Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival
2009; Elsevier BV; Volume: 77; Issue: 6 Linguagem: Inglês
10.1038/ki.2009.502
ISSN1523-1755
AutoresRaghavan Murugan, Vijay Karajala-Subramanyam, Min Jae Lee, Sachin Yende, Lan Kong, Melinda Carter, Derek C. Angus, John A. Kellum,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoWhile sepsis is a leading cause of acute kidney injury in critically ill patients, the relationship between immune response and acute kidney injury in less severely ill patients with infection is not known. Here we studied the epidemiology, 1-year mortality, and immune response associated with acute kidney injury in 1836 hospitalized patients with community-acquired severe and non-severe pneumonia. Acute kidney injury developed in 631 patients of whom 329 had severe and 302 had non-severe sepsis. Depending on the subgroup classification, 16–25% of the patients with non-severe pneumonia also developed acute kidney injury. In general, patients with acute kidney injury were older, had more comorbidity, and had higher biomarker concentrations (interleukin-6, tumor necrosis factor, D-dimer) even among patients without severe sepsis. The risk of death associated with acute kidney injury varied when assessed by Gray's survival model and after adjusting for differences in age, gender, ethnicity, and comorbidity. This risk was significantly higher immediately after hospitalization but gradually fell over time in the overall cohort and in those with non-severe pneumonia. A significantly higher risk of death (hazard ratio 1.29) was also present in those never admitted to an intensive care unit. Hence acute kidney injury is common even among patients with non-severe pneumonia and is associated with higher immune response and an increased risk of death. While sepsis is a leading cause of acute kidney injury in critically ill patients, the relationship between immune response and acute kidney injury in less severely ill patients with infection is not known. Here we studied the epidemiology, 1-year mortality, and immune response associated with acute kidney injury in 1836 hospitalized patients with community-acquired severe and non-severe pneumonia. Acute kidney injury developed in 631 patients of whom 329 had severe and 302 had non-severe sepsis. Depending on the subgroup classification, 16–25% of the patients with non-severe pneumonia also developed acute kidney injury. In general, patients with acute kidney injury were older, had more comorbidity, and had higher biomarker concentrations (interleukin-6, tumor necrosis factor, D-dimer) even among patients without severe sepsis. The risk of death associated with acute kidney injury varied when assessed by Gray's survival model and after adjusting for differences in age, gender, ethnicity, and comorbidity. This risk was significantly higher immediately after hospitalization but gradually fell over time in the overall cohort and in those with non-severe pneumonia. A significantly higher risk of death (hazard ratio 1.29) was also present in those never admitted to an intensive care unit. Hence acute kidney injury is common even among patients with non-severe pneumonia and is associated with higher immune response and an increased risk of death. Sepsis, an immune response to infection, is a leading cause of acute kidney injury (AKI) in severely ill patients,1.Uchino S. Kellum J.A. Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (2838) Google Scholar, 2.Bagshaw S.M. Uchino S. Bellomo R. et al.Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes.Clin J Am Soc Nephrol. 2007; 2: 431-439Crossref PubMed Scopus (518) Google Scholar, 3.Schrier R.W. Wang W. Acute renal failure and sepsis.N Engl J Med. 2004; 351: 159-169Crossref PubMed Scopus (875) Google Scholar and development of AKI is associated with increased risk of death.2.Bagshaw S.M. Uchino S. Bellomo R. et al.Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes.Clin J Am Soc Nephrol. 2007; 2: 431-439Crossref PubMed Scopus (518) Google Scholar,4.Chen Y.C. Jenq C.C. Tian Y.C. et al.RIFLE classification for predicting in-hospital mortality in critically ill sepsis patients.Shock. 2009; 31: 139-145Crossref PubMed Scopus (46) Google Scholar Although several studies reported outcome of sepsis-induced AKI in critically ill patients,1.Uchino S. Kellum J.A. Bellomo R. et al.Acute renal failure in critically ill patients: a multinational, multicenter study.JAMA. 2005; 294: 813-818Crossref PubMed Scopus (2838) Google Scholar, 2.Bagshaw S.M. Uchino S. 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Geers C. et al.Sepsis-related acute kidney injury: a protective effect of drotrecogin alpha (activated) treatment?.Acta Anaesthesiol Scand. 2008; 52: 1259-1264Crossref PubMed Scopus (14) Google Scholar, 8.Lopes J.A. Jorge S. Resina C. et al.Acute kidney injury in patients with sepsis: a contemporary analysis.Int J Infect Dis. 2009; 13: 176-181Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar less attention has been paid to infected patients with AKI who are less severely ill. For instance, community-acquired pneumonia (CAP) is a common, infectious cause of hospitalization in developed countries.9.Angus D.C. Linde-Zwirble W.T. Lidicker J. et al.Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med. 2001; 29: 1303-1310Crossref PubMed Scopus (6259) Google Scholar Most patients with CAP are not severely ill and are often treated in non-intensive care settings. However, the epidemiology and outcome of AKI in patients with non-severe CAP is unknown. Furthermore, patients with CAP who develop milder forms of AKI will not meet existing criteria for severe sepsis (i.e., sepsis with coexisting severe acute organ dysfunction),10.Vincent J.L. Moreno R. Takala J. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6146) Google Scholar and are therefore unlikely to be enrolled in therapeutic trials of sepsis.11.Abraham E. Reinhart K. Opal S. et al.Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.JAMA. 2003; 290: 238-247Crossref PubMed Scopus (778) Google Scholar, 12.Bernard G.R. Vincent J.L. Laterre P.F. et al.Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699-709Crossref PubMed Scopus (4919) Google Scholar, 13.Warren B.L. Eid A. Singer P. et al.Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.JAMA. 2001; 286: 1869-1878Crossref PubMed Scopus (1084) Google Scholar If AKI is associated with increased risk of death in patients with non-severe CAP and in those without severe sepsis, then early recognition and treatment could improve outcome from AKI. Inflammation is thought to have a causal role in sepsis-induced AKI in animals,14.Fiedler V.B. Loof I. Sander E. et al.Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys.J Lab Clin Med. 1992; 120: 574-588PubMed Google Scholar, 15.Knotek M. Rogachev B. Wang W. et al.Endotoxemic renal failure in mice: role of tumor necrosis factor independent of inducible nitric oxide synthase.Kidney Int. 2001; 59: 2243-2249Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 16.Cunningham P.N. Dyanov H.M. Park P. et al.Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney.J Immunol. 2002; 168: 5817-5823Crossref PubMed Scopus (297) Google Scholar but data in humans are inconclusive. Several authors found increased concentrations of inflammatory, coagulation, and fibrinolysis markers in critically ill patients with AKI.17.Chawla L.S. Seneff M.G. Nelson D.R. et al.Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.Clin J Am Soc Nephrol. 2007; 2: 22-30Crossref PubMed Scopus (129) Google Scholar, 18.Iglesias J. Marik P.E. Levine J.S. Elevated serum levels of the type I and type II receptors for tumor necrosis factor-alpha as predictive factors for ARF in patients with septic shock.Am J Kidney Dis. 2003; 41: 62-75Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 19.Garcia-Fernandez N. Montes R. Purroy A. et al.Hemostatic disturbances in patients with systemic inflammatory response syndrome (SIRS) and associated acute renal failure (ARF).Thromb Res. 2000; 100: 19-25Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar However, an important limitation of these studies is that it is unclear whether immune markers were associated with AKI itself, or coexisting severe organ dysfunction (severe sepsis) that may have contributed to increased immune response.20.Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (1816) Google Scholar,21.Scaffidi P. Misteli T. Bianchi M.E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature. 2002; 418: 191-195Crossref PubMed Scopus (3096) Google Scholar Understanding immune response associated with AKI in patients without severe sepsis is essential for development of immune modulating therapies for AKI. Using Risk, Injury, and Failure (RIFLE) criteria to classify AKI in a large multicenter cohort of patients hospitalized with CAP, the goals of this prospective observational study were threefold. First, to describe differences in baseline characteristics and outcomes between hospitalized CAP patients with and without AKI. Second, to examine the risk of AKI in patients with milder forms of CAP and whether development of AKI in an otherwise non-severe pneumonia is associated with adverse outcomes. We used the Pneumonia Severity Index classes I–III,22.Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3516) Google Scholar confusion, uremia, respiratory rate, low blood pressure, age 65 years or older (CURB-65) group 1,23.Lim W.S. van der Eerden M.M. Laing R. et al.Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study.Thorax. 2003; 58: 377-382Crossref PubMed Scopus (1897) Google Scholar those who never developed severe sepsis,24.Levy M.M. Fink M.P. Marshall J.C. et al.2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med. 2003; 31: 1250-1256Crossref PubMed Scopus (4320) Google Scholar and those who were never admitted to intensive care unit, as proxies for non-severe CAP. Third, to examine immune, coagulation, and fibrinolysis pathways among patients with and without AKI, in those who do and do not develop severe sepsis. Of the 2320 patients enrolled in the study, 291 were excluded because they were discharged from the emergency department, and another 134 patients were excluded because the clinical team ruled out CAP during the first 3 days of hospitalization. Of the remaining 1895 patients with CAP, we excluded patients who were either receiving dialysis or had history of end-stage renal disease (n=48), and in whom serum creatinine was never obtained (n=11). Of the 1836 patients who formed the study cohort (Figure 1), premorbid baseline creatinine was estimated in 1745 patients using the recommended Modification of Diet in Renal Disease equation. Of the 631 patients (34%) who met criteria for AKI, 307 (49%), 135 (21%), and 189 (30%) reached maximum RIFLE stages, respectively, during hospitalization. Of the 91 patients with known premorbid baseline creatinine, we found moderate agreement between premorbid creatinine and the estimated creatinine to classify patients with AKI (Cohen's κ coefficient=0.70, 95% CI 0.52–0.87, P<0.0001). Nearly two-thirds of patients developing AKI had already done so at hospital admission (n=399, 63.2% of patients with AKI). Table 1 shows the demographic characteristics and severity of illness on day 1 of hospital admission stratified by AKI, and by severity of AKI. Patients with AKI were predominantly older, of white race, had more preexisting comorbidity, and had more severe CAP.Table 1Baseline characteristics of patients with AKI following CAPNo. (%)CharacteristicAKIaPatients were classified to have developed AKI if they met any of Risk, Injury, or Failure stages at any time during hospitalization as proposed by the Acute Dialysis Quality Initiative.30 (n=631)No AKI (n=1205)P-valueRiskbFor severity of AKI, patients were classified according to the maximum RIFLE stage (Risk, Injury, or Failure) reached during the entire hospitalization as proposed by the Acute Dialysis Quality Initiative.30 (n=307)InjurybFor severity of AKI, patients were classified according to the maximum RIFLE stage (Risk, Injury, or Failure) reached during the entire hospitalization as proposed by the Acute Dialysis Quality Initiative.30 (n=135)FailurebFor severity of AKI, patients were classified according to the maximum RIFLE stage (Risk, Injury, or Failure) reached during the entire hospitalization as proposed by the Acute Dialysis Quality Initiative.30 (n=189)P-valueAge, mean (s.d.), years73.4 (14.5)65.2 (17.1)<0.00174.2 (14)76.4 (13)70 (15.4)<0.001Male gender320 (51)634 (53)0.43153 (24)63 (10)103 (16)0.303White race542 (85)951 (79)0.003273 (43)114 (18)155 (24)0.085Baseline creatinine0.93 (0.3)0.89 (0.2)<0.0010.9 (0.1)0.9 (0.1)0.9 (0.5)0.042Charlson Comorbidity IndexcAccording to the method of Charlson et al.33 Mean (s.d.)2.1 (2.2)1.7 (2.1) 0491 (77.8)831 (68.9)0.0001239 (77.8)111 (82.2)141 (74.6)0.266 Chronic kidney disease24 (3.8)9 (0.7)<0.0015 (1.6)9 (6.6)10 (5.3)0.017 Cardiac disease207 (38.2)260 (24.1)<0.001111 (53.6)49 (23.7)47 (22.7)0.116 Lung disease225 (36)478 (40)0.093117 (52)49 (21.8)59 (26.2)0.293 Diabetes151 (23.9)210 (17.4)0.00169 (22.5)42 (31.1)40 (21.1)0.083Prior antibiotic use101 (16)222 (18.4)0.2052 (17)18 (13.3)31 (16.4)0.541Pneumonia severity index, mean (s.d.)dPneumonia Severity Index was measured according to criteria by Fine et al.22 in the emergency department in 1546 (84.2%) subjects. There were no significant differences between subjects who did and did not have a Pneumonia Severity Index measured.105.5 (31.4)78.5 (28.5)<0.001116.5 (37.6)126.8 (34.5)124.5 (39.4)0.009Pneumonia severity index class I and II81 (13)487 (40.4)<0.00126 (62)4 (9.5)12 (28.5)0.035 III128 (20.3)334 (28)52 (59.1)17 (19.3)19 (21.6) IV283 (45)330 (27.3)134 (48.5)55 (20)87 (31.5) V139 (22)54 (4.5)95 (42.3)59 (26.2)71 (31.5)CURB-65 score, mean (s.d.)eAccording to criteria by Lim et al.232.4 (1.0)1.4 (1.0)<0.0012.3 (1.07)2.6 (0.9)2.3 (1.1)0.0042CURB-65 group I132 (21)674 (56)<0.00173 (23.8)14 (10.4)45 (24)0.013 II195 (31)331 (27.4)92 (30)43 (32)60 (31.7) III304 (48)200 (16.6)142 (46.2)78 (58)84 (44.5)APACHE III score, mean (s.d.)fAPACHE III score assessed on first hospital day regardless of whether subject was admitted to an intensive care unit or not.3447 (15.2)36.7 (11.8)<0.00144.8 (14)47.1 (14)50.3 (17)<0.001SOFA score, mean (s.d.)gSOFA score assessed on the first day of hospital admission according to criteria by Vincent et al.103.3 (2.2)1.8 (1.4)<0.0012.8 (2)3.6 (1.9)4 (2.5)<0.001Severe sepsis on day 1hDefined as sepsis plus acute organ dysfunction according to 2001 international consensus criteria for severe sepsis.24165 (26.1)102 (8.46)<0.00159 (19.2)26 (19.2)80 (42.3)<0.001Abbreviations: AKI, acute kidney injury; APACHE, Acute Physiology and Chronic Health Evaluation; CURB-65, confusion, uremia, respiratory rate, low blood pressure, age 65 years or older; s.d., standard deviation; SOFA, Sequential Organ Failure Assessment.a Patients were classified to have developed AKI if they met any of Risk, Injury, or Failure stages at any time during hospitalization as proposed by the Acute Dialysis Quality Initiative.30.Bellomo R. Ronco C. Kellum J.A. et al.Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Crit Care. 2004; 8: R204-R212Crossref PubMed Google Scholarb For severity of AKI, patients were classified according to the maximum RIFLE stage (Risk, Injury, or Failure) reached during the entire hospitalization as proposed by the Acute Dialysis Quality Initiative.30.Bellomo R. Ronco C. Kellum J.A. et al.Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.Crit Care. 2004; 8: R204-R212Crossref PubMed Google Scholarc According to the method of Charlson et al.33.Charlson M.E. Pompei P. Ales K.L. et al.A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.J Chronic Dis. 1987; 40: 373-383Abstract Full Text PDF PubMed Scopus (29673) Google Scholard Pneumonia Severity Index was measured according to criteria by Fine et al.22.Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3516) Google Scholar in the emergency department in 1546 (84.2%) subjects. There were no significant differences between subjects who did and did not have a Pneumonia Severity Index measured.e According to criteria by Lim et al.23.Lim W.S. van der Eerden M.M. Laing R. et al.Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study.Thorax. 2003; 58: 377-382Crossref PubMed Scopus (1897) Google Scholarf APACHE III score assessed on first hospital day regardless of whether subject was admitted to an intensive care unit or not.34.Knaus W.A. Wagner D.P. Draper E.A. et al.The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults.Chest. 1991; 100: 1619-1636Crossref PubMed Scopus (2864) Google Scholarg SOFA score assessed on the first day of hospital admission according to criteria by Vincent et al.10.Vincent J.L. Moreno R. Takala J. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6146) Google Scholarh Defined as sepsis plus acute organ dysfunction according to 2001 international consensus criteria for severe sepsis.24.Levy M.M. Fink M.P. Marshall J.C. et al.2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med. 2003; 31: 1250-1256Crossref PubMed Scopus (4320) Google Scholar Open table in a new tab Abbreviations: AKI, acute kidney injury; APACHE, Acute Physiology and Chronic Health Evaluation; CURB-65, confusion, uremia, respiratory rate, low blood pressure, age 65 years or older; s.d., standard deviation; SOFA, Sequential Organ Failure Assessment. Table 2 shows hospital course and outcomes for patients with and without AKI. One-third (31.1%, n=572) of CAP patients developed severe sepsis (i.e., had a Sequential Organ Failure Assessment (SOFA) score10.Vincent J.L. Moreno R. Takala J. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6146) Google Scholar of ≥3 in at least one organ system during the entire hospitalization), of which more than one-half (57.5%) developed AKI (n=329). Although overall intensive care use was only 16%, more than a third of patients with AKI (39%) were admitted to the intensive care unit at some point during hospitalization, of which 18% received mechanical ventilation. Patients with AKI, on an average, incurred higher median hospital length of stay compared to patients without AKI (8 vs 5 days, P<0.001).Table 2Hospital course and outcomes in patients with and without AKI in the overall cohortNo. (%)CharacteristicaHospital course and outcome in the entire cohort of 1836 patients with community-acquired pneumonia.AKINo AKIP-valueDeveloped severe sepsis329 (52.1)243 (20.1)<0.001Intensive care unit admission245 (39)47 (4)<0.001Mechanical ventilation116 (18.4)13 (1)<0.001Length of hospital stay, median (IQR)8 (12–5)5 (7–4)<0.001Hospital mortality70 (11.1)16 (1.3)<0.00190-day mortality151 (24)118 (9.8)<0.0011-year mortality229 (36.3)242 (20.1)<0.001Abbreviations: AKI, acute kidney injury; IQR, interquartile range.a Hospital course and outcome in the entire cohort of 1836 patients with community-acquired pneumonia. Open table in a new tab Abbreviations: AKI, acute kidney injury; IQR, interquartile range. Patients with AKI had a higher risk of death at each time point, such as by hospital discharge (11 vs 1.3%, P<0.001), by 90 days (24 vs. 9.8%, P<0.001), and by 1 year (36.3 vs 20.1%, P<0.001; Table 2). Mortality increased with increased severity of AKI and was 29.6, 40.7, and 43.9% for maximum stages RIFLE, respectively, at 1 year (P<0.001; Figure 2a). Using Gray's survival model, we found that the hazard ratios for association between AKI and risk of death varied significantly over 365 days after hospitalization for CAP. The unadjusted hazard ratios were highest during the first 100 days after presentation, subsequently decreased, but nevertheless persisted over the entire 1 year of follow-up (hazard ratio range 1.45–2.79, P<0.001; Table 4). When adjusted for differences in age, gender, race, and the Charlson Comorbidity Index the hazard ratios were attenuated (adjusted hazard ratio range 1.10–2.10, P<0.001; Table 4), but nevertheless remained significant up to 100 days after CAP (Figure 3a). Similar risk of death was present when absolute (adjusted hazard ratio 1.12, 95% CI 1.04–1.20, P=0.001), relative (adjusted hazard ratio 1.12, 95% CI 1.04–1.19, P=0.002), as well as ratio (adjusted hazard ratio 1.10, 95% CI 1.04–1.17, P=0.001) of change in glomerular filtration rate were used in the model instead of AKI. We also found that the mortality rates were not different between patients who presented with AKI at hospital admission and those who developed AKI during hospitalization. Similarly, there was no difference in mortality associated with AKI among those with and without chronic kidney disease (data not shown). Not surprisingly, the risk of AKI was lower in patients with non-severe CAP. Of the 1030 patients within Pneumonia Severity Index classes I–III, 20.3% of patients (n=209) developed AKI. Of the 806 patients within CURB-65 group 1, 16.4% of patients (n=132) developed AKI. Of patients who never developed severe sepsis (n=1264) and those never admitted to the intensive care unit (n=1544), the risk of AKI was 23.8% (n=302) and 25% (n=386). Patients with AKI within Pneumonia Severity Index classes I–III and CURB-65 group 1 were more likely to develop severe sepsis, be admitted to intensive care unit, and be mechanically ventilated (P<0.001; Table 3).Table 3Hospital course and outcomes in patients with and without AKI in non-severe CAP subgroupsNo. (%)CharacteristicAKINo AKIP-valuePneumonia Severity Index classes I–IIIaHospital course and outcome in the subgroup of 1030 non-severe CAP patients as defined by Pneumonia Severity Index classes I–III at presentation to the emergency department according to criteria by Fine et al.22(n=209)(n=821) Developed severe sepsis82 (39.2)109 (13.2)<0.001 Intensive care unit admission74 (35.4)24 (3)<0.001 Mechanical ventilation35 (16.7)5 (0.6)<0.001 Length of hospital stay, median, IQR7 (5–10)5 (4–7)<0.001 Hospital mortality10 (4.8)3 (0.4)<0.001 90-day mortality20 (9.6)40 (4.9)0.009 1-year mortality36 (17.2)89 (10.8)0.011CURB-65 group 1bHospital course and outcome in the subgroup of 806 non-severe CAP patients as defined by CURB-65 group 1 at presentation to the emergency department according to criteria by Lim et al.23(n=132)(n=674) Developed severe sepsis67 (50.8)96 (14.2)<0.001 Intensive care unit admission64 (48.5)20 (3)<0.001 Mechanical ventilation35 (26.5)5 (0.7)<0.001 Length of hospital stay, median, IQR9 (5–15)5 (4–7)<0.001 Hospital mortality9 (6.8)2 (0.3)<0.001 90-day mortality18 (13.6)35 (5.2)<0.001 1-year mortality28 (21.2)79 (11.7)0.003Non-severe sepsis cohortcHospital course and outcome in the subgroup of 1264 non-severe CAP patients as defined by maximum Sequential Organ Failure Assessment score less than 3 during entire hospitalization according to criteria by Vincent et al.10(n=302)(n=962) Intensive care unit admission53 (17.5)30 (2)<0.001 Length of hospital stay, median, IQR6 (5–8)5 (4–7)<0.001 Hospital mortality3 (0.99)1 (0.1)0.016 90-day mortality36 (11.9)67 (6.9)0.006 1-year mortality75 (24.8)152 (15.8)<0.001Non-ICU cohortdHospital course and outcome in the subgroup of 1544 patients who were never admitted to the ICU during the entire hospitalization.(n=386)(n=1158) Developed severe sepsis137 (35.5)216 (18.6)<0.001 Length of hospital stay, median, IQR6 (4–8)5 (4–7)<0.001 Hospital mortality20 (5.1)14 (1.2)<0.001 90-day mortality77 (19.9)108 (9.3)<0.001 1-year mortality132 (34.2)228 (19.7)<0.001Abbreviations: AKI, acute kidney injury; CAP, community-acquired pneumonia; CURB-65, confusion, uremia, respiratory rate, low blood pressure, age 65 years or older; IQR, interquartile range.a Hospital course and outcome in the subgroup of 1030 non-severe CAP patients as defined by Pneumonia Severity Index classes I–III at presentation to the emergency department according to criteria by Fine et al.22.Fine M.J. Auble T.E. Yealy D.M. et al.A prediction rule to identify low-risk patients with community-acquired pneumonia.N Engl J Med. 1997; 336: 243-250Crossref PubMed Scopus (3516) Google Scholarb Hospital course and outcome in the subgroup of 806 non-severe CAP patients as defined by CURB-65 group 1 at presentation to the emergency department according to criteria by Lim et al.23.Lim W.S. van der Eerden M.M. Laing R. et al.Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study.Thorax. 2003; 58: 377-382Crossref PubMed Scopus (1897) Google Scholarc Hospital course and outcome in the subgroup of 1264 non-severe CAP patients as defined by maximum Sequential Organ Failure Assessment score less than 3 during entire hospitalization according to criteria by Vincent et al.10.Vincent J.L. Moreno R. Takala J. et al.The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (6146) Google Scholard Hospital course and outcome in the subgroup of 1544 patients who were never admitted to the ICU during the entire hospitalization. Open table in a new tab Abbreviations: AKI, acute kidney injury; CAP, community-acquired pneumonia; CURB-65, confusion, uremia, respiratory rate, low blood pressure, age 65 years or older; IQR, interquartile range. Non-severe CAP patients with AKI incurred higher length of hospital stay, in-hospital and 90-day mortality (Table 3). At 1 year, mortality varied from 17.2 to 34.2% for patients with AKI within the four non-severe CAP subgroups (Figure 2b). Patients admitted to medical wards with AKI had higher mortality compared to those without AKI (34.2 vs 19.7%, P<0.001). This increased risk of death was not only seen with more severe AKI. Of patients with stage Risk (61%), the mortality was higher with AKI (30.1 vs 19.6%, P<0.001) (hazard ratio 1.67, 95% CI 1.28–2.18, P<0.001). The unadjusted hazard ratios for 1-year mortality ranged from 1.03 to 3.65 within the four non-severe CAP subgroups (Table 4). The hazard ratios remained unchanged when adjusted for age, gender, race, and the Charlson Comorbidity Index for those admitted to medical wards with AKI (adjusted hazard ratio 1.29, 95% CI 1.03–1.60, P<0.023). Using Gray's model, we found that the adjusted hazard ratio for death in patients within CURB-65 group 1 varied over the 1-year follow-up (adjusted hazard ratio range 0.85–2.97, P=0.001). The risk of death associated with AKI was high immediately after CAP in patients admitted to hospital (hazard ratio 2.73, 95% CI 1.52–4.92). Subsequently, although the hazard ratios declined, the risk of death associated with AKI nevertheless remained significant up to 50 days (Figure 3b).Table 4Hazard ratios for association between AKI and 1-year mortalityCharacteristicHazard ratio for mortality in patients with AKI95% CIP-valueUnadjusted Overall cohortaHazard ratio
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