2. Review of the literature
2.4 Chronic kidney disease among joint replacement patients
2.4.6 Acute kidney injury in joint replacement surgery
The incidence of postoperative AKI after TJA varies between 0.5 and 15% (Ferguson et al., 2017; Jafari et al., 2010; Kimmel et al., 2014; Nowicka & Selvaraj, 2016;
Perregaard et al., 2016). It increases short and long-term mortality regardless of need for dialysis in general population (Lafrance & Miller, 2010; Sawhney et al., 2017).
There is also one review article supporting this finding among knee replacement patients (Siddiqi et al., 2017).
Major risk factors for AKI in joint replacement populations are pre-existing CKD, obesity, diabetes, chronic obstructive pulmonary disease, liver disease, congestive heart failure, hypertension and vascular disease (Jafari et al., 2010; Tan et al., 2016;
Weingarten et al., 2012). Perioperatively, general anesthesia and blood transfusions are also associated with postoperative AKI (Weingarten et al., 2012). American Society of Anesthesiologists (ASA) score as an indicator of morbidity burden (Saklad, 1941) has also been studied as a risk predictor for AKI (Jafari et al., 2010; Kimmel et al., 2014), but surprisingly, no connection was reported. It has been suggested that nephrotoxic antibiotics such as aminoglycosides, as an intravenous prophylaxis or in bone cement,
37
could trigger AKI in joint replacement patients (Bell et al., 2014; Craxford et al., 2014;
Curtis et al., 2005; Lau & Kumar, 2013; Patrick et al., 2006; Ross et al., 2013). There are also a case report of rhabdomyolysis followed by AKI after tourniquet use in knee replacement (Palmer & Graham, 1994). There is moreover a trend for longer
operating time to be associated with postoperative AKI, but the results did not reach statistical significance (Jafari et al., 2010; Kimmel et al., 2014; Weingarten et al., 2012).
There is no information about the triggering factor or underlying causes for AKI in arthroplasty population and thus its prevention is difficult. Also, the association between operation duration and ASA score with AKI is yet to be defined.
36
Thus, there is a paucity of long-term data concerning the effect of CKD on overall revision rate after TJA. Also, there are contradictory results as to whether CKD has an association with PJI. Also, revision has competing risks, such as death. Therefore, competing risk analysis is recommended instead of traditional Kaplan-Meier and Cox regression analyses whenever performing survival analysis (Lacny et al., 2015).
Cumulative incidence function (CIF) and Fine and Gray analyses are thus the preferred methods in assessing association in the presence of competing risk. (Lacny et al., 2015; Ranstam & Robertsson, 2017; Van Der Pas et al., 2018). None of these (previous) studies included death as a competing risk in their analyses.
2.4.6 Acute kidney injury in joint replacement surgery
The incidence of postoperative AKI after TJA varies between 0.5 and 15% (Ferguson et al., 2017; Jafari et al., 2010; Kimmel et al., 2014; Nowicka & Selvaraj, 2016;
Perregaard et al., 2016). It increases short and long-term mortality regardless of need for dialysis in general population (Lafrance & Miller, 2010; Sawhney et al., 2017).
There is also one review article supporting this finding among knee replacement patients (Siddiqi et al., 2017).
Major risk factors for AKI in joint replacement populations are pre-existing CKD, obesity, diabetes, chronic obstructive pulmonary disease, liver disease, congestive heart failure, hypertension and vascular disease (Jafari et al., 2010; Tan et al., 2016;
Weingarten et al., 2012). Perioperatively, general anesthesia and blood transfusions are also associated with postoperative AKI (Weingarten et al., 2012). American Society of Anesthesiologists (ASA) score as an indicator of morbidity burden (Saklad, 1941) has also been studied as a risk predictor for AKI (Jafari et al., 2010; Kimmel et al., 2014), but surprisingly, no connection was reported. It has been suggested that nephrotoxic antibiotics such as aminoglycosides, as an intravenous prophylaxis or in bone cement,
37
could trigger AKI in joint replacement patients (Bell et al., 2014; Craxford et al., 2014;
Curtis et al., 2005; Lau & Kumar, 2013; Patrick et al., 2006; Ross et al., 2013). There are also a case report of rhabdomyolysis followed by AKI after tourniquet use in knee replacement (Palmer & Graham, 1994). There is moreover a trend for longer
operating time to be associated with postoperative AKI, but the results did not reach statistical significance (Jafari et al., 2010; Kimmel et al., 2014; Weingarten et al., 2012).
There is no information about the triggering factor or underlying causes for AKI in arthroplasty population and thus its prevention is difficult. Also, the association between operation duration and ASA score with AKI is yet to be defined.
38
3. Aims
The aim of this study is to investigate preoperative renal function and its effects on postoperative complications and postoperative renal function impairment after lower extremity joint replacement. Four different studies, published in peer reviewed medical journals, comprise an academic dissertation with the aims presented in detail below:
1. To study the incidence and risk factors of acute kidney injury after joint replacement and long-term mortality of AKI patients postoperatively.
2. To study the prevalence of CKD, to ascertain which patients have the greatest prevalence of CKD and to assess the accuracy of serum creatinine in the prediction of CKD established by eGFR formulas.
3. To study the effect of renal function on short- and long-term mortality after joint replacement.
4. To study the effect of renal function on implant survival and PJI-free survival after joint replacement.
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4. Materials and methods
4.1 Study setting and design
The study was performed in Coxa Hospital for Joint Replacement, a large publicly funded tertiary orthopedic center specializing solely in joint replacement operations.
Annually, over 5,000 joint primary and revision joint replacements are performed.
This hospital is responsible for all joint replacement operations in its catchment area (approx. 515,000 inhabitants), but also treats more complex referral patients outside its area. Coxa has a comprehensive electronic database, the Coxa Datapool, that includes systematically and prospectively collected data pre- peri- and postoperative data including up-to-date information on revisions performed in Coxa and deaths of patients. Mortality data is collated with Statistics Finland on a weekly basis.
4.2 Study population (Studies 1-3)
The study population consisted of all consecutive primary and revision hip and knee joint replacement operations performed between September 2002 and December 2011 (n=20,575). A total of 1,031 (5%) patients were excluded due to lack of preoperatively measured SCr value. A further 969 (5%) patients were excluded due to undergoing an emergency operation. Thus, all remaining 18,575 operations were elective. Among the excluded patients there were fewer females (59 vs. 63%; p < 0.001), fewer knee replacements (31 vs. 53%; p < 0.001) and lower body mass index (BMI) (median 27.5 vs. 28.6kg/m2; p < 0.001) than in the study population.
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3. Aims
The aim of this study is to investigate preoperative renal function and its effects on postoperative complications and postoperative renal function impairment after lower extremity joint replacement. Four different studies, published in peer reviewed medical journals, comprise an academic dissertation with the aims presented in detail below:
1. To study the incidence and risk factors of acute kidney injury after joint replacement and long-term mortality of AKI patients postoperatively.
2. To study the prevalence of CKD, to ascertain which patients have the greatest prevalence of CKD and to assess the accuracy of serum creatinine in the prediction of CKD established by eGFR formulas.
3. To study the effect of renal function on short- and long-term mortality after joint replacement.
4. To study the effect of renal function on implant survival and PJI-free survival after joint replacement.
39
4. Materials and methods
4.1 Study setting and design
The study was performed in Coxa Hospital for Joint Replacement, a large publicly funded tertiary orthopedic center specializing solely in joint replacement operations.
Annually, over 5,000 joint primary and revision joint replacements are performed.
This hospital is responsible for all joint replacement operations in its catchment area (approx. 515,000 inhabitants), but also treats more complex referral patients outside its area. Coxa has a comprehensive electronic database, the Coxa Datapool, that includes systematically and prospectively collected data pre- peri- and postoperative data including up-to-date information on revisions performed in Coxa and deaths of patients. Mortality data is collated with Statistics Finland on a weekly basis.
4.2 Study population (Studies 1-3)
The study population consisted of all consecutive primary and revision hip and knee joint replacement operations performed between September 2002 and December 2011 (n=20,575). A total of 1,031 (5%) patients were excluded due to lack of preoperatively measured SCr value. A further 969 (5%) patients were excluded due to undergoing an emergency operation. Thus, all remaining 18,575 operations were elective. Among the excluded patients there were fewer females (59 vs. 63%; p < 0.001), fewer knee replacements (31 vs. 53%; p < 0.001) and lower body mass index (BMI) (median 27.5 vs. 28.6kg/m2; p < 0.001) than in the study population.
40
4.3 Study population (Study 4)
The study population consisted of all elective primary hip and knee replacements performed for primary osteoarthritis between February 1, 2008 and May 30, 2017 (n = 19,779). Eight hundred (4%) of the patients were excluded due to lacking preoperative SCr. After exclusion, 18,979 joint replacements were used in the analyses. The
excluded group had more males (4.7% vs. 3.7%; p < 0.001) and hip replacements (4.8% vs. 3.5%; p <0.001) than were included in the study population. BMI was also lower in the excluded group (medians 28 vs. 29 p <0.001).
4.4 Data collection
4.4.1 Preoperative data
Patient demographics; Age, sex, height, weight, BMI, preoperative Harris hip score, Knee Society score and preoperative diagnosis were collected from the electronic database. Preoperative SCr and hemoglobin were collected from the local laboratory that provides laboratory services to the hospital district and most of the municipalities in the catchment area. SCr is usually measured as a part of pre-anesthesia evaluation one to two months prior to the operation. However, SCr measurements taken six months prior to the operation were accepted in Studies 1-3 and SCr measurements taken 12 months prior to the operation in Study 4. If there were multiple SCr measurements prior to the operation, the most recent one was used.
41
In Studies 1-3, major comorbidities; diabetes mellitus, hypertension, congestive heart failure (CHF), coronary disease (CD), and information on dialysis were collected from the national medication reimbursement register. Finnish citizens are entitled to partial reimbursement for their medication expenses if they have been issued with a written statement by their physician. The criteria for reimbursement in these diseases are presented in Table 4. Reimbursement is a major financial benefit for the patients and therefore most patients use it when eligible. It is noteworthy that the reimbursement criteria for hypertension medication are stricter than the diagnostic criteria and therefore not all patients with hypertension were identified. In Study 4, all comorbid conditions were obtained from the Coxa Datapool that contains patient´s self-reported medical conditions. For Study 1, patients with postoperative AKI, patients´
medical records were reviewed to ascertain if a patient was taking NSAIDs, diuretics, angiotensin converting enzyme inhibitors or angiotensin receptor blockers
preoperatively.
Table 4. Reimbursement criteria
Morbidity Criteria for reimbursement
Diabetes If fasting plasma or capillary blood glucose concentration exceeds 7.0mmol/l in two separate measurements on two different days, if plasma glucose level exceeds 11.0mmol/l once, positive glucose tolerance test (2h value exceeding 11mmol/l) is obtained, or if glycosylated hemoglobin A (HbA1c) level exceeds 48mmol/mol (6.5%). If diagnosis is based on glucose tolerance test and typical symptoms of diabetes are lacking, measurements have to be repeated once. Before 4th November 2010: 1. Among overweight (BMI over 25kg/m2) patients with diabetes type II, 6 months of diet therapy was required before reimbursement. 2. Patients with diabetes type II had to be treated for 6 months with diabetes medications to gain reimbursement.
Hypertension If systolic or diastolic blood pressure (BP) ≥200mmHg or ≥105 in repeated measurements.
Patients with age < 50 in male or < 40 in female, severe vascular morbidities in family at young age, diabetes, dyslipidemia, sign of organ dysfunction caused by elevated blood pressure or systolic BP repeatedly ≥180mmHg can achieve reimbursement right for hypertension medication if their diastolic BP exceeds 95mmHg in repeated measurements.
Patients with CKD, proven aneurysms, or chronic bleeding can also be granted reimbursement regardless of their BP values.
Coronary disease Reimbursement for coronary disease requires persistent angina pectoris symptoms that relieves with medication. If resting electrocardiogram (ECG) does not show clear sign of existence of coronary disease, an exercise test has to be carried out. Reimbursement is also granted if a patient has had a myocardial infarction, has undergone coronary artery bypass or angioplasty, or if a patient has chest pain with proven coronary artery constriction in coronary angiography.
Uremia requiring
dialysis A statement by a specialist is required.
Anemia of chronic
kidney disease A statement from a nephrologist, hematologist, pediatrist, or specialist in internal medicine is required.
Source: Kela. http://www.kela.fi/laakkeet-ja-laakekorvaukset_erityiskorvaus (19.10.2016) (Finnish).
40
4.3 Study population (Study 4)
The study population consisted of all elective primary hip and knee replacements performed for primary osteoarthritis between February 1, 2008 and May 30, 2017 (n = 19,779). Eight hundred (4%) of the patients were excluded due to lacking preoperative SCr. After exclusion, 18,979 joint replacements were used in the analyses. The
excluded group had more males (4.7% vs. 3.7%; p < 0.001) and hip replacements (4.8% vs. 3.5%; p <0.001) than were included in the study population. BMI was also lower in the excluded group (medians 28 vs. 29 p <0.001).
4.4 Data collection
4.4.1 Preoperative data
Patient demographics; Age, sex, height, weight, BMI, preoperative Harris hip score, Knee Society score and preoperative diagnosis were collected from the electronic database. Preoperative SCr and hemoglobin were collected from the local laboratory that provides laboratory services to the hospital district and most of the municipalities in the catchment area. SCr is usually measured as a part of pre-anesthesia evaluation one to two months prior to the operation. However, SCr measurements taken six months prior to the operation were accepted in Studies 1-3 and SCr measurements taken 12 months prior to the operation in Study 4. If there were multiple SCr measurements prior to the operation, the most recent one was used.
41
In Studies 1-3, major comorbidities; diabetes mellitus, hypertension, congestive heart failure (CHF), coronary disease (CD), and information on dialysis were collected from the national medication reimbursement register. Finnish citizens are entitled to partial reimbursement for their medication expenses if they have been issued with a written statement by their physician. The criteria for reimbursement in these diseases are presented in Table 4. Reimbursement is a major financial benefit for the patients and therefore most patients use it when eligible. It is noteworthy that the reimbursement criteria for hypertension medication are stricter than the diagnostic criteria and therefore not all patients with hypertension were identified. In Study 4, all comorbid conditions were obtained from the Coxa Datapool that contains patient´s self-reported medical conditions. For Study 1, patients with postoperative AKI, patients´
medical records were reviewed to ascertain if a patient was taking NSAIDs, diuretics, angiotensin converting enzyme inhibitors or angiotensin receptor blockers
preoperatively.
Table 4. Reimbursement criteria
Morbidity Criteria for reimbursement
Diabetes If fasting plasma or capillary blood glucose concentration exceeds 7.0mmol/l in two separate measurements on two different days, if plasma glucose level exceeds 11.0mmol/l once, positive glucose tolerance test (2h value exceeding 11mmol/l) is obtained, or if glycosylated hemoglobin A (HbA1c) level exceeds 48mmol/mol (6.5%). If diagnosis is based on glucose tolerance test and typical symptoms of diabetes are lacking, measurements have to be repeated once. Before 4th November 2010: 1. Among overweight (BMI over 25kg/m2) patients with diabetes type II, 6 months of diet therapy was required before reimbursement. 2. Patients with diabetes type II had to be treated for 6 months with diabetes medications to gain reimbursement.
Hypertension If systolic or diastolic blood pressure (BP) ≥200mmHg or ≥105 in repeated measurements.
Patients with age < 50 in male or < 40 in female, severe vascular morbidities in family at young age, diabetes, dyslipidemia, sign of organ dysfunction caused by elevated blood pressure or systolic BP repeatedly ≥180mmHg can achieve reimbursement right for hypertension medication if their diastolic BP exceeds 95mmHg in repeated measurements.
Patients with CKD, proven aneurysms, or chronic bleeding can also be granted reimbursement regardless of their BP values.
Coronary disease Reimbursement for coronary disease requires persistent angina pectoris symptoms that relieves with medication. If resting electrocardiogram (ECG) does not show clear sign of existence of coronary disease, an exercise test has to be carried out. Reimbursement is also granted if a patient has had a myocardial infarction, has undergone coronary artery bypass or angioplasty, or if a patient has chest pain with proven coronary artery constriction in coronary angiography.
Uremia requiring
dialysis A statement by a specialist is required.
Anemia of chronic
kidney disease A statement from a nephrologist, hematologist, pediatrist, or specialist in internal medicine is required.
Source: Kela. http://www.kela.fi/laakkeet-ja-laakekorvaukset_erityiskorvaus (19.10.2016) (Finnish).
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4.4.2 Perioperative data
Perioperative data was collected from the Coxa Datapool including operated joint, operation type (primary or revision), surgical approach, operating time, laterality (uni- or bilateral operation), use of antibiotic bone cement, intravenous antibiotic
prophylaxis, and anesthesia modality. For Study 1, perioperative contributing factors to AKI were collected from patients´ medical records including; baseline systolic blood pressure, blood transfusions, perioperative NSAIDs or use of vasoactive substances such as atropine of etilefrine.
4.4.3 Postoperative data
Postoperative mortality data was collected from the Coxa Datapool, which obtains the data from the Finnish, nationwide population register, that also includes separately reported deaths from abroad. Thus, only unreported deaths occurring abroad are lacking and the mortality data are practically complete. In Studies 1 and 3, deaths were recorded until April 9, 2016. In Study 4, data on revision operations and deaths were obtained from the Coxa Datapool until September 20, 2019. The datapool includes only revision operations performed in Coxa. Nevertheless, the datapool includes over 95% of all revisions performed. Revision was defined as removal or exchange of any prosthesis component after primary operation. Revisions for PJI were also obtained from this database. In Study 4, patients were followed up until revision replacement, death or September 20, 2019, whichever occurred first.
To assess postoperative AKI in Study 1, all SCr values were collected during seven postoperative days. Due to the retrospective nature of the study, postoperatively SCr was measured only when clinically relevant. Such measurements were available for
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only 5,609 patients (30%). These patients differed from the rest of the patients. They had lower eGFR preoperatively (76ml/min/1.72m2 vs. 87ml/min/1.72m2), older age (76 vs. 67 years) higher ASA classification (median ASA grade 3 vs. 2) and longer duration of operation (105 vs. 100 min). Also, 5,361 (29%) patients had a different laboratory register in their home municipality and thus after discharge from the hospital, postoperative SCr values were not obtained. Patient files of AKI patients were reviewed to assess potential causes of AKI, need for postoperative dialysis and to make sure that none of the AKI cases were on dialysis preoperatively.
4.5 Data processing
Preoperative SCr values and patient demographics were used to calculate eGFR value (Table 5) (Cockcroft & Gault, 1976; Levey, A. S. et al., 1999; Levey, Andrew S. et al., 2009). All patients were presumed to be Caucasians. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used in Studies 1, 3, and 4 while CKD-EPI, Cockcroft Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations were used in Study 2. According to the eGFR value, patients were classified into five different CKD stages (Table 1) in Studies 1, 3, and 4 (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013; Levey, Andrew S. et al., 2003), while in Study 2, patients were classified as having CKD, or not having CKD, CKD being defined as eGFR < 60ml/min/1.72m2. When using CKD stage in statistical analysis (Studies 3 and 4) CKD stages 4-5 were combined due to the small number of patients to increase the statistical power. Dialysis patients were classified to CKD stage 5 regardless of their preoperative eGFR values. Proteinuria or albuminuria was not considered when assessing the severity of CKD (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013). Anemia was defined as hemoglobin value lower than 117g/L in females and lower than 134 g/L in males. In Studies 2 and 3, SCr lower than 90µmol/l in females and 100µmol/l in males was considered
42
4.4.2 Perioperative data
Perioperative data was collected from the Coxa Datapool including operated joint, operation type (primary or revision), surgical approach, operating time, laterality (uni- or bilateral operation), use of antibiotic bone cement, intravenous antibiotic
prophylaxis, and anesthesia modality. For Study 1, perioperative contributing factors to AKI were collected from patients´ medical records including; baseline systolic blood pressure, blood transfusions, perioperative NSAIDs or use of vasoactive substances such as atropine of etilefrine.
4.4.3 Postoperative data
Postoperative mortality data was collected from the Coxa Datapool, which obtains the data from the Finnish, nationwide population register, that also includes separately
Postoperative mortality data was collected from the Coxa Datapool, which obtains the data from the Finnish, nationwide population register, that also includes separately