Chronic Kidney Disease in Patients Undergoing Hip or Knee Joint Replacement

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Tampere University Dissertations 489

PYRY JÄMSÄ

Chronic Kidney Disease in Patients Undergoing Hip or Knee Joint

Replacement

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PYRY JÄMSÄ Chronic Kidney Disease in Patients Undergoing Hip or Knee Joint Replacement

ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Medicine and Health Technology

of Tampere University,

for public discussion in the F115 auditorium of the Arvo building, Arvo ylpön katu 34, Tampere,

on 26 November 2021, at 13 o’clock.

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PYRY JÄMSÄ Chronic Kidney Disease in Patients Undergoing Hip or Knee Joint Replacement

ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Medicine and Health Technology

of Tampere University,

for public discussion in the F115 auditorium of the Arvo building, Arvo ylpön katu 34, Tampere,

on 26 November 2021, at 13 o’clock.

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ACADEMIC DISSERTATION

Tampere University, Faculty of Medicine and Health Technology Finland

Responsible supervisor and Custos

Professor Niku Oksala Tampere University Finland

Supervisors Docent Antti Eskelinen Tampere University Finland

Professor tenure track Esa Jämsen Tampere University

Finland Pre-examiners Docent Anne Vakkuri

University of Helsinki Finland

Docent Hannu Miettinen University of Eastern Finland Finland

Opponent Docent Petri Virolainen University of Turku Finland

The originality of this thesis has been checked using the Turnitin OriginalityCheck service.

ISBN 978-952-03-2138-3 (print) ISBN 978-952-03-2139-0 (pdf) ISSN 2489-9860 (print)

ISSN 2490-0028 (pdf)

http://urn.fi/URN:ISBN:978-952-03-2139-0

PunaMusta Oy – Yliopistopaino Joensuu 2021

iii Silmät suljen, lipuu elämäni paatti

Kipparina sosiaalidemokraatti Mutten mieti sitä kuka vastaa laivasta Kun katson sinitaivasta

- Juha Vainio, kun aurinko lämmittää

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ACADEMIC DISSERTATION

Tampere University, Faculty of Medicine and Health Technology Finland

Responsible supervisor and Custos

Professor Niku Oksala Tampere University Finland

Supervisors Docent Antti Eskelinen Tampere University Finland

Professor tenure track Esa Jämsen Tampere University

Finland Pre-examiners Docent Anne Vakkuri

University of Helsinki Finland

Docent Hannu Miettinen University of Eastern Finland Finland

Opponent Docent Petri Virolainen University of Turku Finland

The originality of this thesis has been checked using the Turnitin OriginalityCheck service.

ISBN 978-952-03-2138-3 (print) ISBN 978-952-03-2139-0 (pdf) ISSN 2489-9860 (print)

ISSN 2490-0028 (pdf)

http://urn.fi/URN:ISBN:978-952-03-2139-0

PunaMusta Oy – Yliopistopaino Joensuu 2021

iii Silmät suljen, lipuu elämäni paatti

Kipparina sosiaalidemokraatti Mutten mieti sitä kuka vastaa laivasta Kun katson sinitaivasta

- Juha Vainio, kun aurinko lämmittää

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iv v

ABSTRACT

Chronic kidney disease (CKD) is a common comorbidity in patients undergoing hip or knee replacement. Kidney function can be classified into five different CKD stages, where CKD stage 1 denotes normal function, and CKD stage 5 denotes kidney failure.

CKD stages 3-5 correspond to the traditional definition of CKD; glomerular filtration rate (GFR) lower than 60mL/min/1.73m². CKD increases postoperative morbidity, affects drug dosages and perioperative care, predisposes to risk for postoperative kidney injury and the most severe forms of CKD are known to be associated with increased postoperative mortality. It is not known whether the most CKD stages 2-3, affects mortality or not after total joint arthroplasty. It is not known if renal impairment reduces implant survival in the long term, while earlier studies reporting on implant survival have not considered the competing risk of death in CKD patients. Also, there are some unclear risk factors for postoperative acute kidney injury (AKI). The present study sought to ascertain how common renal impairment and postoperative AKI are and whether serum creatinine (SCr) value discriminates between patients with CKD and those without CKD. The study also examined the risk factors associated with AKI and ascertained whether long-term mortality or implant survival is associated with renal function.

The present study used a large cohort of patient and follow-up data from a single centre with all its consecutive hip and knee replacements to answer the study questions.

Mortality data was linked to the study from the exclusive national Population Register Centre.

Supported by earlier literature, prevalence of CKD varied from nine to thirteen percent depending on the calculation method, while two thirds of patients had decreased kidney

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iv v

ABSTRACT

Chronic kidney disease (CKD) is a common comorbidity in patients undergoing hip or knee replacement. Kidney function can be classified into five different CKD stages, where CKD stage 1 denotes normal function, and CKD stage 5 denotes kidney failure.

CKD stages 3-5 correspond to the traditional definition of CKD; glomerular filtration rate (GFR) lower than 60mL/min/1.73m². CKD increases postoperative morbidity, affects drug dosages and perioperative care, predisposes to risk for postoperative kidney injury and the most severe forms of CKD are known to be associated with increased postoperative mortality. It is not known whether the most CKD stages 2-3, affects mortality or not after total joint arthroplasty. It is not known if renal impairment reduces implant survival in the long term, while earlier studies reporting on implant survival have not considered the competing risk of death in CKD patients. Also, there are some unclear risk factors for postoperative acute kidney injury (AKI). The present study sought to ascertain how common renal impairment and postoperative AKI are and whether serum creatinine (SCr) value discriminates between patients with CKD and those without CKD. The study also examined the risk factors associated with AKI and ascertained whether long-term mortality or implant survival is associated with renal function.

The present study used a large cohort of patient and follow-up data from a single centre with all its consecutive hip and knee replacements to answer the study questions.

Mortality data was linked to the study from the exclusive national Population Register Centre.

Supported by earlier literature, prevalence of CKD varied from nine to thirteen percent depending on the calculation method, while two thirds of patients had decreased kidney

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vi

function (CKD stage > 1). Preoperative CKD was most common in older female patients, knee replacement patients and also in patients with other comorbidities. If clinicians were to use increased SCr to filter CKD, they would miss up to 7% of CKD patients. However, among older female patients and older normal weight patients, a remarkable amount (up to 70%) of CKD would have gone unnoticed. Incidence of postoperative AKI was only 3.3/1,000 (95% CI 2.5-4.5/ 1,000 operations). In multivariable analysis, independent risk factors associated with postoperative AKI were duration of the operation, ASA-class, body mass index (BMI) and preoperative eGFR, in which duration of the operation was not reported earlier. Early prosthetic joint infections (PJIs) were most dominantly found to be the main trigger for AKI.

When considering confounding factors, at median follow-up of 7.8 years, when comparing to patients with CKD stage 1, adjusted Hazard Ratio for death was 1.9 (95%

CI 1.8-2.1) in stage 2, 3.8 (95% CI 3.4-4.2) in stage 3, and 8.1 (95% CI 6.3-10.3) in patients with stage 4-5. CKD patients had a surprisingly high mortality rate; at five and ten years postoperatively, 21% and 68% of the patients with CKD stage 3 had died, while the corresponding numbers were 47% and 87% in patients with CKD 4-5.

However, renal function had no significant association with implant survival or infection free survival even when considering high mortality of patients with CKD stages 3-5 as a competing risk. Due to a lack of patients with the most severe forms of CKD (CKD stages 4-5) it was not possible to show if these patients are at increased risk for revision.

In clinical practice, after taking note of the results of this study, it is recommended always to calculate eGFR when considering a TJA. eGFR based classification of CKD stages should be reviewed alongside with other major comorbid conditions when assessing the risks and benefits of the operation. In order to prevent AKI, we could recommend considering patients’ BMI, ASA grade, BMI preoperatively and initiate interventions prior to. Postoperatively, it might be useful to pay attention to patients’

SCr and urine output whenever the operating time exceeds two hours.

vii

TIIVISTELMÄ

Munuaisten vajaatoiminnassa munuaiskeräsen suodattumisnopeus (eGFR) on alle 60mL/min/1.73m². Munuaistoiminta voidaan myös jakaa tarkemmin viiteen luokkaan (CKD-luokka), jossa CKD luokka 1 vastaa täysin normaalia munuaisten toimintaa ja luokka 5 käytännössä menetettyä munuaistoimintaa. Munuaisten vajaatoiminta lisää leikkauksenjälkeistä sairastuvuutta ja riskiä akuutille munuaisvauriolle leikkauksen jälkeen. Se vaikuttaa potilaan hoitoon leikkausta edeltävästä ajasta aina leikkauksen jälkeiseen aikaan. Myös tiedetään sen vakavimpien muotojen lisäävän leikkauksenjälkeistä kuolleisuutta. Munuaisten vajaatoiminnan tunnistaminen ennen leikkausta on tärkeää, jotta potilaalla ja hoitavalla lääkärillä on riittävät tiedot potilaaseen kohdistuvista riskeistä, potilaan tarvitsemasta erityishoidosta ja leikkauksen hyöty- haittasuhteesta. Ei tiedetä, vaikuttaako munuaisten vajaatoiminnan lievä muoto potilaan kuolleisuuteen. Myöskään munuaisten vajaatoiminnan vaikutus uusintaleikkausriskiin pitkällä aikavälillä on ei ole tiedossa. Aiemmissa tutkimuksissa munuaisten vajaatoimintapotilaiden lisääntynyttä kuolleisuutta ei ole otettu huomioon uusintaleikkausriskiä arvioitaessa. Lisäksi akuutin munuaisvaurion riskitekijöistä on ristiriitaisia tuloksia. Tutkimuksessa selvitetään munuaisten vajaatoiminnan ja toimenpiteen jälkeisen akuutin munuaisvaurion yleisyys ja riskitekijät tekonivelpotilailla sekä selvitetään, voidaanko seerumin kreatiniinimäärityksen perusteella erotella munuaisten vajaatoimintapotilaat muista. Tutkimuksessa selvennetään myös munuaisten vajaatoiminnan eri asteiden vaikutusta tekonivelleikkauksen jälkeiseen kuolleisuuteen ja uusintaleikkausriskiin.

Osatöissä 1-3 käytettiin aineistona tekonivelsairaala Coxan 18,757 peräkkäistä, vuosina 2002-2011 leikattua polvi- ja lonkkatekonivelpotilasta. Osatyössä 4 tutkimusaineiston muodostivat 18,979 vuosina 2008-2017 leikattua potilasta. Potilaiden tiedot on kerätty

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vi

function (CKD stage > 1). Preoperative CKD was most common in older female patients, knee replacement patients and also in patients with other comorbidities. If clinicians were to use increased SCr to filter CKD, they would miss up to 7% of CKD patients. However, among older female patients and older normal weight patients, a remarkable amount (up to 70%) of CKD would have gone unnoticed. Incidence of postoperative AKI was only 3.3/1,000 (95% CI 2.5-4.5/ 1,000 operations). In multivariable analysis, independent risk factors associated with postoperative AKI were duration of the operation, ASA-class, body mass index (BMI) and preoperative eGFR, in which duration of the operation was not reported earlier. Early prosthetic joint infections (PJIs) were most dominantly found to be the main trigger for AKI.

When considering confounding factors, at median follow-up of 7.8 years, when comparing to patients with CKD stage 1, adjusted Hazard Ratio for death was 1.9 (95%

CI 1.8-2.1) in stage 2, 3.8 (95% CI 3.4-4.2) in stage 3, and 8.1 (95% CI 6.3-10.3) in patients with stage 4-5. CKD patients had a surprisingly high mortality rate; at five and ten years postoperatively, 21% and 68% of the patients with CKD stage 3 had died, while the corresponding numbers were 47% and 87% in patients with CKD 4-5.

However, renal function had no significant association with implant survival or infection free survival even when considering high mortality of patients with CKD stages 3-5 as a competing risk. Due to a lack of patients with the most severe forms of CKD (CKD stages 4-5) it was not possible to show if these patients are at increased risk for revision.

In clinical practice, after taking note of the results of this study, it is recommended always to calculate eGFR when considering a TJA. eGFR based classification of CKD stages should be reviewed alongside with other major comorbid conditions when assessing the risks and benefits of the operation. In order to prevent AKI, we could recommend considering patients’ BMI, ASA grade, BMI preoperatively and initiate interventions prior to. Postoperatively, it might be useful to pay attention to patients’

SCr and urine output whenever the operating time exceeds two hours.

vii

TIIVISTELMÄ

Munuaisten vajaatoiminnassa munuaiskeräsen suodattumisnopeus (eGFR) on alle 60mL/min/1.73m². Munuaistoiminta voidaan myös jakaa tarkemmin viiteen luokkaan (CKD-luokka), jossa CKD luokka 1 vastaa täysin normaalia munuaisten toimintaa ja luokka 5 käytännössä menetettyä munuaistoimintaa. Munuaisten vajaatoiminta lisää leikkauksenjälkeistä sairastuvuutta ja riskiä akuutille munuaisvauriolle leikkauksen jälkeen. Se vaikuttaa potilaan hoitoon leikkausta edeltävästä ajasta aina leikkauksen jälkeiseen aikaan. Myös tiedetään sen vakavimpien muotojen lisäävän leikkauksenjälkeistä kuolleisuutta. Munuaisten vajaatoiminnan tunnistaminen ennen leikkausta on tärkeää, jotta potilaalla ja hoitavalla lääkärillä on riittävät tiedot potilaaseen kohdistuvista riskeistä, potilaan tarvitsemasta erityishoidosta ja leikkauksen hyöty- haittasuhteesta. Ei tiedetä, vaikuttaako munuaisten vajaatoiminnan lievä muoto potilaan kuolleisuuteen. Myöskään munuaisten vajaatoiminnan vaikutus uusintaleikkausriskiin pitkällä aikavälillä on ei ole tiedossa. Aiemmissa tutkimuksissa munuaisten vajaatoimintapotilaiden lisääntynyttä kuolleisuutta ei ole otettu huomioon uusintaleikkausriskiä arvioitaessa. Lisäksi akuutin munuaisvaurion riskitekijöistä on ristiriitaisia tuloksia. Tutkimuksessa selvitetään munuaisten vajaatoiminnan ja toimenpiteen jälkeisen akuutin munuaisvaurion yleisyys ja riskitekijät tekonivelpotilailla sekä selvitetään, voidaanko seerumin kreatiniinimäärityksen perusteella erotella munuaisten vajaatoimintapotilaat muista. Tutkimuksessa selvennetään myös munuaisten vajaatoiminnan eri asteiden vaikutusta tekonivelleikkauksen jälkeiseen kuolleisuuteen ja uusintaleikkausriskiin.

Osatöissä 1-3 käytettiin aineistona tekonivelsairaala Coxan 18,757 peräkkäistä, vuosina 2002-2011 leikattua polvi- ja lonkkatekonivelpotilasta. Osatyössä 4 tutkimusaineiston muodostivat 18,979 vuosina 2008-2017 leikattua potilasta. Potilaiden tiedot on kerätty

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viii

Coxan tietoaltaasta, väestörekisterikeskukselta, Fimlabin laboratoriojärjestelmästä ja Kelan korvattavuusrekisteristä.

Leikkausta edeltävän munuaisten vajaatoiminnan esiintyvyys vaihteli yhdeksästä kolmeentoista prosenttiin. Kuitenkin vain kolmanneksella potilaista oli normaali munuaistoiminta (CKD luokka 1). Munuaisten vajaatoiminta oli yleisintä vanhoilla naisilla, polvitekonivelpotilailla ja potilailla, joilla oli muitakin sairauksia. Seerumin kreatiniinipitoisuus tunnisti vajaatoiminnan huonosti vanhemmilla naisilla ja normaalipainoisilla; jopa kaksi kolmesta tapauksesta jäi huomaamatta.

Leikkauksenjälkeisen munuaisvaurion ilmaantuvuus oli 3,3 (95% LV 2,5-4,5) tapausta tuhatta leikkausta kohden. Monimuuttujamallissa riippumattomia riskitekijöitä olivat ASA-luokka, painoindeksi, eGFR ja leikkauksen kesto, joista leikkauksen kesto on aiemmin raportoimaton löydös. Tutkimuksen perusteella ei ollut viitteitä aminoglykosidipitoisen luusementin ja munuaisvaurion yhteydestä. Leikkauksen jälkeiset infektiot olivat yleisin syy munuaisvauriolle.

Tekonivelpotilaan ennuste kuoleman suhteen huononi CKD luokan kasvaessa. Kun verrokkina käytettiin CKD luokan 1 potilaita, CKD luokassa 2 (HR 1,9; 95% LV 1,8- 2,1), 3 (HR 3,8; 95% LV 3,4-4,2) ja 4-5 (HR 8.1; 95% LV 6,3-10,3) oli merkittävästi suurempi riski kuolleisuudelle keskimäärin lähes 8 vuoden seurannassa. Kuitenkaan CKD luokalla ei ollut yhteyttä uusintaleikkausriskiin tai tekonivelinfektioriskiin, kun munuaisten vajaatoimintapotilaiden lisääntynyt kuolemanriski otettiin huomioon. CKD luokan 4-5 potilaiden määrä ei riittänyt johtopäätösten tekemiseen.

Tutkimuksemme pohjalta suosittelemme eGFR ja CKD luokan määrittämistä jokaiselle tekonivelpotilaalle. Siihen tulisi suhtautua samoin kuin muihin riskitekijöihin, kun potilaan leikkauskelpoisuutta ja hyöty-haittasuhdetta puntaroidaan. Tutkimuksen perusteella voidaan suositella leikkausta edeltävää interventiota potilaille, joilla on munuaisvaurion riskitekijöitä ja tarkkaa leikkauksenjälkeistä munuaistoiminnan seurantaa potilaille, joilla leikkauksen kesto ylittää 120 minuuttia.

ix

LIST OF ORIGINAL PUBLICATIONS

This thesis was written based on the following peer reviewed journal articles. Some unpublished analyses and data are presented in the thesis.

1. Jämsä, P, Jämsen, E, Lyytikäinen, L, Kalliovalkama, J, Eskelinen, A and Oksala, N, 2017. Risk factors associated with acute kidney injury in a cohort of 20,575 arthroplasty patients. Acta Orthopaedica, 88(4), pp. 370-376.

2. Jämsä, PP, Oksala, NKJ., Eskelinen, AP and Jämsen, ER, 2018. Chronic Kidney Diseases Among Patients Undergoing Elective Arthroplasty: Risk Groups and the Value of Serum Creatinine. The Journal of Arthroplasty, 33(1), pp. 230-234.e1.

3. Jämsä, P, Jämsen, E, Huhtala, H, Eskelinen, A and Oksala, N, 2018.

Moderate to Severe Renal Insufficiency Is Associated with High Mortality After Hip and Knee Replacement. Clinical Orthopaedics and Related Research, 476(6), pp. 1284-1292.

4. Jämsä, P, Reito, A, Oksala N, Eskelinen A, Jämsen E. 2021. Does chronic kidney disease affect implant survival after primary hip and knee replacements? The Bone & Joint Journal, 103-B(3), pp.689-695.

The original articles are reproduced here with permission of the copyright holders Pyry Jämsä (1.), Elsevier (2.) and Wolters Kluwer (3. Accepted manuscript version of the article, not permitted to publish in the electronic version of the thesis). 4 Unedited, pre- publication draft reproduced with permission and copyright © of the British Editorial Society of Bone and Joint Surgery

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viii

Coxan tietoaltaasta, väestörekisterikeskukselta, Fimlabin laboratoriojärjestelmästä ja Kelan korvattavuusrekisteristä.

Leikkausta edeltävän munuaisten vajaatoiminnan esiintyvyys vaihteli yhdeksästä kolmeentoista prosenttiin. Kuitenkin vain kolmanneksella potilaista oli normaali munuaistoiminta (CKD luokka 1). Munuaisten vajaatoiminta oli yleisintä vanhoilla naisilla, polvitekonivelpotilailla ja potilailla, joilla oli muitakin sairauksia. Seerumin kreatiniinipitoisuus tunnisti vajaatoiminnan huonosti vanhemmilla naisilla ja normaalipainoisilla; jopa kaksi kolmesta tapauksesta jäi huomaamatta.

Leikkauksenjälkeisen munuaisvaurion ilmaantuvuus oli 3,3 (95% LV 2,5-4,5) tapausta tuhatta leikkausta kohden. Monimuuttujamallissa riippumattomia riskitekijöitä olivat ASA-luokka, painoindeksi, eGFR ja leikkauksen kesto, joista leikkauksen kesto on aiemmin raportoimaton löydös. Tutkimuksen perusteella ei ollut viitteitä aminoglykosidipitoisen luusementin ja munuaisvaurion yhteydestä. Leikkauksen jälkeiset infektiot olivat yleisin syy munuaisvauriolle.

Tekonivelpotilaan ennuste kuoleman suhteen huononi CKD luokan kasvaessa. Kun verrokkina käytettiin CKD luokan 1 potilaita, CKD luokassa 2 (HR 1,9; 95% LV 1,8- 2,1), 3 (HR 3,8; 95% LV 3,4-4,2) ja 4-5 (HR 8.1; 95% LV 6,3-10,3) oli merkittävästi suurempi riski kuolleisuudelle keskimäärin lähes 8 vuoden seurannassa. Kuitenkaan CKD luokalla ei ollut yhteyttä uusintaleikkausriskiin tai tekonivelinfektioriskiin, kun munuaisten vajaatoimintapotilaiden lisääntynyt kuolemanriski otettiin huomioon. CKD luokan 4-5 potilaiden määrä ei riittänyt johtopäätösten tekemiseen.

Tutkimuksemme pohjalta suosittelemme eGFR ja CKD luokan määrittämistä jokaiselle tekonivelpotilaalle. Siihen tulisi suhtautua samoin kuin muihin riskitekijöihin, kun potilaan leikkauskelpoisuutta ja hyöty-haittasuhdetta puntaroidaan. Tutkimuksen perusteella voidaan suositella leikkausta edeltävää interventiota potilaille, joilla on munuaisvaurion riskitekijöitä ja tarkkaa leikkauksenjälkeistä munuaistoiminnan seurantaa potilaille, joilla leikkauksen kesto ylittää 120 minuuttia.

ix

LIST OF ORIGINAL PUBLICATIONS

This thesis was written based on the following peer reviewed journal articles. Some unpublished analyses and data are presented in the thesis.

1. Jämsä, P, Jämsen, E, Lyytikäinen, L, Kalliovalkama, J, Eskelinen, A and Oksala, N, 2017. Risk factors associated with acute kidney injury in a cohort of 20,575 arthroplasty patients. Acta Orthopaedica, 88(4), pp. 370-376.

2. Jämsä, PP, Oksala, NKJ., Eskelinen, AP and Jämsen, ER, 2018. Chronic Kidney Diseases Among Patients Undergoing Elective Arthroplasty: Risk Groups and the Value of Serum Creatinine. The Journal of Arthroplasty, 33(1), pp. 230-234.e1.

3. Jämsä, P, Jämsen, E, Huhtala, H, Eskelinen, A and Oksala, N, 2018.

Moderate to Severe Renal Insufficiency Is Associated with High Mortality After Hip and Knee Replacement. Clinical Orthopaedics and Related Research, 476(6), pp. 1284-1292.

4. Jämsä, P, Reito, A, Oksala N, Eskelinen A, Jämsen E. 2021. Does chronic kidney disease affect implant survival after primary hip and knee replacements? The Bone & Joint Journal, 103-B(3), pp.689-695.

The original articles are reproduced here with permission of the copyright holders Pyry Jämsä (1.), Elsevier (2.) and Wolters Kluwer (3. Accepted manuscript version of the article, not permitted to publish in the electronic version of the thesis). 4 Unedited, pre- publication draft reproduced with permission and copyright © of the British Editorial Society of Bone and Joint Surgery

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x xi

ABBREVIATIONS

ACS Acute coronary syndrome

ADH Antidiuretic hormone

AKI Acute kidney injury

ASA American Society of Anesthesiologists BCIS Bone cement implantation syndrome

BMI Body mass index

BP Blood pressure

CABG Coronary artery bypass grafting

CD Coronary disease

CHF Congestive heart failure

CI Confidence interval

CIF Cumulative incidence function

CKD Chronic kidney disease

CKD-EPI Chronic kidney disease epidemiology collaboration

CG Cockcroft-Gault

DAG Directed acyclic graph

DVT Deep vein thrombosis

eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate

HR Hazard ratio

ICD International classification of diseases

IQR Interquartile range

K/DOQI Kidney Disease Outcomes Quality Initiative KDIGO Kidney Disease: Improving Global Outcomes MDRD Modification of diet in renal disease

NSAID Non-steroidal anti-inflammatory drug

OR Odds ratio

PCI Percutaneous coronary intervention

PE Pulmonary embolism

PJI Prosthetic joint infection

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x xi

ABBREVIATIONS

ACS Acute coronary syndrome

ADH Antidiuretic hormone

AKI Acute kidney injury

ASA American Society of Anesthesiologists BCIS Bone cement implantation syndrome

BMI Body mass index

BP Blood pressure

CABG Coronary artery bypass grafting

CD Coronary disease

CHF Congestive heart failure

CI Confidence interval

CIF Cumulative incidence function

CKD Chronic kidney disease

CKD-EPI Chronic kidney disease epidemiology collaboration

CG Cockcroft-Gault

DAG Directed acyclic graph

DVT Deep vein thrombosis

eGFR Estimated glomerular filtration rate GFR Glomerular filtration rate

HR Hazard ratio

ICD International classification of diseases

IQR Interquartile range

K/DOQI Kidney Disease Outcomes Quality Initiative KDIGO Kidney Disease: Improving Global Outcomes MDRD Modification of diet in renal disease

NSAID Non-steroidal anti-inflammatory drug

OR Odds ratio

PCI Percutaneous coronary intervention

PE Pulmonary embolism

PJI Prosthetic joint infection

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xii QALY

RIFLE

Quality adjusted life year

Risk, injury, failure, loss of kidney function and end stage kidney disease

SCr TJATKA

Serum creatinine Total joint arthroplasty Total knee arthroplasty

xiii

1. Introduction

Joint replacement of the hip or knee is a common procedure aiming to improve mobility and relieve pain. Most of all, joint replacement operations aim at improved quality of life. When successful, they improve quality of life and are also cost effective (Chang et al., 1996; Elmallah et al., 2017; Walker et al., 2002). In the era before the Corona virus pandemic, over 10,000 primary hip and over 12,000 knee replacements were performed in Finland annually (Finnish Arthroplasty Register, 2020). From the patient’s perspective, revision joint replacement alongside other major complications, such as pulmonary embolism, is probably the worst that could happen after the primary operation. Over 2,000 hip or knee revision joint replacements were

performed in 2019. Other adverse events may also occur. Major surgery together with operation related changes, such as immobilization, predispose to a risk of pneumonia, thromboembolic complications, renal complications, strokes and acute myocardial events. At worst, these can lead to death. Clinicians therefore need to know which patients are at risk of increased complications and adverse events so that they can inform the patient of these increased risks and even decline to perform the operation if the risks are estimated to outweigh the benefits. Some adverse events can also be avoided if the risks are known in advance.

The risk factors for adverse events and compromised implant survival are mainly well known. One of the well-known factors is chronic kidney disease (CKD). This is known to increase the likelihood of many postoperative adverse events and predispose to risk for short-term mortality after joint replacement. It is also necessary to avoid some medications and also otherwise consider CKD in perioperative period.

Therefore, preoperative recognition is important. There is lack of information on

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xvi 17

1. Introduction

Joint replacement of the hip or knee is a common procedure aiming to improve mobility and relieve pain. Most of all, joint replacement operations aim at improved quality of life. When successful, they improve quality of life and are also cost effective (Chang et al., 1996; Elmallah et al., 2017; Walker et al., 2002). In the era before the Corona virus pandemic, over 10,000 primary hip and over 12,000 knee replacements were performed in Finland annually (Finnish Arthroplasty Register, 2020). From the patient’s perspective, revision joint replacement alongside other major complications, such as pulmonary embolism, is probably the worst that could happen after the primary operation. Over 2,000 hip or knee revision joint replacements were

performed in 2019. Other adverse events may also occur. Major surgery together with operation related changes, such as immobilization, predispose to a risk of pneumonia, thromboembolic complications, renal complications, strokes and acute myocardial events. At worst, these can lead to death. Clinicians therefore need to know which patients are at risk of increased complications and adverse events so that they can inform the patient of these increased risks and even decline to perform the operation if the risks are estimated to outweigh the benefits. Some adverse events can also be avoided if the risks are known in advance.

The risk factors for adverse events and compromised implant survival are mainly well known. One of the well-known factors is chronic kidney disease (CKD). This is known to increase the likelihood of many postoperative adverse events and predispose to risk for short-term mortality after joint replacement. It is also necessary to avoid some medications and also otherwise consider CKD in perioperative period.

Therefore, preoperative recognition is important. There is lack of information on

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18

some kidney related issues concerning joint replacement operations. Not enough is known of the patient characteristics of those joint replacement patients who have chronic kidney disease. Acute kidney injury (AKI) after joint replacement is a rare but potentially preventable adverse event with some unaddressed risk factors. Some of its risk factors are still uncharted. After TJA, short-term mortality risk after joint

replacement remains elevated for approximately 90 days, while the most common reasons for mortality are ischemic heart disease, cerebrovascular events, and pulmonary embolism (Berstock, J. R. et al., 2014; Berstock, J. R. et al., 2018). After this period, mortality is no longer affected by the operation itself. Information on short- and long-term mortality of patients undergoing operations aiming to improve quality of life is important when preoperatively evaluating the risks and benefits of the operation, but also the cost effectiveness of the operation. Many comorbidities are known to affect short- and long-term mortality after joint replacement, but the role of different CKD stages in postoperative mortality is yet to be established.

The present study ascertains the unknown issues in the relationship between renal function and the outcomes of joint replacement operations, and addresses recognition of CKD in these patients. This includes investigating the risk factors for AKI,

reporting the patient groups with high prevalence of CKD, studying the performance of SCr as a predictor of CKD and analyzing mortality and implant survival in different CKD stages.

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2. Review of the literature

2.1 Anatomy and physiology of the kidneys and measurement of kidney function

2.1.1 Anatomy and physiology of the kidneys

The kidney is a bean shaped, bilateral retroperitoneal organ. It is constructed of renal cortex, underlying renal pyramids, urine collection system, and vasculature. It is enclosed in a fibrous capsule surrounded by perinephric fat. Blood supply is carried by the renal artery emerging from the aorta just below the superior mesenteric artery. The renal vein leads blood into the inferior vena cava. On the left side, the renal vein passes under the superior mesenteric artery. On the left side, the gonadal vein merges with the renal vein. Urine secreted from the kidney is led to the urinary bladder through the calyxes, the renal pelvis, and the ureter. The ureter, renal vein, and renal artery pass the kidney through the renal hilum on the medial side of the kidney.

Lymphatic fluid from the kidney drains into the lumbar lymph nodes. (Figure 1) (Drake et al., 2010)

The kidney is composed of approximately 1 million nephrons, which is the basic unit of a kidney. A nephron consists of the afferent arteriole, efferent arteriole, glomerulus, proximal tubule, the loop of Henle, the distal tubule and a collection duct that leads urine into the renal papilla leading to the calyxes. The afferent arteriole brings blood to the glomerulus and the efferent arteriole leads blood out from the glomerulus. The glomerulus and its capillary structures are supported by mesangial cells. There is

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some kidney related issues concerning joint replacement operations. Not enough is known of the patient characteristics of those joint replacement patients who have chronic kidney disease. Acute kidney injury (AKI) after joint replacement is a rare but potentially preventable adverse event with some unaddressed risk factors. Some of its risk factors are still uncharted. After TJA, short-term mortality risk after joint

replacement remains elevated for approximately 90 days, while the most common reasons for mortality are ischemic heart disease, cerebrovascular events, and pulmonary embolism (Berstock, J. R. et al., 2014; Berstock, J. R. et al., 2018). After this period, mortality is no longer affected by the operation itself. Information on short- and long-term mortality of patients undergoing operations aiming to improve quality of life is important when preoperatively evaluating the risks and benefits of the operation, but also the cost effectiveness of the operation. Many comorbidities are known to affect short- and long-term mortality after joint replacement, but the role of different CKD stages in postoperative mortality is yet to be established.

The present study ascertains the unknown issues in the relationship between renal function and the outcomes of joint replacement operations, and addresses recognition of CKD in these patients. This includes investigating the risk factors for AKI,

reporting the patient groups with high prevalence of CKD, studying the performance of SCr as a predictor of CKD and analyzing mortality and implant survival in different CKD stages.

19

2. Review of the literature

2.1 Anatomy and physiology of the kidneys and measurement of kidney function

2.1.1 Anatomy and physiology of the kidneys

The kidney is a bean shaped, bilateral retroperitoneal organ. It is constructed of renal cortex, underlying renal pyramids, urine collection system, and vasculature. It is enclosed in a fibrous capsule surrounded by perinephric fat. Blood supply is carried by the renal artery emerging from the aorta just below the superior mesenteric artery. The renal vein leads blood into the inferior vena cava. On the left side, the renal vein passes under the superior mesenteric artery. On the left side, the gonadal vein merges with the renal vein. Urine secreted from the kidney is led to the urinary bladder through the calyxes, the renal pelvis, and the ureter. The ureter, renal vein, and renal artery pass the kidney through the renal hilum on the medial side of the kidney.

Lymphatic fluid from the kidney drains into the lumbar lymph nodes. (Figure 1) (Drake et al., 2010)

The kidney is composed of approximately 1 million nephrons, which is the basic unit of a kidney. A nephron consists of the afferent arteriole, efferent arteriole, glomerulus, proximal tubule, the loop of Henle, the distal tubule and a collection duct that leads urine into the renal papilla leading to the calyxes. The afferent arteriole brings blood to the glomerulus and the efferent arteriole leads blood out from the glomerulus. The glomerulus and its capillary structures are supported by mesangial cells. There is

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autoregulation that adjusts the constriction in the afferent and efferent arterioles, thereby maintaining the ideal pressure on the glomerulus. The aim of the

autoregulation is to keep the glomerular filtration rate (GFR) stable in different arterial pressure conditions. Autoregulation works when mean arterial pressure exceeds 70mmHg. Between the afferent and efferent arteriole, lies the macula densa, which senses the chemical changes in tubular fluid and regulates constriction of the afferent arteriole, thereby keeping the glomerular perfusion stable. There are also other factors influencing capillary blood flow such as sympathetic activity, angiotensin, natriuretic peptide and nitric oxide. When the circulating blood volume is decreased, angiotensin constricts the efferent arteriole three times more than the afferent arteriole, resulting in stable GFR as the hydrostatic pressure increases inside Bowman´s capsule. In these situations, prostaglandins decrease constriction of the afferent arteriole and prevent excessive constriction that would result in a decrease in GFR. By this mechanism, non-steroidal anti-inflammatory drugs (NSAID´s), decreasing the number of prostaglandins, can impair glomerular blood flow and decrease GFR. Besides NSAIDs, use of diuretics and angiotensin receptor blockers also affectglomerular perfusion (Fournier et al., 2014; Lee et al., 2007). The efferent arteriole proceeds to the lower parts of the kidney and forms a network of capillaries around the tubule structures. In the glomerulus, water and small soluble molecules are filtrated through the glomerular capillaries to the Bowman’s capsule. This glomerular filtrate is

processed into urine in the tubules. GFR is the indicator of kidney function. Besides the glomerular blood flow, characteristics of the glomerular capillaries, underlying the basal membrane and visceral part of Bowman’s capsule also affect filtration. The tubules reabsorb most of the useful filtrated substances such as water, glucose, and sodium back into the circulation. The tubules also secrete smaller sized, water soluble organic products and pharmacological agents in to the filtrate. The tubules also take care of electrolyte balance, acid and base balance. From the tubules, urine is secreted into the collection duct that leads eventually to the calyxes. The osmolality of the urine is regulated by antidiuretic hormone (ADH). When ADH is present, the collector

21

ducts become more permeable to the water and therefore water is reabsorbed making the urine hyperosmotic. Besides their secretion and reabsorption function, the kidneys have a remarkable role in erythropoiesis, the secretion of renin, and bone mineral regulation. (Boron, Walter F., and Emile L. Boulpaep., 2016; Wein et al., 2016)

Figure 1. Anatomy of the kidneys (modified from Gray’s Anatomy for Students) (Drake et al., 2010)

2.1.2 Measurement of kidney function

As mentioned earlier, GFR is the indicator of kidney function. Determining GFR, however, is time consuming and impractical as it entails continuous infusion of medical substances and simultaneous urine collection (Soveri et al., 2014). Therefore, more practical methods have been developed to estimate the true GFR. In clinical practice, various equations have been provided to make an estimated GFR (eGFR)

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autoregulation that adjusts the constriction in the afferent and efferent arterioles, thereby maintaining the ideal pressure on the glomerulus. The aim of the

autoregulation is to keep the glomerular filtration rate (GFR) stable in different arterial pressure conditions. Autoregulation works when mean arterial pressure exceeds 70mmHg. Between the afferent and efferent arteriole, lies the macula densa, which senses the chemical changes in tubular fluid and regulates constriction of the afferent arteriole, thereby keeping the glomerular perfusion stable. There are also other factors influencing capillary blood flow such as sympathetic activity, angiotensin, natriuretic peptide and nitric oxide. When the circulating blood volume is decreased, angiotensin constricts the efferent arteriole three times more than the afferent arteriole, resulting in stable GFR as the hydrostatic pressure increases inside Bowman´s capsule. In these situations, prostaglandins decrease constriction of the afferent arteriole and prevent excessive constriction that would result in a decrease in GFR. By this mechanism, non-steroidal anti-inflammatory drugs (NSAID´s), decreasing the number of prostaglandins, can impair glomerular blood flow and decrease GFR. Besides NSAIDs, use of diuretics and angiotensin receptor blockers also affectglomerular perfusion (Fournier et al., 2014; Lee et al., 2007). The efferent arteriole proceeds to the lower parts of the kidney and forms a network of capillaries around the tubule structures. In the glomerulus, water and small soluble molecules are filtrated through the glomerular capillaries to the Bowman’s capsule. This glomerular filtrate is

processed into urine in the tubules. GFR is the indicator of kidney function. Besides the glomerular blood flow, characteristics of the glomerular capillaries, underlying the basal membrane and visceral part of Bowman’s capsule also affect filtration. The tubules reabsorb most of the useful filtrated substances such as water, glucose, and sodium back into the circulation. The tubules also secrete smaller sized, water soluble organic products and pharmacological agents in to the filtrate. The tubules also take care of electrolyte balance, acid and base balance. From the tubules, urine is secreted into the collection duct that leads eventually to the calyxes. The osmolality of the urine is regulated by antidiuretic hormone (ADH). When ADH is present, the collector

21

ducts become more permeable to the water and therefore water is reabsorbed making the urine hyperosmotic. Besides their secretion and reabsorption function, the kidneys have a remarkable role in erythropoiesis, the secretion of renin, and bone mineral regulation. (Boron, Walter F., and Emile L. Boulpaep., 2016; Wein et al., 2016)

Figure 1. Anatomy of the kidneys (modified from Gray’s Anatomy for Students) (Drake et al., 2010)

2.1.2 Measurement of kidney function

As mentioned earlier, GFR is the indicator of kidney function. Determining GFR, however, is time consuming and impractical as it entails continuous infusion of medical substances and simultaneous urine collection (Soveri et al., 2014). Therefore, more practical methods have been developed to estimate the true GFR. In clinical practice, various equations have been provided to make an estimated GFR (eGFR)

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using patients’ plasma creatinine value with some demographic data (Cockcroft &

Gault, 1976; Levey, A. S. et al., 1999; Levey, Andrew S. et al., 2009). Today, the chronic kidney disease epidemiology collaboration (CKD-EPI) equation including patients age, sex, race alongside serum creatinine is the most preferred option (Matsushita et al., 2012). It should be noted that regardless of eGFR equation used, eGFR is a biasedmethod compared to the true, measured GFR (Murata et al., 2011).

This is mainly because plasma creatinine value, besides renal clearance, is closely associated with muscle mass (Baxmann et al., 2008). Plasma cystatin c, being less associated with muscle mass (Baxmann et al., 2008), has been developed for better accuracy in eGFR equations (Meeusen et al., 2015), but this method is not used as widely in clinical practice probably due to its increased costs (Shardlow et al., 2017).

Kidney function can be also evaluated by assessing the albumin concentration of the urine (Levey, Andrew S. et al., 2009).

2.2 Chronic kidney disease

2.2.1 Definition of CKD and classification of kidney function

CKD is defined by GFR lower than 60mL/min/1,73m² (Tonelli et al., 2006). With this GFR, it is estimated that half of kidney function is lost (Levey, Andrew S. et al., 2003). Kidney function is further classified into five different CKD stages (Table 1) (Levey, Andrew S. et al., 2003). Another clear sign of renal disease is albuminuria caused by increased glomerular permeability (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013; Satchell & Tooke, 2008).

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Table 1. CKD stages according to K/DOQI (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013)

Stage Description of kidney function GFR mL/min/1.73m²

1 Normal ≥90

2 Mildly decreased 60-89

3 Moderately decreased 30-59

4 Severely decreased 15-29

5 Kidney failure <15 or dialysis

K/DOQI = Kidney Disease Outcomes Quality Initiative

2.2.2 Etiology and pathophysiology

The most common etiology for CKD is diabetes and hypertension accounting for up to 65% of all CKD cases (Levey, Andrew S. et al., 2003; Vassalotti et al., 2016;

Webster et al., 2017). However, CKD may be initiated by glomerulonephritis, renovascular diseases, urological diseases or infectious diseases alongside rarer causes (Webster et al., 2017).

Hyperglycemia, hypertension and glomerulonephritis impair glomerular autoregulation and thus increase the glomerular pressure. Elevated glomerular pressure stretches the visceral part of Bowman’s capsule, making it more permeable to macromolecules such as albumin. It also initiates microinflammation that causes the mesangium to expand, eventually leading to glomerulosclerosis. As the expanding mesangium surrounds the glomerulus, it leads to a decrease in GFR. The glomerulus leaks large sized molecules causing an inflammatory reaction in the tubular epithelial cells. This inflammation causes fibrosis that eventually leads to apoptosis atrophy of the tubular cells and fibrosis of the interstitial tissue. The decline in GFR is caused by a decrease in functional nephrons. (Cove-Smith & Hendry, 2008; Webster et al., 2017)

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using patients’ plasma creatinine value with some demographic data (Cockcroft &

Gault, 1976; Levey, A. S. et al., 1999; Levey, Andrew S. et al., 2009). Today, the chronic kidney disease epidemiology collaboration (CKD-EPI) equation including patients age, sex, race alongside serum creatinine is the most preferred option (Matsushita et al., 2012). It should be noted that regardless of eGFR equation used, eGFR is a biasedmethod compared to the true, measured GFR (Murata et al., 2011).

This is mainly because plasma creatinine value, besides renal clearance, is closely associated with muscle mass (Baxmann et al., 2008). Plasma cystatin c, being less associated with muscle mass (Baxmann et al., 2008), has been developed for better accuracy in eGFR equations (Meeusen et al., 2015), but this method is not used as widely in clinical practice probably due to its increased costs (Shardlow et al., 2017).

Kidney function can be also evaluated by assessing the albumin concentration of the urine (Levey, Andrew S. et al., 2009).

2.2 Chronic kidney disease

2.2.1 Definition of CKD and classification of kidney function

CKD is defined by GFR lower than 60mL/min/1,73m² (Tonelli et al., 2006). With this GFR, it is estimated that half of kidney function is lost (Levey, Andrew S. et al., 2003). Kidney function is further classified into five different CKD stages (Table 1) (Levey, Andrew S. et al., 2003). Another clear sign of renal disease is albuminuria caused by increased glomerular permeability (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013; Satchell & Tooke, 2008).

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Table 1. CKD stages according to K/DOQI (Kidney Disease: Improving Global Outcomes (KDIGO) Work Group, 2013)

Stage Description of kidney function GFR mL/min/1.73m²

1 Normal ≥90

2 Mildly decreased 60-89

3 Moderately decreased 30-59

4 Severely decreased 15-29

5 Kidney failure <15 or dialysis

K/DOQI = Kidney Disease Outcomes Quality Initiative

2.2.2 Etiology and pathophysiology

The most common etiology for CKD is diabetes and hypertension accounting for up to 65% of all CKD cases (Levey, Andrew S. et al., 2003; Vassalotti et al., 2016;

Webster et al., 2017). However, CKD may be initiated by glomerulonephritis, renovascular diseases, urological diseases or infectious diseases alongside rarer causes (Webster et al., 2017).

Hyperglycemia, hypertension and glomerulonephritis impair glomerular autoregulation and thus increase the glomerular pressure. Elevated glomerular pressure stretches the visceral part of Bowman’s capsule, making it more permeable to macromolecules such as albumin. It also initiates microinflammation that causes the mesangium to expand, eventually leading to glomerulosclerosis. As the expanding mesangium surrounds the glomerulus, it leads to a decrease in GFR. The glomerulus leaks large sized molecules causing an inflammatory reaction in the tubular epithelial cells. This inflammation causes fibrosis that eventually leads to apoptosis atrophy of the tubular cells and fibrosis of the interstitial tissue. The decline in GFR is caused by a decrease in functional nephrons. (Cove-Smith & Hendry, 2008; Webster et al., 2017)

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2.2.3 Epidemiology

In European general population, it is estimated that the prevalence of CKD is 6% in general adult population (So et al., 2015). In older patients, the prevalence of CKD is increased; in patients over 60 years of age prevalence of CKD is 17% whereas in patients older than 75 years of age the prevalence is 34%. (Browne et al., 2012; Levey, Andrew S. et al., 2003; Tomonaga et al., 2013).

2.2.4 Impact on life expectancy and morbidity

Patients with CKD are at increased risk for various diseases such as cardiovascular diseases, anemia, and endocrine disorders (Carney, 2020; Kuczera et al., 2015; Shaikh

& Aeddula, 2020). The most common cause of death in CKD patients is cardiovascular diseases. Due to increased plasma volume, CKD elevates blood pressure. It also increases the amount of circulating atherogenic low density

lipoprotein, causes chronic inflammation, and causes hyperphosphatemia, all of which increase vascular calcification. Calcification alongside increased plasma volume causes left ventricular hypertrophy. CKD, alongside functional kidney tissue due to fibrosis, decreases the formation of erythropoietin, leading to anemia. Also, renal failure (CKD stage 5) usually leads to uremia which without dialysis, is fatal. (Afsar et al., 2014;

Carney, 2020; Heaf & Mortensen, 2011; Kuczera et al., 2015; Shaikh & Aeddula, 2020;

Temgoua et al., 2017)

In general population, life expectancy decreases as CKD stage progresses (Turin et al., 2012). Co-presence of proteinuria with decreased eGFR is associated with poorer life expectancy (Hemmelgarn et al., 2010).

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2.2.5 Acute kidney injury

In AKI, glomerular filtration rate suddenly decreases leading to a decrease in urine output, electrolyte disorders and fluid retention. Major causes for AKI are ischemia (lack of blood supply), inflammation (cytokines and other pro-inflammatory

mediators) and rhabdomyolysis (Persson, 2013). Surgery related AKI is a multifactorial problem and many different surgery related factors contribute to AKI. These include anesthesia and fasting induced hypoperfusion, surgery induced mediators that lead to apoptosis and fluid retention, and nephrotoxins that all lead eventually in a decrease in the glomerular filtration rate temporarily or terminally (Gameiro et al., 2018). Also, inappropriate combination of medication such as antihypertensive medication, NSAID´s and diuretics can induce AKI (Fournier et al., 2014).

There are many definitions for AKI, but the most widely used is the risk injury failure loss and end stage (RIFLE) criteria. These define AKI incrementally in postoperative serum creatinine compared to the preoperative value. Postoperatively risk-stage patients have a 50%, injury patients have a 100% and failure patients a 200% increase in SCr from the preoperative value. Loss-stage patients have complete loss of renal function for over four weeks but under three months. End-stage patients have loss of renal function for over three months (Bellomo et al., 2007).

2.3 Hip and knee replacement operation

2.3.1 Indications

Lower extremity joint replacement operations are a treatment option for chronic arthritis, primary osteoarthritis being the most common indication. TJA is indicated

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2.2.3 Epidemiology

In European general population, it is estimated that the prevalence of CKD is 6% in general adult population (So et al., 2015). In older patients, the prevalence of CKD is increased; in patients over 60 years of age prevalence of CKD is 17% whereas in patients older than 75 years of age the prevalence is 34%. (Browne et al., 2012; Levey, Andrew S. et al., 2003; Tomonaga et al., 2013).

2.2.4 Impact on life expectancy and morbidity

Patients with CKD are at increased risk for various diseases such as cardiovascular diseases, anemia, and endocrine disorders (Carney, 2020; Kuczera et al., 2015; Shaikh

& Aeddula, 2020). The most common cause of death in CKD patients is cardiovascular diseases. Due to increased plasma volume, CKD elevates blood pressure. It also increases the amount of circulating atherogenic low density

lipoprotein, causes chronic inflammation, and causes hyperphosphatemia, all of which increase vascular calcification. Calcification alongside increased plasma volume causes left ventricular hypertrophy. CKD, alongside functional kidney tissue due to fibrosis, decreases the formation of erythropoietin, leading to anemia. Also, renal failure (CKD stage 5) usually leads to uremia which without dialysis, is fatal. (Afsar et al., 2014;

Carney, 2020; Heaf & Mortensen, 2011; Kuczera et al., 2015; Shaikh & Aeddula, 2020;

Temgoua et al., 2017)

In general population, life expectancy decreases as CKD stage progresses (Turin et al., 2012). Co-presence of proteinuria with decreased eGFR is associated with poorer life expectancy (Hemmelgarn et al., 2010).

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2.2.5 Acute kidney injury

In AKI, glomerular filtration rate suddenly decreases leading to a decrease in urine output, electrolyte disorders and fluid retention. Major causes for AKI are ischemia (lack of blood supply), inflammation (cytokines and other pro-inflammatory

mediators) and rhabdomyolysis (Persson, 2013). Surgery related AKI is a multifactorial problem and many different surgery related factors contribute to AKI. These include anesthesia and fasting induced hypoperfusion, surgery induced mediators that lead to apoptosis and fluid retention, and nephrotoxins that all lead eventually in a decrease in the glomerular filtration rate temporarily or terminally (Gameiro et al., 2018). Also, inappropriate combination of medication such as antihypertensive medication, NSAID´s and diuretics can induce AKI (Fournier et al., 2014).

There are many definitions for AKI, but the most widely used is the risk injury failure loss and end stage (RIFLE) criteria. These define AKI incrementally in postoperative serum creatinine compared to the preoperative value. Postoperatively risk-stage patients have a 50%, injury patients have a 100% and failure patients a 200% increase in SCr from the preoperative value. Loss-stage patients have complete loss of renal function for over four weeks but under three months. End-stage patients have loss of renal function for over three months (Bellomo et al., 2007).

2.3 Hip and knee replacement operation

2.3.1 Indications

Lower extremity joint replacement operations are a treatment option for chronic arthritis, primary osteoarthritis being the most common indication. TJA is indicated

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when a patient has pain and constricted range of motion in the joint during motion and rest that causes difficulties in daily living, along with radiological findings. Before proceeding to surgery, attempts at conservative treatment should been undergone first. These include weight loss, increased exercise, and analgesics. As there are no established cut off points in any of these indications, the decision to operate is made individually for every patient taking into account that patient’s characteristics.

(Gademan et al., 2016; Pivec et al., 2012; Price et al., 2018)

2.3.2 Operation techniques and perioperative care

In joint replacement operations, the damaged articulating surfaces are removed and replaced by a prosthesis. In hip replacement, the posterior approach is used most commonly to access the joint (Chechik et al., 2013; Varacallo et al., 2020a). With the posterior approach, the joint is reached through the gluteus maximus muscle and the distal fascia lata, from the posterior side of the gluteus medius muscle. The hip abductors are retained, but part of the external rotator muscles of the hip are cut through near the femur (Jolles & Bogoch, 2006). Then, the joint capsule is opened and the joint is revealed. Next, femoral head is cut and removed. The acetabular labrum is then removed and the sclerotic acetabular cup is reamed until healthy bone is reached.

Then the femur is prepared for the implants. Implant sizes are tested until the length, motion, and stability of the joint are appropriate. The femoral head is typically ceramic or made of metallic alloy, while the acetabular counterpart is typically made of

polyethene. Implants are placed either using bone cement or press-fitted. Cementless fixation of the prothesis components is mainly recommended in younger patients, while cemented fixation is more recommended for use among elderly patients (Jämsen et al., 2014; Stea et al., 2014). The joint capsule and external rotator muscles are sutured in place. In the more superficial layer, the gluteus maximus and fascia lata are closed, then the subcutaneous layer followed by skin. (Varacallo et al., 2020a)

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In total knee replacement, a medial parapatellar approach is the standard technique (Peng et al., 2015). In this approach, the joint is accessed medially by dividing the lower aspect of the quadriceps tendon, the joint capsule medial to the patella extending near the patellar tendon distally. The medial and lateral meniscus are removed. Then, with guiding instrumentation, tibial and femoral surfaces are shaped to match the implants. The implant sizes are tested and implants selected. Femoral and tibial components are made of metallic alloys and there is a polyethene liner between the components. Sometimes the patella is resurfaced. Most implants are cemented in place (Prudhon & Verdier, 2017). Bone cement is often impregnated with antibiotic agents to reduce the risk of infection (Martínez-Moreno et al., 2017).

Perioperatively, insertion of bone cement has a rare but possibly lethal consequence known as bone cement implantation syndrome (BCIS), manifesting as hypoxia, hypotension or both (Khanna & Cernovsky, 2012). The incidence of lethal BCIS is 0.1% (Ereth et al., 1992). After bone cement implantation, the wounds are closed in three layers. (Varacallo et al., 2020b)

Besides the antibiotic agents in bone cement, most patients also receive intravenous antibiotic prophylaxis prior to surgery (de Beer et al., 2009; Jämsen, Peltola et al., 2013a; Siddiqi et al., 2019). On average, TJA is a 60 to 90 min operation with

transfusion rates of 13 to 16% (Carling et al., 2015; Jämsen et al., 2015). A tourniquet is traditionally used in knee replacement minimizing blood loss (Palanne et al., 2020) and operating time (Zhang et al., 2014). Although with modern fast-track surgical protocols, usage of tourniquet has decreased as earlier it was standard care in knee replacements (Tai et al., 2010). Most joint replacement procedures are made under spinal anesthesia but general anesthesia is also used (Perlas et al., 2016).

Chronic Kidney Disease in Patients Undergoing Hip or Knee Joint Replacement

PYRY JÄMSÄ