| |
Discrete variables are expressed as counts (percentage) and continuous variables are expressed as mean ± standard deviation (SD) or medians and inter-quartile range (IQR). Mann-Whitney U test and Yates' chi-square test were used to compare the demographic and clinical variables. The Kaplan-Meier product-limit estimation with the Log Rank test was used to compare survival among the groups. The Spearman correlation test was used when appropriate. All P-values are two-tailed and a P-value ≤0.05 was considered statistically significant. Data analysis was conducted using PASW Statistics 18 software (Chicago, IL, USA).
The authors had full access to the data and took the responsibility for its integrity. All authors have read and agreed to the paper as written.
| Results|| |
Fifty-nine RRT-requiring individuals with ILI were registered during the study period. Fifteen patients were excluded from the analysis: Eight because of previous diagnosis of ESRD and seven because they were empirically treated with oseltamivir without viral confirmation.
Forty-four ILI individuals with RT-PCR confirmed diagnosis of H 1N1 infection were included in this analysis. All of them were admitted to the ICU because of SARF. 56.8% of these patients were men aged 20-49 years (mean: 46.6). Of the total patients included in the study, 34% were young adults (18-39 years), 52% were middle aged (40-59 years) and 14% were elderly (≥60 years).
Thirty-one individuals (70.5%) displayed at least one associated comorbid condition; most frequently, it was high blood pressure, obesity, chronic obstructive pulmonary disease or asthma and chronic renal disease [Table 1].
|Table 1: Most frequent associated co-morbid conditions among patients suffering from the H1N1 infection.|
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Commencement of RRT
Forty-one patients (93.2%) were receiving oseltamivir at the time of commencement of RRT. The inclusion into RRT occurred within EW 25, 26 and 27 in 33 patients (75%). By EW 26, 28 patients (63.3%) were already on RRT [Figure 1]. The average time from ICU admission to commencement of RRT was 3.16 ± 2.6 days. All patients were treated with intermittent hemodialysis (HD), except two, who received continuous veno-venous hemofiltration.
|Figure 1: Patients under renal replacement therapy during the H1N1 pandemic.|
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Forty out of the 44 participants (90.9%) were on mechanical ventilation at the time of initiation of RRT; 67.5% of this group (27/40) had PaO 2 /FiO 2 <150. 79.5% of the total number of subjects required inotropic support, while 63.6% of them showed doubling of liver enzymes above the normal value. Parameters of renal function immediately before initiation of RRT were: Creatinine 5.6 ± 1.9 mg/dL; urea 156 ± 43 mg/dL; serum potassium 5.3 ± 1.1 mmol/L; arterial pH 7.23 ± 0.15 and serum bicarbonate 19.1 ± 6.6 mmol/L. 22.7% presented with oliguria.
Serum creatinine-kinase levels (CK) were assessed in 24 patients prior to RRT; five of them showed values >5000 U/L (range 60 -46,570 U/L; median 1388, ICR 185-3983). CK levels correlated with serum creatinine (r: 0.423; P <0.05) but not with serum potassium (r: 0.068; P = NS) or with blood pH (r: 0.273; P = NS).
During a mean follow-up period of 8.7 ± 5.4 days, 5.3 ± 1.3 HD sessions/patient/week were carried out. The net mortality rate was 81.8%, while the cumulative mortality was 9.1% after 48 h, 40.9% after one week and 52.3% after 10 days. Those patients with PaO 2 /FiO 2 <150 at the time of initiation of RRT had a significantly higher mortality in a shorter period of time (cumulative survival up to 28 days: 3.7 ± 3.6% vs 41.2 ± 11.9%; Log-rank 14.1; P <0.0001) [Figure 2]).
|Figure 2: Cumulative survival of H1N1-diagnosed patients who required renal replacement therapy (censored at 28 days). The sample was grouped according to the baseline PaO2/FiO2 value.|
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The individuals with fatal outcome required mechanical ventilation (97.2% vs. 62.5%) (P = 0.016) and vasoactive support (88.9% vs. 37.5%) (P = 0.006) more frequently and displayed elevated liver alanine amino transferase (72.2% vs. 25%; P = 0.035) before initiation of RRT. The main baseline characteristics of both groups are shown in [Table 2].
|Table 2: Characteristics of the 44 patients with confirmed H1N1 infection and acute kidney injury requiring renal replacement therapy, according to outcome.|
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| Discussion|| |
It has been described that the early cases of H1N1 reported from Mexico, USA and Canada developed severe respiratory failure, ,, while some of them had RRT-requiring AKI. In Argentina, the first wave of the pandemic occurred between EW 21 and 32 (May 24 to August 8), and the peak incidence was in EW 25, with 29.7 cases of ILI/10,000 inhabitants.  An increasing and progressive requirement of ICU admissions due to SARF, sometimes associated with AKI, was documented those days. It has been estimated that 28.5-33% of the individuals with SARF developed AKI. ,,
All the cases reported here involved adult individuals, and almost all of them had associated comorbid conditions such as obesity, high blood pressure and/or previous respiratory disease; they evolved within 72 h following ICU admission with respiratory failure and AKI.
The reported characteristics of AKI with H 1N1 are not different from those reported for seasonal influenza.  The renal involvement became part of a systemic inflammatory response syndrome (SIRS) of viral origin named "viral sepsis," with multi-organ failure. Renal involvement during sepsis is due to cytokines and endopeptide-induced renal hypoperfusion.  Most of our patients presented with severe respiratory, renal, hemodynamic and liver failure.
Because the most severely affected parenchyma as a consequence of influenza infection is the lung, a possible mechanism of renal involvement is ischemia secondary to sustained and severe hypoxemia. The renal ischemia/reperfusion injury, in turn, results in increased pulmonary capillary permeability. 
The ultimate mechanism by which a diseased organ affects another organ is not completely known. The proposed influence of the acute lung injury on renal function may be related to mechanical ventilation-induced renal hypoperfusion. Additionally, the diseased lung could express large quantities of cytokines, including interleukin-6 and tumor necrosis factor-α. ,,, Rello et al observed that 25% of the individuals suffering from H 1N1-associated pneumonitis displayed refractory hypoxemia. 
Ninety percent of the registered patients required mechanical ventilation prior to RRT due to hypoxemia and PaO 2 /FiO 2 <150. Although treated with daily HD, this severely hypoxemic group had a fatal outcome.
Lastly, rhabdomyolysis is the most frequently reported cause of seasonal influenza-associated renal damage. ,,,,,,,, Muscle breakdown induces injury due to vasoconstriction, tubular cast formation and hem-associated direct toxicity.  In our study, only five patients showed CK >5000 U/L, while none of them showed levels higher than 50,000 U/L.
No association was found in the study patients between the CK levels and serum potassium and blood pH, the two most common metabolic alterations seen in association with rhabdomyolysis.
The clearance of CK is mainly renal; therefore, the CK levels might increase in renal failure, sustained muscle ischemia and shock. 
Although a direct cytopathic influenza virus-associated renal injury has not been reported yet, some authors suggest it may be a cause of AKI.  This mechanism of renal injury seems to be highly improbable because of the transient viremia and the mild extra-pulmonary tissue damage. 
Most of the reported adult cases of ILI studied with viral laboratory techniques during the current pandemic in Argentina were confirmed as influenza A. During the first wave of the pandemic, in the Metropolitan Area and the Buenos Aires Province, approximately 200,000 cases of ILI were notified. One percent required hospitalization while 1/5 th needed ICU support, and most of them required mechanical ventilation. , Although the possibility that an infected individual progresses to respiratory failure and AKI is lower than 0.5%, our initial experience confirmed a mortality rate >80% in this group.
A characteristic of this pandemic is that the number of reported cases moves progressively upwards to a "peak," which, in Argentina, occurred during EW 26. This "peak" was related to an increased number of dialysis-requiring individuals, 75% of whom turned up within a three-week period. This extraordinarily high demand of experienced renal support brought an alert to the public health system.
In conclusion, the H1N1-infected patients who developed RRT-requiring AKI in the context of multi-organ failure displayed a high mortality rate, and most of them showed up in a short period of time. We believe that in order to improve the current results, it is mandatory that elaborate strategies are implemented that are aimed at anticipating potential renal complications in future pandemics.
| Disclosures|| |
There is no grant, sponsoring, business interest or consultancy that could lead to a conflict of interest.
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Nephrology and Kidney Transplant Unit, Argerich Hospital, Buenos Aires City
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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