Publications by authors named "José Agapito Fonseca"

13 Publications

  • Page 1 of 1

Acute kidney injury in hospitalized patients with COVID-19: A Portuguese cohort.

Nefrologia 2021 May 14. Epub 2021 May 14.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Introduction: The incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients ranges from 0.5% to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19.

Methods: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions.

Results: In this cohort of COVID-19 patients, 55.2% developed AKI (n=106). The majority of AKI patients had persistent AKI (n=64, 60.4%). Overall, in-hospital mortality was 18.2% (n=35) and was higher in AKI patients (28.3% vs. 5.9%, p<0.001, unadjusted OR 6.03 (2.22-16.37), p<0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02-1.11), p=0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60-0.98), p=0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p=0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p=0.006) were independent predictors of mortality.

Conclusion: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.
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http://dx.doi.org/10.1016/j.nefro.2021.04.002DOI Listing
May 2021

Acute kidney injury in hospitalized patients with COVID-19: a Portuguese cohort.

Nefrologia (Engl Ed) 2021 May 14. Epub 2021 May 14.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Introduction: The incidence of AKI in coronavirus disease 2019 (COVID-19) patients ranges from 0.5 to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19.

Methods: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and Transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions.

Results: In this cohort of COVID-19 patients, 55.2% developed AKI (n=106). The majority of AKI patients had persistent AKI (n=64, 60.4%). Overall, in-hospital mortality was 18.2% (n=35) and was higher in AKI patients (28.3% vs 5.9%, p<0.001, unadjusted OR 6.03 (2.22-16.37), p<0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02-1.11), p=0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60-0.98), p=0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p=0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p=0.006) were independent predictors of mortality.

Conclusion: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.
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http://dx.doi.org/10.1016/j.nefro.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120482PMC
May 2021

Acute kidney disease and long-term outcomes in critically ill acute kidney injury patients with sepsis: a cohort analysis.

Clin Kidney J 2021 May 27;14(5):1379-1387. Epub 2020 Sep 27.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Lisboa, Portugal.

Background: Acute kidney injury (AKI) is frequent during hospitalization and may contribute to adverse short- and long-term consequences. Acute kidney disease (AKD) reflects the continuing pathological processes and adverse events developing after AKI. We aimed to evaluate the association of AKD, long-term adverse renal function and mortality in a cohort of patients with sepsis.

Methods: We performed a retrospective analysis of adult patients with septic AKI admitted to the Division of Intensive Medicine of the Centro Hospitalar Lisboa Norte (Lisbon, Portugal) between January 2008 and December 2014. Patients were categorized according to the development of AKI using the Kidney Disease: Improving Global Outcomes (KDIGO) classification. AKI was defined as an increase in absolute serum creatinine (SCr) ≥0.3 mg/dL or by a percentage increase in SCr ≥50% and/or by a decrease in urine output to <0.5 mL/kg/h for >6 h. AKD was defined as presenting at least KDIGO Stage 1 criteria for >7 days after an AKI initiating event. Adverse renal outcomes (need for long-term dialysis and/or a 25% decrease in estimated glomerular filtration rate after hospital discharge) and mortality after discharge were evaluated.

Results: From 256 selected patients with septic AKI, 53.9% developed AKD. The 30-day mortality rate was 24.5% ( = 55). The mean long-term follow-up was 45.9 ± 43.3 months. The majority of patients experience an adverse renal outcome [ = 158 (61.7%)] and 44.1% ( = 113) of patients died during follow-up. Adverse renal outcomes, 30-day mortality and long-term mortality after hospital discharge were more frequent among AKD patients [77.5 versus 43.2% (P < 0.001), 34.1 versus 6.8% (P < 0.001) and 64.8 versus 49.1% (P = 0.025), respectively]. The 5-year cumulative probability of survival was 23.2% for AKD patients, while it was 47.5% for patients with no AKD (log-rank test, P < 0.0001). In multivariate analysis, AKD was independently associated with adverse renal outcomes {adjusted hazard ratio [HR] 2.87 [95% confidence interval (CI) 2.0-4.1]; P < 0.001} and long-term mortality [adjusted HR 1.51 (95% CI 1.0-2.2); P = 0.040].

Conclusions: AKD after septic AKI was independently associated with the risk of long-term need for dialysis and/or renal function decline and with the risk of death after hospital discharge.
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http://dx.doi.org/10.1093/ckj/sfaa130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087131PMC
May 2021

The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study.

Nefrologia (Engl Ed) 2021 May-Jun;41(3):321-328. Epub 2020 Dec 11.

Division of Nephrology and Renal Transplantation, Department of Medicine. Centro Hospitalar Universitário Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Introduction: Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a multisystemic disease. Despite the improvement in mortality rate since the introduction of immunosuppression, long-term prognosis is still uncertain not only because of the disease activity but also due to treatment associated adverse effects. The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated as an inflammatory marker in multiple settings. In this study, we aimed to investigate the prognostic ability of the NLR in AAV patients.

Methods: We conducted a retrospective analysis of the clinical records of all adult patients with AVV admitted to the Nephrology and Renal Transplantation Department of Centro Hospitalar Universitário Lisboa Norte from January 2006 to December 2019. NLR was calculated at admission. The outcomes measured were severe infection at 3 months and one-year mortality. The prognostic ability of the NLR was determined using the receiver operating characteristic (ROC) curve. A cut-off value was defined as that with the highest validity. All variables underwent univariate analysis to determine statistically significant factors that may have outcomes. Only variables which significantly differed were used in the multivariate analysis using the logistic regression method.

Results: We registered 45 cases of AVV. The mean age at diagnosis was 67.5±12.1 years and 23 patients were male. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 26.0±10.4. Twenty-nine patients were ANCA-MPO positive, 7 ANCA-PR3 positive and 9 were considered negative ANCA vasculitis. At admission, mean serum creatinine (SCr) was 4.9±2.5mg/dL, erythrocyte sedimentation rate (ESR) was 76.9±33.8mm/h, hemoglobin was 9.5±1.7g/dL, C-reactive protein was 13.2±5.8mg/dL and NLR was 8.5±6.8. Thirty-five patients were treated with cyclophosphamide, eight patients with rituximab for induction therapy. Twenty patients developed severe infection within the first three months after starting induction immunosuppression. In a multivariate analysis, older age (73.6±10.5 vs. 62.6±11.3, p=0.002, adjusted OR 1.08 [95% CI 1.01-1.16], p=0.035) and higher NLR (11.9±7.4 vs. 5.9±5.0, p=0.002, adjusted OR 1.14 [95% CI 1.01-1.29], p=0.035) were predictors of severe infection at 3 months. NLR ≥4.04 predicted severe infection at 3 months with a sensitivity of 95% and specificity of 52% and the AUROC curve was 0.0794 (95% CI 0.647-0.900). Nine patients died within the first year. Severe infection at 3 months was independently associated with mortality within the first year (OR 6.19 [95% CI 1.12-34.32], p=0.037).

Conclusions: NLR at diagnosis was an independent predictor of severe infection within the first 3 months after immunosuppression start, and severe infection within the first three months was consequently correlated with one-year mortality. NLR is an easily calculated and low-cost laboratory inflammation biomarker and can prove useful in identifying AAV patients at risk of infection and poorer prognosis.
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http://dx.doi.org/10.1016/j.nefro.2020.07.013DOI Listing
December 2020

Management of Acute Kidney Injury Following Major Abdominal Surgery: A Contemporary Review.

J Clin Med 2020 Aug 18;9(8). Epub 2020 Aug 18.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE. Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Acute kidney injury (AKI) is a frequent occurrence following major abdominal surgery and is independently associated with both in-hospital and long-term mortality, as well as with a higher risk of progressing to chronic kidney disease (CKD) and cardiovascular events. Postoperative AKI can account for up to 40% of in-hospital AKI cases. Given the differences in patient characteristics and the pathophysiology of postoperative AKI, it is inappropriate to assume that the management after noncardiac and nonvascular surgery are the same as those after cardiac and vascular surgery. This article provides a comprehensive review on the available evidence on the management of postoperative AKI in the setting of major abdominal surgery.
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http://dx.doi.org/10.3390/jcm9082679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463962PMC
August 2020

Acute Kidney Injury: From Diagnosis to Prevention and Treatment Strategies.

J Clin Med 2020 Jun 2;9(6). Epub 2020 Jun 2.

Department of Medicine, Division of Nephrology and Renal Transplantation, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Acute kidney injury (AKI) is characterized by an acute decrease in renal function that can be multifactorial in its origin and is associated with complex pathophysiological mechanisms. In the short term, AKI is associated with an increased length of hospital stay, health care costs, and in-hospital mortality, and its impact extends into the long term, with AKI being associated with increased risks of cardiovascular events, progression to chronic kidney disease (CKD), and long-term mortality. Given the impact of the prognosis of AKI, it is important to recognize at-risk patients and improve preventive, diagnostic, and therapy strategies. The authors provide a comprehensive review on available diagnostic, preventive, and treatment strategies for AKI.
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http://dx.doi.org/10.3390/jcm9061704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357116PMC
June 2020

Timing of Initiation of Renal Replacement Therapy in Sepsis-Associated Acute Kidney Injury.

J Clin Med 2020 May 10;9(5). Epub 2020 May 10.

Division of Nephrology and Renal Transplantation, Department of Medicine Centro Hospitalar Lisboa Norte, EPE Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Sepsis-associated acute kidney injury (SA-AKI) is a major issue in medical, surgical and intensive care settings and is an independent risk factor for increased mortality, as well as hospital length of stay and cost. SA-AKI encompasses a proper pathophysiology where renal and systemic inflammation play an essential role, surpassing the classic concept of acute tubular necrosis. No specific treatment has been defined yet, and renal replacement therapy (RRT) remains the cornerstone supportive therapy for the most severe cases. The timing to start RRT, however, remains controversial, with early and late strategies providing conflicting results. This article provides a comprehensive review on the available evidence on the timing to start RRT in patients with SA-AKI.
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http://dx.doi.org/10.3390/jcm9051413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290350PMC
May 2020

Transient and Persistent AKI and Outcomes in Patients Undergoing Major Abdominal Surgery.

Nephron 2020 21;144(5):236-244. Epub 2020 Apr 21.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Lisbon, Portugal.

Introduction: Acute kidney injury (AKI) is a frequent diagnosis in surgical patients which has a detrimental effect on short-term and long-term outcomes. The purpose of this study was to evaluate the incidence and predictive factors of transient and persistent postoperative AKI in patients submitted to major abdominal surgery and to characterize the impact of AKI on in-hospital mortality.

Methods: This study was a cross-examination of a retrospective analysis of clinical data of 450 patients who underwent major abdominal surgery from January 2010 to February 2011. Only AKI developing in the first 48 h after surgery was considered. AKI was diagnosed using the Kidney Disease: Improving Global Outcome (KDIGO) classification based on both serum creatinine (SCr) and urine output criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions.

Results: In our study, 22.4% of patients developed AKI in the first 48 h post-surgery (n = 101), and 48% of patients had persistent AKI (n = 49), defined as postoperative AKI, with a duration of more than 48 h. Older age (adjusted odds ratio [OR] 1.06 [1.00-1.11], p = 0.039), hypertension (adjusted OR 4.60 [1.17-18.11], p = 0.029), and higher preoperative SCr (adjusted OR 22.67 [4.00-128.46], p < 0.001) were independent predictors of persistent AKI. The overall in-hospital mortality was 6.4% (n = 29). Persistent AKI was associated with higher mortality than transient AKI (51.9 vs. 20.7%; unadjusted OR 13.03 [5.78-29.36], p < 0.001; adjusted OR 4.20 [1.02-17.27], p = 0.047).

Conclusion: In this cohort of patients submitted to major abdominal surgery, persistent AKI was an independent predictor of in-hospital mortality in contrast to transient AKI.
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http://dx.doi.org/10.1159/000506397DOI Listing
May 2021

Neutrophil, lymphocyte and platelet ratio as a predictor of mortality in septic-acute kidney injury patients.

Nefrologia (Engl Ed) 2020 Jul - Aug;40(4):461-468. Epub 2020 Jan 13.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Background: AKI is frequent in critically ill patients, in whom the leading cause of AKI is sepsis. The role of intrarenal and systemic inflammation appears to be significant in the pathophysiology of septic-AKI. The neutrophils to lymphocytes and platelets (N/LP) ratio is an indirect marker of inflammation. The aim of this study was to evaluate the prognostic ability of N/LP ratio at admission in septic-AKI patients admitted to an intensive care unit (ICU).

Methods: This is a retrospective analysis of 399 septic-AKI patients admitted to the Division of Intensive Medicine of the Centro Hospitalar Universitário Lisboa Norte between January 2008 and December 2014. The Kidney Disease Improving Global Outcomes (KDIGO) classification was used to define AKI. N/LP ratio was calculated as: (Neutrophil count×100)/(Lymphocyte count×Platelet count).

Results: Fifty-two percent of patients were KDIGO stage 3, 25.8% KDIGO stage 2 and 22.3% KDIGO stage 1. A higher N/LP ratio was an independent predictor of increased risk of in-hospital mortality in septic-AKI patients regardless of KDIGO stage (31.59±126.8 vs 13.66±22.64, p=0.028; unadjusted OR 1.01 (95% CI 1.00-1.02), p=0.027; adjusted OR 1.01 (95% CI 1.00-1.02), p=0.015). The AUC for mortality prediction in septic-AKI was of 0.565 (95% CI (0.515-0.615), p=0.034).

Conclusions: The N/LP ratio at ICU admission was independently associated with in-hospital mortality in septic-AKI patients.
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http://dx.doi.org/10.1016/j.nefro.2019.11.006DOI Listing
January 2020

Neutrophil, lymphocyte and platelet ratio as a predictor of postoperative acute kidney injury in major abdominal surgery.

BMC Nephrol 2018 11 12;19(1):320. Epub 2018 Nov 12.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035, Lisbon, Portugal.

Background: Surgery is one of the leading causes of acute kidney injury (AKI) in hospitalized patients. Major abdominal surgery has the second higher incidences of AKI, after cardiac surgery. AKI results from a complex interaction between hemodynamic, toxic and inflammatory factors. The pathogenesis of AKI following major abdominal surgery is distinct from cardiac and vascular surgery. The neutrophil, lymphocytes and platelets (N/LP) ratio has been demonstrated as an inflammatory marker and an independent predictor for AKI and mortality after cardiovascular surgery. The aim of this study was to evaluate the prognostic ability of the post-operative N/LP ratio after major abdominal surgery.

Methods: We cross-examined data of a retrospective analysis of 450 patients who underwent elective or urgent major nonvascular abdominal surgery at the Department of Surgery II of Centro Hospitalar Lisboa Norte from January 2010 to February 2011. N/LP ratio was determined using maximal neutrophil counts and minimal lymphocyte and platelet counts in the first 12 h after surgery. AKI was considered when developed within 48 h after surgery.

Results: One-hundred and one patients (22.4%) developed AKI. Patients with higher N/LP ratio had an increased risk of developing postoperative AKI (6.36 ± 7.34 vs 4.33 ± 3.36, p < 0.001; unadjusted OR 1.1 (95% CI 1.04-1.16), p = 0.001; adjusted OR 1.05 (95% CI 1.00-1.10), p = 0.048). Twenty-nine patients died (6.44%). AKI was an independent predictor of mortality (20.8 vs 2.3%, p < 0.0001; unadjusted OR 11.2, 95% CI 4. 8-26.2, p < 0.0001; adjusted OR 3.56, 95% CI 1.0 2-12.43, p = 0.046). In a multivariate analysis higher N/LP ratio was not associated with increased in-hospital mortality.

Conclusion: Postoperative N/LP ratio was independently associated with AKI after major abdominal surgery, although there was no association with in-hospital mortality.
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http://dx.doi.org/10.1186/s12882-018-1073-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231266PMC
November 2018

Acute Kidney Injury Definition and Diagnosis: A Narrative Review.

J Clin Med 2018 Sep 28;7(10). Epub 2018 Sep 28.

Division of Nephrology and Renal Transplantation, Department of Medicine Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.

Acute kidney injury (AKI) is a complex syndrome characterized by a decrease in renal function and associated with numerous etiologies and pathophysiological mechanisms. It is a common diagnosis in hospitalized patients, with increasing incidence in recent decades, and associated with poorer short- and long-term outcomes and increased health care costs. Considering its impact on patient prognosis, research has focused on methods to assess patients at risk of developing AKI and diagnose subclinical AKI, as well as prevention and treatment strategies, for which an understanding of the epidemiology of AKI is crucial. In this review, we discuss the evolving definition and classification of AKI, and novel diagnostic methods.
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http://dx.doi.org/10.3390/jcm7100307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211018PMC
September 2018

Prediction of acute kidney injury in cirrhotic patients: a new score combining renal, liver and inflammatory markers.

Int J Nephrol Renovasc Dis 2018 24;11:149-154. Epub 2018 Apr 24.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, Lisboa, Portugal.

Introduction: Acute kidney injury (AKI) is common in hospitalized patients with cirrhosis and is associated with poor prognosis. A risk prediction score combining values easily measured at admission could be valuable to stratify patients for prevention, monitoring and early intervention, ultimately improving patient care and outcomes. The aim of this study was to develop a risk score for AKI in a cohort of cirrhotic patients.

Patients And Methods: We cross-examined the data from a retrospective analysis of 186 patients with cirrhosis admitted to the Gastroenterology and Hepatology Service of Centro Hospitalar Lisboa Norte from January 2003 to December 2005. AKI was defined as an increase in serum creatinine (SCr)≥0.3 mg/dL within 48 hours or a percentage increase in SCr≥50% from baseline. Neutrophil-to-lymphocyte ratio (NLR) was used as a marker for inflammation. A receiver operating characteristic (ROC) curve was produced to assess the discriminative ability of the variables. Cutoff values were defined as those with highest validity. The final AKI risk score model was assessed using the ROC curve.

Results: A total of 52 patients (28%) developed AKI. Higher baseline SCr (<0.001), more severe liver disease as evaluated by the modified Model of End-stage Liver Disease (MELD)-Na score (<0.001) and higher NLR (=0.028) were independently associated with AKI. The area under the ROC (AUROC) curve for the prediction of AKI was 0.791 (95% CI 0.726-0.847) for SCr, 0.771 (95% CI 0.704-0.829) for modified MELD-Na and 0.757 (95% CI 0.689-0.817) for NLR. Cutoff values with the highest validity for predicting AKI were determined and defined as 0.9 for the SCr, 21.7 for the modified MELD-Na and 6 for the NLR. The risk score was created allowing 3 points if the SCr is higher than 0.9, 1 point if the modified MELD-Na is higher than 21.7 and 1 point if the NLR is higher than 6. The AUROC curve of the risk prediction score for AKI was 0.861. A risk score of ≥2 points predicts AKI in cirrhotic patients with a sensitivity of 88.5% and specificity of 72.4%.

Conclusion: A new score combining SCr, MELD-Na and NLR demonstrated a strong discriminative ability to predict AKI in cirrhotic patients.
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http://dx.doi.org/10.2147/IJNRD.S163602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923222PMC
April 2018

Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes.

Ann Intensive Care 2018 Feb 9;8(1):22. Epub 2018 Feb 9.

Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035, Lisbon, Portugal.

Acute kidney injury (AKI) is a common complication in patients undergoing major abdominal surgery. Various recent studies using modern standardized classifications for AKI reported a variable incidence of AKI after major abdominal surgery ranging from 3 to 35%. Several patient-related, procedure-related factors and postoperative complications were identified as risk factors for AKI in this setting. AKI following major abdominal surgery has been shown to be associated with poor short- and long-term outcomes. Herein, we provide a contemporary and critical review of AKI after major abdominal surgery focusing on its incidence, risk factors, pathogeny and outcomes.
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http://dx.doi.org/10.1186/s13613-018-0369-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807256PMC
February 2018