West Midlands - Transplant First Audit & Education Event. Tea/Coffee break Kidney Quality Improvement Partnership Yorks & Humber 1

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1 West Midlands - Transplant First Audit & Education Event Tea/Coffee break Kidney Quality Improvement Partnership Yorks & Humber 1

2 West Midlands - Transplant First Audit & Education Event Fatigue in transplantation Richard Borrows Kidney Quality Improvement Partnership Yorks & Humber 2

3 Fatigue in Prevalent Kidney Transplant Recipients Richard Borrows

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5 Wilson and Cleary. JAMA 1995

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15 What do we know so far?

16 Inclusion Criteria Study Design Cross-sectional Study (Observational) Received a kidney transplant > 1 year ago. No episodes of acute rejection within the last 6 months. No evidence of sepsis in the last 6 weeks. No known active malignancy. Able to give written informed consent.

17 Identifying factors associated with severity of fatigue Multiple Regression Analysis Explanatory Variables Dependent Variables Multi-Dimensional Fatigue Inventory (MFI-20) - MFI-20 General Fatigue - MFI-20 Physical Fatigue - MFI-20 Reduced Activity - MFI-20 Reduced Motivation - MFI-20 Mental Fatigue Age Gender Index of Co-existing Disease (ICD) Time Post Transplantation Haemoglobin (Hb) High Sensitive C-Reactive Protein (hscrp) Estimated Glomerular Filtration Rate (egrf) Anxiety [Hospital Anxiety & Depression Scale, HADS] Depression [HADS] Sleep Quality [Pittsburgh Sleep Quality Index]

18 Multi-Dimensional Fatigue Inventory MFI-20 Measures 5 primary dimensions of fatigue: - General Fatigue - Physical Fatigue - Reduced Activity - Reduced Motivation - Mental Fatigue Measures Physical Dimension A total score is calculated for each dimension. Scores ranged from 4 to 20. Higher scores indicating more fatigue. Measures Behavioural, Emotional and Cognitive Dimensions

19 Population Characteristics Characteristics Sample Size n = 106 Mean Age Gender Mean time post transplantation 51 (±14) years 56% Male; 44% Female 8 (± 7) years Mean ICD Score 2.13 (± 0.44) Mean Hb Mean hscrp Mean egfr 12.6 (± 1.6) g/dl 4.3 (± 6.1) g/dl 43.9 (± 18.5) ml/min

20 % Patients Anxiety, Depression & Sleep Quality Characteristics of Anxiety, Depression & Sleep Quality % 20% 63% Anxiety Depression Poor Sleep Quality Symptom

21 % Patients Results: Nutritional Status Bio-impedance Measurements of Body Composition 70% 60% *Compared with ageand gender- adjusted 61% 57% LTI FTI 50% 40% 30% 20% 10% 38% 5% 1% 38% 48% of subjects with high FTI 0% Below Reference Range*Within Reference Range*Above Reference Range*

22 Mean Score (± SD) by Dimensions Results: Fatigue Transplant Patients *Healthy *Chronically Unwell *CFS-like General Fatigue (± 4.05) 8.42 (± 3.59) (± 3.84) (± 2.73) Physical Fatigue (± 4.74) 7.77 (± 3.36) (± 3.76) (± 3.79) Reduced Activity (± 4.70) 6.76 (± 2.67) 9.06 (± 3.75) (± 4.37) Reduced Motivation 9.36 (± 3.61) 6.82 (± 2.91) 9.29 (± 3.35) (± 3.53) Mental Fatigue 9.67 (± 4.54) 7.23 (± 3.07) (± 4.00) (± 3.77) *Lin JMS et al., Further validation of the Multidimensional Fatigue Inventory in a US population sample. Population Health Metrics 2009, 7: 18

23 Impact of Fatigue on Quality of Life Correlation Analysis SF-36 Physical Health SF-36 Mental Health SF-36 Total Score General Fatigue -0.68* -0.67* -0.68* Physical Fatigue -0.78* -0.71* -0.74* Reduced Activity -0.72* -0.67* -0.71* Reduced Motivation -0.66* -0.69* -0.69* Mental Fatigue -0.33* -0.50* -0.42* *p < 0.001

24 Predicting Factors for General Fatigue Beta Standard Error p HADS Depression <0.01 egfr PSQI Score Age

25 Predicting Factors for Mental Fatigue Beta Standard Error p HADS Anxiety <0.01 HADS Depression Age

26 Predicting Factors for Reduced Motivation Beta Standard Error p HADS Depression <0.01 Time post transplantation Female

27 Predicting Factors for Physical Fatigue Beta Standard Error p HADS - Depression <0.01 egfr <0.01 LTI <0.01 Female <0.01

28 Predicting Factors for Reduced Activity Beta Standard Error p HADS Depression <0.01 Age <0.01 hscrp <0.01

29 Interim Summary Subjective sensation of profound and persistent tiredness Fatigue Complex and multi-dimensional Involves physical, cognitive, emotional and functional components

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36 Wilson and Cleary. JAMA 1995

37 Wilson and Cleary. JAMA 1995

38 Wilson and Cleary. JAMA 1995

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40 Peripheral Mechanisms Central Mechanisms Cardiorespiratory function Muscle mass Muscle power Perception of effort Delivery of oxygen & nutrients to muscles Responses to afferent feedback from working body Physical Fatigue Exhaustion Muscle Physical Weakness Sensations of Tiredness Physical Underperformance

41 Background Mental Fatigue Inability to focus and maintain cognitive function

42 Objectives Investigate the aetiology of physical fatigue through examinations of: - Muscle mass - Muscle function - Cardiorespiratory function - Perceived exertion Examine the role of mental fatigue on heightened perception.

43 Study Design Cross-sectional Study (n = 55) Inclusion Criteria Received a kidney transplant >1 year ago. No episodes of acute rejection within the last 6 months. No evidence of sepsis in the last 6 weeks. No known malignancy or chronic infection. No history of thyroid disease or adrenal insufficiency. No history of unstable angina No history of acute coronary syndrome No history of aortic stenosis. Sufficiently mobile for investigations.

44 Identifying mechanisms associated with Physical Fatigue Univariate Regression Analysis Explanatory Variables Dependent Variable Cardiovascular Fitness (VO 2 max) - A Submaximal Exercise Test Multi-Dimensional Fatigue Inventory (MFI-20): Physical Fatigue

45 Sub-Maximal Exercise Test Performed on cycle ergometer. Warm-up 10W (2 mins) Exercise 25W (3 mins) 50W (3 mins) 75W (3 mins) Breathe through a mouthpiece with nose clipped during exercise Connected to a closed gas analysis system. Oxygen uptake (VO 2 ) and Heart Rate (HR) were measured and recorded continuously.

46 VO 2 (ml/min/kg) Maximal Oxygen Consumption (VO 2 max) VO 2 max Estimation y = x R² = Age-Predicted Maximum HR = (0.685 x Age) Heart Rate (bpm)

47 Identifying mechanisms associated with Physical Fatigue Univariate Regression Analysis Explanatory Variables Cardiovascular Fitness (VO 2 max) - A Submaximal Exercise Test Dependent Variable Multi-Dimensional Fatigue Inventory (MFI-20): Perception of Exertion (Exercise) - Age-adjusted Borg Ratings Physical Fatigue

48 Perception of Exertion Rating of Perceived Exertion: Borg Scale Borg (1998) Perceived Exertion Rating is directly proportional to Heart Rate in the ratio of approximately 10? Age-predicted maximum heart rate Perceived Exertion

49 Identifying mechanisms associated with Physical Fatigue Univariate Regression Analysis Explanatory Variables Cardiovascular Fitness (VO 2 max) - A Submaximal Exercise Test Dependent Variable Multi-Dimensional Fatigue Inventory (MFI-20): Physical Fatigue Perception of Exertion (Exercise) - Age-adjusted Borg Ratings Lean Tissue Mass & Legs Lean Tissue Mass - DEXA Scanning Muscle Function - Jumping Mechanography - Perform Counter Movement Jump - Leonardo Mechanography Ground Reaction Force Platform

50 Results: Univariate Associations Physical Fatigue VO 2 max Muscle Mass Muscle Function Muscle Quality

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52 Identifying factors associated with Perceived Exertion Multivariate Regression Analysis Dependent Variable RPE index (Perceived Exertion) Explanatory Variables Psychosocial & Behavioural Parameters: Mental Fatigue [MFI-20] Anxiety Depression Sleep Quality [Pittsburgh Sleep Quality Index] Demographic Parameters: Age Gender Marital Status Ethnicity Time Post-Transplantation Smoking Status Alcohol Intake Clinical & Biochemical Parameters: Index of Co-Existing Disease (ICED) Presence of Diabetes Previous Episodes of Acute Rejection Immunosuppressive Medication Usage High Sensitive C-Reactive Protein (hscrp) Haemoglobin (Hb) Estimated Glomerular Filtration Rate (egfr) Body Composition: Lean Tissue Mass [DEXA Scanning] Fat Mass [DEXA Scanning] [Hospital Anxiety and Depression Scale]

53 Predicting Factors for Perceived Exertion β 95% Confidence Interval p Mental fatigue , Anxiety , Alcohol intake , Use of cyclosporine , New onset diabetes after transplantation ,

54 Conclusion Physical Fatigue Modifiable Predictors: Physical Sensations of Tiredness Physical Underperformance Mental fatigue Peripheral Anxiety Central Mechanisms Diabetes Mechanisms CNI Cardiorespiratory Muscle Muscle Alcohol intake Perception of function power mass effort Delivery of oxygen & nutrients to muscles Responses to afferent feedback from working body Physical Fatigue Exhaustion Muscle Physical Weakness Sensations of Tiredness Physical Underperformance

55 The way ahead: forget about the blood results Psychological Intervention/Cognitive behavioural therapy Mental Fatigue Centrally-acting pharmacological therapies Perception of effort Physical Fatigue

56 Wilson and Cleary. JAMA 1995

57 Acknowledgements: Dr Winnie Chan The British Renal Society Research Committee West Midlands Strategic Health Authority Supervisors: Dr Anna Phillips Dr Jos Bosch Research Assistants: Ms Okdeep Kaur Ms Davina Scott Ms Katerina McCann Ms Tina Tang Wellcome Trust Clinical Research Facility Renal Outpatients Department Collaborators: Prof David Jones Dr Andrew McClean Prof Lorraine Harper Dr Alison Whitelegg Dr Mark Drayson Dr Anne Bevins Mrs Sue Moore Mr Nick Inston Prof Philip McTernan Dr Alison Harte

58 West Midlands - Transplant First Audit & Education Event Debate: The quality of deceased donor organs currently available means that Transplant First is not the best choice for every patient Simon Ball and Nick Inston Chair - Richard Burrows Kidney Quality Improvement Partnership Yorks & Humber 58

59 Heated Debate: The quality of deceased donor organs currently available means that Transplant First is not the best choice for every patient

60 Heated Debate: The quality of deceased donor organs currently available means that Transplant First is not the best choice for every patient What treatment is the best choice for an individual patient Is it Transplant First? Is it Transplant best? What do we mean by quality of a deceased donor organs

61 How do we chose which treatment? We have alternative options for renal replacement therapy Quantity of Life Quality of life Cost

62 Quantity of life = survival 1 st 30 days transplantation worse survival

63 After 30 days Survival better in transplant vs dialysis

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65 Risk of dying on transplant list Risk of dying after a DD kidney transplant 7% / year 4% 1 st year At 5 years listed >28% vs Tx 12%

66 Cardiac disease is less in transplant patients than dialysis patients

67 Quality of life is better in transplant patients than in dialysis patients

68 Kidney transplantation vs dialysis Better survival Better QoL Transplant First must be the best choice for every patient

69 Is this really true? The data we are using is for a selected group Transplant (Listed) patients are less ill than non listed Cause of death in dialysis populations = contra-indications for transplant listing Listed patients are younger and fitter so Transplant gives better QoL Historic data Most studies >10 years old Pre-ECD Pre- extra-ecd

70 Transplant patients UK

71 The quality of deceased donor organs currently available means that Transplant First is not the best choice for every patient How do we define donor organ quality? Subjective Donor history Retrieval surgeon description DBD vs DCD? SCD vs ECD? Expanded criteria donors included all deceased donors aged 60 years and older, and those aged over years with at least two of the following three conditions: cerebrovascular cause of death, serum creatinine greater than 1.5 mg/dl (132.6 μmol/l), or a history of hypertension Objective Biopsy? Biomarkers? Perfusion parameters?

72 Case Donor 68m DBD CVA ICH 2 Anti-hypertensives NIDDM smoker Creatinine 120 No other history available Recipient 21m Congenital small kidneys GFR11 On W/L 55 days 222 MM Accept or decline?

73 BMJ 2015;351:h3557 doi: /bmj.h3557 Prospective study n=6891 Patients receiving ECD transplants vs standard criteria donors (80% v 88%, P<0.001). HR graft loss for a ECD vs SCD ECD : 55.8% had died of cerebrovascular causes. 24.4% donors had hypertension (5.5% donors presented with diabetes mellitus) CIT longer cold ischaemia time (>12 h) was associated with a 2.6-fold decrease in seven year allograft survival.

74 Use of ECD kidney donors in the UK ECD = aged 60 or with two of the following: history of hypertension, creatinine > 130 μmol/l, death due to intracranial haemorrhage DBD ECD SCD 18% 23% 20%22%26% 26%26% 26% 33%35% 33%34% ECD SCD 15% 18%18%21% DCD 42% 41% 40% 29% 25% 41% 41% 22% What is the post-transplant survival for ECD kidneys compared to SCD kidneys? Is it better to accept the offer of an ECD kidney or wait for a potential SCD kidney?

75 Post transplant adult kidney only survival, Jan 06 Dec 13 Deceased donor transplant survival DBD patient survival p< p< SCD ECD N % Surv 95% CI SCD DBD (81, 84) SCD DCD (79, 83) ECD DCD (67, 73) ECD DBD (67, 72) End point HR 95% CI 1 year years Adjusted analysis DBD patient survival Recipient age, primary renal disease, dialysis at registration, waiting time, transplant unit Significantly greater risk of death following ECD transplantation relative to SCD (5-year adjusted HR: 1.3; 95% CI: )

76 Is it better to wait for a good kidney than take a bad one? This is for ECD what about the super- or extra extended criteria donors

77 Case Donor 70m DBD ICH IDDM 20 years Hypertension 3 agents Smoker Creatinine 160 (?AKI) (on admission 100) Recipient 57f CAPD On dialysis 1.5 years well Wants to retire and travel Accept or decline? Biopsy?

78 Of the recovered ECD kidneys, 5139 (41%) were discarded. Both the performance of a biopsy (AOR = 1.21, p = 0.02) and the degree of glomerulosclerosis (GS) on biopsy were significantly associated with increased odds of discard.

79 Case Donor 55m DCD Traumatic HI Cr 95 BMI 45 Poor perfusion Recipient 50m Wait time 500 days Diabetes Hypertension HD on an AVF No LD CRF 0% Accept or decline?

80 Kidney offer declined 66m donor Hypertension, Smoker CVA Cr f donor Hypertension,ICH Cr 110

81 reason for turndown QEHB en bloc BBV infection mailgnancy Medical history (marginal/age MM/function/donor history) Logistics Perfusion/damage 37.1 Recipient unsuitable /uncontactable didn t retrieve/asystole

82 There is a difference between a gamble and a calculated risk. Edmund H. North Historically Donor kidney = good kidney Recipient desperate Now Kidneys worse Recipients not on dialysis

83 UK policy: Donor recipient matching is based on Tissue type, sensitization and wait time Not on risk vs benefit Donors and recipients have changed Allocation needs to change Donor : recipient risk matching is required e.g.. KDRI/ KDPI + PTDB Tanriover et al Am J Transplant Feb; 14(2): Gandolfini et al Am J Transplant Nov; 14(11):

84 The quality of deceased donor organs currently available means that Transplant First is not the best choice for every patient Allocation Donor recipient risk matching Data to support high risk transplantation is lacking Super ECD in particular

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86 West Midlands - Transplant First Audit & Education Event Close Kidney Quality Improvement Partnership Yorks & Humber 86