| Abstract|| |
Influenza A (H1N1) infection in 2009 spread rapidly all over the world. Mortality was high in patients with H1N1-associated acute kidney injury (AKI). We estimated the incidence, risk factors of AKI and mortality associated with H1N1 infection. This is a prospective observational study, including 158 adult patients with H1N1 infection confirmed with real-time reverse transcriptase-polymerase chain reaction conducted between August 2016 and September 2017. AKIN criteria were used to define AKI. Of 158 patients in this study, 112 were male and the mean age was 46.4. Fifteen patients (9.5%) were found to have AKI. The mean age was higher (56.13 ± 10.02) in the AKI group compared to non-AKI (45.48 ± 16.26) (P = 0.007). Presence of shock, multiple organ dysfunction syndrome (MODS), ventilatory support were observed more in the AKI group (P = 0.000). Among AKI patients, the requirement of dialysis was more than 50% (n = 8/15, 53.3%). Eighteen patients died following H1N1 infection (11.4%).Shock (n = 8/18, 44.4%, P = 0.000), MODS (n = 13/18, 72.2%, P = 0.000), intensive care unit (ICU) care (n = 17/18, 94.4%, P = 0.000), ventilatory support (n = 18/18, 100% P = 0.000), AKI (n = 11/18, 61.1%, P = 0.000), and requiring dialysis (n = 7/18, 38.9%, P = 0.000) were significantly associated with mortality compared to patients who survived. The incidence of H1N1 AKI was 9.5%, with > 50% requiring dialysis. Risk factors for AKI included older age, underlying chronic kidney disease, presentation with sepsis, shock, MODS, ICU care, and mechanical ventilation. Mortality was high in patients with AKI compared to non-AKI patients.
|How to cite this article:|
Indhumathi E, Krishna Makkena V, Mamidi V, Jayaprakash V, Jayakumar M. Influenza A (H1N1) Virus Infection Associated Acute Kidney Injury - A Study from a Tertiary Care Center in South India. Saudi J Kidney Dis Transpl 2020;31:759-66
|How to cite this URL:|
Indhumathi E, Krishna Makkena V, Mamidi V, Jayaprakash V, Jayakumar M. Influenza A (H1N1) Virus Infection Associated Acute Kidney Injury - A Study from a Tertiary Care Center in South India. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Sep 27];31:759-66. Available from: http://www.sjkdt.org/text.asp?2020/31/4/759/292309
| Introduction|| |
Influenza A viruses cause recurrent epidemics and global pandemics. Pandemic Influenza A (H1N1) virus infection occurred in June 2009. In India, 30197 patients were found to be positive for H1N1 virus infection. World Health Organization (WHO) reported that H1N1 infection would continue as seasonal viral infection. Sporadic H1N1 cases, as well as localized outbreaks of varying magnitude, occurred after the 2009 pandemic period. Cases were reported throughout the year with bi-modal peaks, one in July–August and then in December–February.,, Until December 2009, there were 967 deaths in India giving a case-fatality rate of 3.7%. As there is no routine influenza vaccination program in India, identifying the risk factors earlier for the worst outcome would be beneficial.
Severe infection with H1N1 is characterized by acute respiratory distress syndrome with respiratory failure, hemodynamic instability, and multiple organ failure., There is a scarcity of studies on acute kidney injury (AKI) in H1N1 infection, which is more common in severe H1N1 infection with the incidence of 50%–60%.,, Twenty-five percent of patients develop a severe form of AKI requiring dialysis., AKI is associated with an increased risk of mortality.,,, Among those survive, there are case reports of patients who did not fully recover their kidney function, months after hospital discharge.,,
In one study, all patients who underwent renal biopsy had varying degrees of tubular changes. Although the prerenal component was the main cause of AKI, other associated factors such as prolonged systemic hypoxia, rhabdomyolysis, and severe inflammatory response also play a role in the development of AKI in H1N1 positive patients. The WHO announced that patients with H1N1 virus infection might develop mild to severe renal failure requiring dialysis,,,, and those requiring intensive care unit (ICU) care, development of AKI are associated with high mortality and a risk factor for chronic kidney disease (CKD).
The objective of this study was to estimate the incidence, risk factors and outcome of patients with AKI in comparison to non-AKI patients associated with H1N1 infection.
| Materials and Methods|| |
The study population included patients presented to Sri Ramachandra Institute of Higher Education and Research, Chennai between August 2016 and September 2017 with symptoms of fever, cough, dyspnea, influenza like illness and found to be positive real-time reverse transcriptase-polymerase chain reaction (RT-PCR) throat swab for H1N1 virus.
RT-PCR assay was a TaqMan based realtime detection of recently circulating H1N1. Probes were designed based on the Centers for Disease Control and Prevention (CDC) probes sequences with 6-carboxyflurescein (FAM) reporter and nonfluorescent quencher coupled with minor groove binders. It was designed for the qualitative detection of pandemic influenza A viruses. Samples from the throat or broncho-alveolar lavage secretions were collected in a sterile, leak-proof container and transported to the laboratory. In the lab, sample processing, RNA extraction, amplification, and detection of DNA were done in separate rooms to avoid contamination. Internal control was done with RNasp to check the quality of sample collection, extraction and to detect the presence of possible inhibitors. The sample that had a crossing point value <40 was considered positive. Negative samples and controls should not have a crossing point. If it was there, the batch was retested. Internal controls for specimens should exhibit a crossing point. Failure to exhibit a crossing point value indicates improper assay set up, improper extraction of RNA extraction or presence of PCR inhibitory substances in the samples, the test was repeated. The sensitivity and specificity of the test were 95% and 100%, respectively.
Limitations of the real time RT-PCR include, requirement of analysts trained well with the interpretation of the assay and false negativity that can occur with inadequate organisms due to improper collection, transportation or handling of the samples or the presence of excess DNA/RNA template in the reaction.
Patients with hemodynamic instability, requiring ventilatory support and renal replacement therapy (RRT) were admitted in intensive care unit and other positive patients were treated in isolation wards. Treatment for H1N1 virus infection was initiated as per CDC guidelines once throat swab was positive for H1N1 virus. All patients were given Oseltamivir 75 mg twice daily for five days except for patients on dialysis in whom 30 mg twice daily for five days. Demographic profile was noted for all patients. Comorbid conditions such as diabetes mellitus, hypertension, heart failure, chronic obstructive pulmonary disease (COPD), obesity, immunosuppressant intake and CKD were recorded. H1N1 infection complicating pregnancy was also included.
AKI was defined as an abrupt rise of serum creatinine > 0.3 mg/dL within 48 h and AKI staging was classified according to AKIN criteria. Stage I if serum creatinine of 1.5–2-fold increase or ≥ 0.3 mg/dL, stage II if serum creatinine increase more than two- to threefold and stage III with serum creatinine increase more than threefold or the need for RRT. Serum creatinine on admission, peak level of creatinine, and discharge creatinine was noted. Dialysis was initiated with severe renal failure, volume overload with pulmonary edema, hyperkalemia, or severe acidosis. Other clinical, biochemical, and microbiological data were collected. Patients were followed up until discharge or death. Development of AKI, requirement of dialysis, and mortality were the outcomes measured in this population.
| Statistical Analysis|| |
Data analysis was done using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA). All categorical variables were expressed as numbers and percentages. AKI and non-AKI groups, survivors and non-survivors were compared using Chi-square and Fischer’s Exact test. Continuous variables were measured as mean ± standard deviation and compared between groups using Student’s t-test. For all the statistical analyses, P < 0.05 was considered statistically significant.
| Results|| |
A total of 158 patients were found to be positive for H1N1 infection during the period between August 2016 and September 2017. Among these 112 were males and mean age was 46.4. Common presenting symptoms were fever (67%), cough (47.4%), sore throat (43%) and dyspnea (50.6%). Comorbidities included were diabetes mellitus (n = 55, 34.8%), hypertension (n = 42, 26.5%) cardiac failure (n = 15, 9.5%), COPD (n = 15, 9.5%) and CKD (n = 4, 2.5%). None of the patients had history of immunosuppressive drug intake in the past. Among the study population, 15 patients (9.5%) were found to have AKI. Eleven females (73.3%) in the AKI group and 101 (70.6%) females in the non-AKI group were included. The mean age was higher (56.13 ± 10.02) in the AKI group compared to non-AKI (45.48 ± 16.26) and found to be statistically significant (P = 0.007). Diabetes and hypertension were present in nearly half of the patients with AKI (n = 8/15, 53.3% and n = 7/15, 46.6%) and it was less in non-AKI group (n = 47/143, 32.8% and n = 35/143, 24.47%). Heart failure and COPD were present in three (20%) and two (13.3%) patients, respectively, in the AKI group. Baseline characteristics of AKI and non-AKI group are given in [Table 1].
Seven patients (46.7%) presented with shock in the AKI group in comparison to three (2.1%) in the non-AKI group (P = 0.000). Similarly, multiple organ dysfunction syndrome (MODS) was significantly higher in AKI group (n = 10/15, 66.67%) compared to non-AKI group (n = 3/143, 2.1%) (P = 0.000). The requirement of mechanical ventilatory support in AKI group (n = 11/15, 73.3%) was higher compared to non-AKI group (n = 7, 6.99%) with P = 0.000. Most of the patients in the AKI group required ICU management (13/15, 86.7%) compared to non-AKI group (15/143, 10.5%) (P = 0.000). The clinical and biochemical profile of AKI and Non-AKI group are given in [Table 2]. Mortality was high in AKI group (n = 11, 73.3%) compared to non-AKI group (n = 7, 4.9%) which was statistically significant (P = 0.000). Hyponatremia (P = 0.016), hyperkalemia and acidosis (P = 0.000) were observed more in patients with AKI compared to non-AKI (P = 0.000).
Elevated liver enzymes and lower albumin levels were noted in patients with AKI. Urine proteinuria (n =13, 86.7%) and urine culture, blood culture for bacterial growth (n = 8, 53.3%) were noted more in patients with AKI than without it.
Analyzing the outcome data, 18 patients died following H1N1 infection (11.4%) with 14 females (77.8%).COPD (n = 4/18, 22.2%, P = 0.05) and CKD (n = 2/18, 11.1%, P = 0.01) were the comorbidities associated with mortality in our study. Shock (n = 8, 44.4%, P = 0.000), MODS (n = 13, 72.2%, P = 0.000), patients requiring ICU care (n = 17, 94.4%, P = 0.000), mechanical ventilatory support (n = 18, 100% P = 0.000) were significantly asso ciated with mortality compared to patients who survived with H1N1 infection. Survival was also poor in patients who developed AKI (n = 11, 73.3%, P = 0.000) compared to non- AKI patients. Majority of the patients who underwent RRT (n = 7/8, 87.5%) died in our study. Comparison of data between survivors and nonsurvivors is given in [Table 3].
Nineteen pediatric patients with H1N1 infection were analyzed and given in [Table 4]. AKI was not present in any of our pediatric patient and none of them had diabetes, hypertension or COPD. Acute lymphocytic leukemia on chemotherapy and dengue fever were present in each one of them. Two children were managed in ICU and were on ventilatory support. All the children with H1N1 infection in our study group survived.
| Discussion|| |
There is a paucity of data of H1N1 associated AKI, world wide,,, though data on pulmonary involvement is available. Presence of AKI in H1N1 infection is associated with high mortality rate.,,,,, Although AKI occurring in H1N1 infection has been attributed to hypotension requiring vasopressors, rhabdomyolysis, secondary bacterial infections, direct renal injury by the virus had been implicated in one study by To et al who demonstrated the presence of virus in the urine in a study of 14 patients with H1N1 infection. Renal biopsy findings in a postmortem study of 21 patients of H1N1 associated AKI were acute tubular necrosis, myoglobin positivity and thrombotic microangiopathy. Possible role of T-cell-mediated injury was reported in one study with severe influenza infection where dysregulated cytokine expression occurred following viral antigen deposition in the kidney. Hypercytokinemia of TH1 and TH17 was found in patients with severe H1N1 infection.
AKI has been reported in severe H1N1, with a reported incidence of around 50%–60%.,, In a Spanish study done during pandemic H1N1 infection, the incidence of AKI was 17.7%, with > 50% of AKI III, which was independently associated with mortality. A study from Argentina had reported the incidence of AKI in H1N1 among 542 patients as 60.9%, with 24.5% requiring RRT. Other studies reported the incidence of AKI as 53% in Brazil, 42% in the United States and 66.7% in Canada.[10 19 23] In our study population, the incidence of H1N1 associated AKI was low (n = 15, 9.5%) compared to all other studies, but the requirement of RRT was more than 50% (n = 8/15, 53.3%). Variability in the incidence of AKI may be related to the severity of H1N1 infection on presentation and the criteria used for the definition of AKI. The risk factors for AKI on univariate analysis in our cohort included older age, CKD, presentation with shock, MODS, requiring ICU management and mechanical ventilation (P = 0.000). Sepsis was significantly associated with AKI (P = 0.000). This is in concurrence with other studies from Argentina, Canada, and USA. Obesity and rhabdomyolysis with elevated creatine kinase levels following viral myositis as risk factors for AKI associated with H1N1 had been reported in some studies,,, though few other studies refuted the association.
Variable mortality rates of 16%, 19%, and 54%, respectively, had been reported with H1N1 infection from Brazil, Argentina, and Canada. Patients with multiple organ failure, sepsis, shock on vasopressor support and requiring mechanical ventilation, AKI requiring dialysis were the risk factors for mortality in these studies. In our study the overall mortality of patients with H1N1 infection was 11.4% (n = 18) and among H1N1 associated AKI patients it was 73.3% (n = 11) compared to mortality in non-AKI group (n = 7, 4.9%) with (P = 0.000). Risk factors for mortality in our study included the presence of COPD, underlying CKD, presentation with shock requiring ICU management, vaso- pressors, MODS, mechanical ventilator support, sepsis, and AKI requiring dialysis. This is similar to other studies though mortality among AKI requiring RRT was very high. Few studies are available regarding the positive correlation of AKI and poor outcomes in patients with H1N1 infection. Demirjian et al in their study from US population reported the mortality in H1N1 AKI patients as 50% and AKI as an independent risk factor for mortality. Contrarily another study from Canada with H1N1 with AKI incidence of 60.9%, reported that AKI was not an independent risk factor for mortality.
To conclude only very few studies are available in the post-pandemic H1N1 AKI worldwide. Our study is a prospective observational study from South India with 158 H1N1 positive patients. The incidence of H1N1 AKI was 9.5%, with more than 50% requiring RRT. The risk factors for AKI included older age, underlying CKD, presentation with shock, sepsis, MODS requiring ICU management, and mechanical ventilation. Mortality among H1N1 AKI patients requiring dialysis was high, with 61% compared to 4.9% in non-AKI patients.
Limitations of the study include a small sample size of H1N1 infected patients and the absence of the inclusion of the control group. Multicenter study regarding H1N1 AKI will be much more useful.
Conflict of interest: None declared.
| References|| |
Choudhry A, Singh S, Khare S, et al. Emergence of pandemic 2009 influenza A H1N1, India. Indian J Med Res 2012;135:534- 7. [Full text]
Broor S, Krishnan A, Roy DS, et al. Dynamic patterns of circulating seasonal and pandemic A(H1N1) pdm09 influenza viruses from 20072010 in and around Delhi, India. PLoS One 2012; 7:e29129.
Lister P, Reynolds F, Parslow R, et al. Swine- origin influenza virus H1N1, seasonal influenza virus, and critical illness in children. Lancet 2009;374:605-7.
Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA 2009; 302:1872-9.
Bagshaw SM, Sood MM, Long J, Fowler RA, Adhikari NK, Canadian Critical Care Trials Group H1N1 Collaborative. Acute kidney injury among critically ill patients with pandemic H1N1 influenza A in Canada: Cohort study. BMC Nephrol 2013;14:123.
Abdulkader RC, Ho YL, de Sousa Santos S, Caires R, Arantes MF, Andrade L. Characteristics of acute kidney injury in patients infected with the 2009 influenza A (H1N1) virus. Clin J Am Soc Nephrol 2010; 5:1916-21.
Martin-Loeches I, Papiol E, Rodríguez A, et al. Acute kidney injury in critical ill patients affected by influenza A (H1N1) virus infection. Crit Care 2011 ;15:R66.
Sevignani G, Soares MF, Marques GL, et al. Acute kidney injury in patients infected by H1N1: Clinical histological correlation in a series of cases. J Bras Nefrol 2013;35:185-90.
Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N
Engl J Med 2009;361:680-9.
Rello J, Rodríguez A, Ibañez P, et al. Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain. Crit Care 2009;13:R148.
ANZIC Influenza Investigators, Webb SA, Pettila V, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N
Engl J Med 2009;361:1925-34.
Estenssoro E, Ríos FG, Apezteguía C, et al. Pandemic 2009 influenza A in Argentina: A study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med 2010;182: 41-8.
Wald R, Quinn RR, Luo J, et al. Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. JAMA 2009; 302:1179-85.
Barrantes F, Tian J, Vazquez R, Amoateng- Adjepong Y, Manthous CA. Acute kidney injury criteria predict outcomes of critically ill patients. Crit Care Med 2008;36:1397-403.
Demirjian SG, Raina R, Bhimraj A, et al. 2009 influenza A infection and acute kidney injury: Incidence, risk factors, and complications. Am J Nephrol 2011;34:1-8.
To KK, Chan KH, Li IW, et al. Viral load in patients infected with pandemic H1N1 2009 influenza A virus. J Med Virol 2010;82:1-7.
Mauad T, Hajjar LA, Callegari GD, et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med 2010;181:72-9.
Bermejo-Martin JF, Ortiz de Lejarazu R, Pumarola T, et al. Th1 and Th17 hyper- cytokinemia as early host response signature in severe pandemic influenza. Crit Care 2009;13:R201.
Sood MM, Rigatto C, Zarychanski R, et al. Acute kidney injury in critically ill patients infected with 2009 pandemic influenza A(H1N1): Report from a Canadian Province. Am J Kidney Dis 2010;55:848-55.
Department of Nephrology, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Ramachandra Nagar, Porur, Chennai - 600 116, Tamil Nadu
[Table 1], [Table 2], [Table 3], [Table 4]