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Standard work-up of the low-risk kidney transplant candidate: a European expert survey of the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States Working Group

Standard work-up of the low-risk kidney transplant candidate: a European expert survey of the... Abstract Background Existing guidelines on the evaluation and preparation of recipients for kidney transplantation target the entire spectrum of patients with end-stage renal disease. Within the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States (DESCARTES) Working Group, it was proposed that in a subset of relatively young patients (<40 years) without significant comorbidities (such as diabetes or cardiovascular disease), the work-up for transplantation could be restricted to a small set of tests. Methods Aiming for agreement between transplant centres across Europe, we surveyed the opinion of 80 transplant professionals from 11 European states on the composition of a minimal work-up. Results We show that there is a wide agreement among European experts that the work-up for kidney transplantation of the low-risk candidate, as opposed to the standard risk candidate, could include a limited number of investigations. However, there is some disagreement regarding the small number of diagnostic procedures, which is related to geographical location within Europe and the professional background of respondents. Conclusions Based on the results of the survey, published guidelines and expert meetings by the DESCARTES Working Group, we have formulated a proposal for the work-up of low-risk kidney transplant candidates. age, ESRD, guidelines, kidney transplantation, pre-dialysis INTRODUCTION Patients wishing to undergo renal transplantation are subjected to screening procedures to assess their suitability for transplantation. Several guidelines for the evaluation of renal transplant candidates have been published [1–5]. Unfortunately, there is no universal agreement between these guidelines. Moreover, they usually aim to cover the entire spectrum of patients and do not necessarily provide specific recommendations for certain subsets of patients. This leaves room for different protocols, and it has indeed been demonstrated that there is significant variation in the assessment practices among various transplant centres [6]. Although many renal transplant candidates are old and have multiple comorbidities, requiring special investigations, there is also a subset of relatively young patients with end-stage renal disease, without significant comorbidities. Within the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States (DESCARTES) Working Group, it was proposed that for these low-risk renal transplant candidates, the work-up could be restricted to a small set of tests in order to reduce the ‘work-up’ time needed and to maximize the chances of pre-emptive transplantation. Moreover, it should be feasible to obtain agreement between transplant centres across Europe on what such a minimal work-up should entail. We present the results of a survey on the opinion of transplant professionals from 11 European states on the composition of a minimal work-up and confirm the variability between the different countries and between nephrologists and surgeons for certain examinations. Based on the results of this survey and on the expert meetings by the DESCARTES Working Group, we have formulated a proposal for the evaluation of a subgroup of relatively young transplant candidates (<40 years) without significant comorbidities (such as diabetes or cardiovascular disease). MATERIALS AND METHODS The process of formulating our proposal consisted of several stages. First, members of the ERA-EDTA DESCARTES Working Group agreed on the definition of a low-risk kidney transplant candidate. This was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation from a deceased or living donor, who has been on dialysis for not >5 years and does not have a diagnosis of diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. Secondly, an initial survey was developed to ask the opinion on a set of diagnostic procedures that could be part of the standard work-up. This comprised of both items on which the DESCARTES Working Group members expected broad agreement regarding their inclusion in a standard work-up (mandatory investigations—see Supplementary data, Appendix S1), as well as a set of items that were expected to be judged as unnecessary by the majority of respondents (laboratory examinations, imaging tests, functional assays and consultations with various specialists—see Question 2, Supplementary data, Appendix S1). This initial survey was sent to 37 and completed by 31 transplant physicians (nephrologists and surgeons) who were approached by members of the DESCARTES Working Group. These colleagues were transplant physicians from academic transplant centres with extensive experience (>5 years) in the work-up of kidney transplant candidates. The answers of this initial survey, including the respondent’s comments, were discussed within the DESCARTES Working Group. It appeared that some questions, especially regarding cancer screening, were misinterpreted by some respondents. This led to several minor modifications in order to improve the survey. The major modification was the inclusion of a general question regarding cancer screening (do you agree or disagree to perform ‘cancer screening according to national guidelines’) as well as a distinct set of tests/examinations regarding cancer screening (Supplementary data, Appendix S2, Question 3: cancer screening). We sent this second version (Supplementary data, Appendix S2) to a larger group of transplant professionals (others than involved in the initial survey), selected as described above, to increase the representability. The second survey was sent to 57 and completed by 49 transplant physicians, resulting in a total response rate for the two surveys of 85%. For the questions that were identical between the two versions of the survey, the answers were pooled (n = 80). Finally, the results of the survey were extensively discussed within the DESCARTES Working Group, taking data from literature and existing guidelines into account. Indeed, it was decided that an examination that was recommended (Grade 1 recommendation) for all kidney transplant candidates by one of the following groups/organizations—American Society of Transplantation (AST) [1], Canadian Society of Transplantation (CTS) [2], Renal Association endorsed by the British Transplantation Society (RA-BTS) [3], Kidney Health Australia-Caring for Australians with Renal Impairment (KH-CARI) [4] and European Best Practice Guideline (ERBP) group [5]—would also be included in the minimal work-up. This ultimately resulted in a set of examinations that were supported by all members of the Working Group. To assess the effect of nationality and profession on the physician’s attitude in including an examination in the standard work-up, we fitted multilevel logistic models by jointly examining the differences between countries (random effects) and between nephrologists and surgeons (fixed effects). From the estimates of the fitted regression models, we calculated the intra-class correlation coefficient to identify the proportion of variability in the physician’s response that was related to intrinsic differences between countries, and the predicted proportion of nephrologists and surgeons supporting the given examination. Empirical Bayes estimates—log (odds ratios)—obtained from the same models were used to express to what extent the intrinsic attitude of each country to endorse an examination deviated from the overall mean of all countries (reference value). We decided to limit our analyses to the four most supported ‘additional’ diagnostic procedures proposed by respondents (with support ranging between 30% and 55%; see Table 3), but not taken up in the final proposal. RESULTS Standard work-up of the low-risk kidney transplant candidate A completed response to the survey was obtained from 52 nephrologists and 28 transplant surgeons, distributed over 56 transplant centres in 11 European countries (Table 1). All respondents agreed on the statement that the evaluation of low-risk renal transplant candidates should include: (i) referral to a nephrologist and surgeon involved in kidney transplantation; (ii) detailed history regarding cardiovascular, urological, infectious and psychological risks; and (iii) a thorough physical examination of the cardiac, abdominal, urogenital and peripheral vascular systems. Table 1 Distribution of respondents according to country and profession for first and second survey Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) A list of all respondents is given in Supplementary data, Appendix S4. a The first figure represents the number of centres covered in this survey; the number in parentheses represents the total number of active kidney transplant centres for each country. Open in new tab Table 1 Distribution of respondents according to country and profession for first and second survey Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) A list of all respondents is given in Supplementary data, Appendix S4. a The first figure represents the number of centres covered in this survey; the number in parentheses represents the total number of active kidney transplant centres for each country. Open in new tab Next, respondents were asked whether they agreed with the individual diagnostic procedures for the standard work-up of a low-risk kidney transplant candidate. For each of the diagnostic procedures included in this proposal, there was agreement by >75% of respondents (Table 2). In addition, respondents had the opportunity to indicate if additional diagnostic procedures (listed in Table 3) should be included in the standard work-up of a low-risk kidney transplant candidate. Of all the items listed in Table 3, only five were thought to belong to a standard work-up by >25% of respondents: ultrasound of the abdomen (54%), echocardiography (45%), blood tests for syphilis (VDRL/TPHA; 40%), referral of female patients to a gynaecologist (33%) and an ultrasound Doppler of the iliac vessels (31%). Table 2 Percentage of respondents who agreed that a diagnostic procedure should be included in the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. HIV, human immunodeficiency virus; PTH, parathyroid hormone; ECG, electrocardiogram. Open in new tab Table 2 Percentage of respondents who agreed that a diagnostic procedure should be included in the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. HIV, human immunodeficiency virus; PTH, parathyroid hormone; ECG, electrocardiogram. Open in new tab Table 3 Percentage of respondents (n = 80) who indicated that a diagnostic procedure should be added to the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension and any abnormality of the urogenital tract. PCR, polymerase chain reaction; ECG, electrocardiogram. Open in new tab Table 3 Percentage of respondents (n = 80) who indicated that a diagnostic procedure should be added to the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension and any abnormality of the urogenital tract. PCR, polymerase chain reaction; ECG, electrocardiogram. Open in new tab What did we find in other guidelines? Kidney Disease: Improving Global Outcome do not address the work-up of kidney transplant candidates. Neither the CTS, KH-CARI, RA-BTS nor the ERBP group provide a list of the minimal work-up that should be undertaken in low-risk kidney transplant candidates. A summary of relevant recommendations from these guidelines for the work-up in general, including the strength and quality of evidence, is provided in Table 4. Table 4 Summary of recommendations in existing guidelines on preparation of a kidney transplant candidate Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C The guidelines of AST and CTS used the following grading system: Grade A—there is good evidence to support; Grade B—there is fair evidence to support; Grade C—the existing evidence is conflicting, but other factors may influence decision-making; Grade D—there is fair evidence to recommend against; Grade E—there is good evidence to recommend against. The guidelines of the RA, KHA-CARI and ERBP used the approach of the GRADE Working Group. The quality of evidence is graded from A (high) to D (very low) and the strength of the recommendation classified as 1 (strong) or 2 (weak). ECG, electrocardiography; LV, left ventricular; LVH, left ventricular hypertrophy; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Table 4 Summary of recommendations in existing guidelines on preparation of a kidney transplant candidate Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C The guidelines of AST and CTS used the following grading system: Grade A—there is good evidence to support; Grade B—there is fair evidence to support; Grade C—the existing evidence is conflicting, but other factors may influence decision-making; Grade D—there is fair evidence to recommend against; Grade E—there is good evidence to recommend against. The guidelines of the RA, KHA-CARI and ERBP used the approach of the GRADE Working Group. The quality of evidence is graded from A (high) to D (very low) and the strength of the recommendation classified as 1 (strong) or 2 (weak). ECG, electrocardiography; LV, left ventricular; LVH, left ventricular hypertrophy; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Consensus opinion of experts As a final step to formulate our proposal, the results of the survey were discussed within the DESCARTES Working Group. The outcome of this process was that the DESCARTES Working Group recommends limiting the examinations performed as a standard work-up of low-risk kidney transplant candidates to the items listed in Table 2. Serology for cytomegalovirus (CMV), Epstein–Barr virus (EBV) and Varicella zoster virus (VZV) was deemed useful for determining the need for CMV prophylaxis, the use of belatacept in EBV-seronegative candidates and potential vaccination for VZV in VZV-seronegative candidates. Although five further items were considered to be universally indicated by >25% of respondents (Table 3), we could not find any data in the literature to support such a policy [1, 2, 3, 4, 5]. Therefore, the DESCARTES Working Group does not recommend performing these investigations for screening purposes only. Of course, there can be valid reasons to perform these or other examinations in selected cases. Therefore, the final proposal for the work-up of young, comorbidity-free kidney transplant candidates is displayed in Table 5. None of the existing guidelines provides recommendations that contradict our present proposal. Table 5 Standard work-up of the low-risk kidney transplant candidate: a European survey and proposal of the ERA-EDTA DESCARTES Working Group Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Table 5 Standard work-up of the low-risk kidney transplant candidate: a European survey and proposal of the ERA-EDTA DESCARTES Working Group Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Effect of nationality and profession on the physician’s attitude to include an examination in the standard work-up There was no general agreement on the need for several examinations as part of the standard work-up. For the four examinations not included in the standard work-up but identified as most frequently supported, we analysed whether the tendency to include them differed by country or professional background (nephrologist or surgeon) of respondents. Table 6 and the figures in Supplementary data, Appendix S3 show that the variation between respondents was in large part (74%) explained by intrinsic differences between countries; this was particularly seen in the wish to perform an abdominal ultrasound. This was far less the case for echocardiography (20%), ultrasound Doppler of the iliac vessels (13%) and VDRL/TPHA (2%). In general, respondents from UK, Denmark and The Netherlands had a more restrictive attitude towards performing screening investigations, while there was a trend by Austrian and Italian respondents to be more exhaustive (Supplementary data, Appendix S3). In addition, we found differences in attitudes between nephrologists and surgeons. In general, after adjusting for country differences, nephrologists were more likely to include examinations in the standard work-up than surgeons. This was especially the case for echocardiography and for VDRL/TPHA (Table 6). Table 6 Role of intrinsic differences between countries and of differences between nephrologists and surgeons in the attitudes of including some examinations in the normal work-up Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 The table shows findings from multilevel logistic models jointly examining the differences between countries (random effects) and the differences between nephrologists and surgeons (fixed effects) in including the examination in the standard work-up. Intra-class correlation coefficient reflects the proportion of variability in the attitude to prescribe the examination that is related to intrinsic difference between countries. Predicted means stands for the predicted proportions of nephrologists and surgeons, respectively, including the examination in the standard work-up. The proportions are estimated from the fitted multilevel logistic model (i.e. after adjusting for differences between countries). CI, confidence interval; US, ultrasound. Open in new tab Table 6 Role of intrinsic differences between countries and of differences between nephrologists and surgeons in the attitudes of including some examinations in the normal work-up Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 The table shows findings from multilevel logistic models jointly examining the differences between countries (random effects) and the differences between nephrologists and surgeons (fixed effects) in including the examination in the standard work-up. Intra-class correlation coefficient reflects the proportion of variability in the attitude to prescribe the examination that is related to intrinsic difference between countries. Predicted means stands for the predicted proportions of nephrologists and surgeons, respectively, including the examination in the standard work-up. The proportions are estimated from the fitted multilevel logistic model (i.e. after adjusting for differences between countries). CI, confidence interval; US, ultrasound. Open in new tab DISCUSSION Our survey shows that there is considerable agreement among experts from all over Europe that the work-up for kidney transplantation for the low-risk candidate, as opposed to the standard-risk candidate, should only include a limited number of examinations. However, there is some disagreement regarding a couple of diagnostic procedures, which is related to geographical location and the professional background of respondents. Existing guidelines on the evaluation and preparation of recipients for kidney transplantation aim to cover the entire spectrum of patients with end-stage renal disease. However, there is a large variation in age and comorbidity between kidney transplant candidates, which can result in considerable differences in the required pre-transplantation work-up. Moreover, global guidelines may be less applicable for areas with a more homogeneous healthcare system like Europe. For older transplant candidates, more specific recommendations have been published, with an emphasis on the assessment of the functional status and on the scoring of frailty [7, 8]. In contrast, no specific recommendations have been reported for low-risk kidney transplant candidates. According to the definition that we used for a low-risk candidate, about 17% of all patients wait-listed in Eurotransplant in 2015 and 2016 belonged to this category (request Eurotransplant 8 December 2017). While older age and comorbidities will induce practice variation, agreement on a uniform policy should be more easily obtained in young and relatively healthy patients. Based on these considerations, the ERA-EDTA DESCARTES Working Group took the initiative to formulate a recommendation on the minimal work-up of low-risk kidney transplant candidates. Limiting the work-up in these patients to a restricted set of examinations could reduce the burden for patients, accelerate listing for transplantation and decrease costs. All respondents agreed on the requirement of a detailed history and a physical examination at the transplant centre. The history should include information on the cause of native kidney disease since many native kidney diseases are associated with recurrence and/or increased risk of complications post-transplantation. This may require review of the native kidney biopsy or genetic testing. Since there is little to no scientific evidence supporting the value of various additional examinations as part of the standard work-up, we used a survey to collect the opinions of a sample of 80 transplant professionals from 11 European countries. Since this was comprised of a selected group of individuals with a rather high response rate, we cannot exclude some selection bias. Moreover, the opinions of these professionals do not necessarily reflect an evidence-based approach, although there was reasonable agreement between the various respondents on most of the items. We therefore feel that the resulting recommendations on a limited set of investigations (Table 5) can guide individual physicians to undertake the work-up for their low-risk patients. There were four tests that >25% of respondents indicated should be added to a standard work-up: abdominal ultrasound, echocardiography, syphilis testing and ultrasound of the iliac vessels. For some examinations, such as US abdomen, we found that geographical location accounted for most of the heterogeneity between respondents. However, the difference reached statistical significance in a limited number of countries (e.g. UK and Denmark being less inclined compared with the others). Overall, about half of respondents were in favour of performing an abdominal ultrasound in uncomplicated, low-risk candidates. The most frequently given argument was that it is a simple and cheap examination, useful for screening for gallstones and malignancies, especially of the kidney. Notably, there are no data in the literature to support this recommendation. The ERBP group guideline included an ungraded statement that suggested screening kidney transplant candidates for the presence of kidney cancer by ultrasound [5]. Other guidelines do not provide recommendations on this issue. With respect to echocardiography, all guidelines summarized in Table 4 indicate that this should only be performed by clinical indication and not routinely in low-risk patients. Although only a very small number of cases of syphilis in kidney transplant patients have been reported, the incidence of syphilis is rising worldwide [9]. Testing for latent syphilis and subsequent treatment in case of a positive test can therefore be useful before transplantation, particularly in high-risk patients, and is recommended by several guidelines although not mentioned in others [10, 11]. There are no data on the cost-effectiveness of ultrasound of the iliac vessels, and this examination is not included in any guideline. One-third of respondents indicated that referral to a gynaecologist should be part of the standard work-up. We expect that the main reason for referral was to exclude gynaecological pathology before transplantation, but the survey did not address this issue. Counselling about contraception and pregnancy post-transplantation could be an alternative reason for gynaecological consultancy. In general, we advocate a restrictive use of examinations for which there is no sound evidence. Unrestricted use of diagnostic procedures, even if they are of low cost, may result in additional investigations, delay of transplantation and decreased transplantation rates, as was shown for prostate cancer screening [12]. Nevertheless, additional tests can be indicated in patients with a specific risk profile, for example, Mantoux test or in vitro tests for exposure to mycobacteria in a patient from an area where mycobacteria are endemic. Furthermore, it should be emphasized that our proposal concerns initial testing and abnormal results may require further examination. Three earlier studies observed significant variation in the evaluation process of kidney transplant candidates in the USA, Europe and UK, respectively [6, 13, 14]. Although these studies were not limited to low-risk patients, similar findings emerged from the current survey. We found a significant effect of the country on the attitude to performing diagnostic tests. Remarkably, in the European study by Fritsche et al. [6] that was published >15 years ago, exactly the same observation was made, with the most restrictive approach by respondents from the UK and Scandinavia [6]. Evidently, cultural factors and organizational aspects of the healthcare system are important and sustained driving forces in medical practice, especially when scientific evidence is missing. Although Fritsche et al. observed limited influence from the professional background of respondents on practice variation, we observed that nephrologists were more likely to perform diagnostic procedures than surgeons. We hope that our recommendations for the standard work-up of low-risk kidney transplant candidates will lead to a timely listing for transplantation. These young patients with no or few comorbidities benefit substantially from transplantation, allowing them to lead a near-normal life in many cases. Individual physicians or transplant centres striving for cost-effective patient care will hopefully feel supported by this consensus report from a group of European opinion leaders. ACKNOWLEDGEMENTS We greatly appreciate the help of M. Pippias in providing linguistic improvements. CONFLICT OF INTEREST STATEMENT None of the authors has a conflict of interest. The results presented in this article have not been published previously. REFERENCES 1 Kasiske BL , Cangro CB , Hariharan S et al. The evaluation of renal transplantation candidates: clinical practice guidelines . Am J Transplant 2001 ; 1 (Suppl 2) : 3 – 95 Google Scholar PubMed WorldCat 2 Knoll G , Cockfield S , Blydt-Hansen T et al. Canadian Society of Transplantation: consensus guidelines on eligibility for kidney transplantation . CMAJ 2005 ; 173 : S1 – S25 Google Scholar Crossref Search ADS PubMed WorldCat 3 Dudley C , Harden P. Renal Association Clinical Practice Guideline on the assessment of the potential kidney transplant recipient . Nephron Clin Pract 2011 ; 118 (Suppl 1) : c209 – c224 Google Scholar Crossref Search ADS PubMed WorldCat 4 Campbell S , Pilmore H , Gracey D et al. KHA-CARI guideline: recipient assessment for transplantation . Nephrology (Carlton) 2013 ; 18 : 455 – 462 Google Scholar Crossref Search ADS PubMed WorldCat 5 Abramowicz D , Cochat P , Claas FH et al. European Renal Best Practice Guideline on kidney donor and recipient evaluation and perioperative care . Nephrol Dial Transplant 2015 ; 30 : 1790 – 1797 Google Scholar Crossref Search ADS PubMed WorldCat 6 Fritsche L , Vanrenterghem Y , Nordal KP et al. Practice variations in the evaluation of adult candidates for cadaveric kidney transplantation: a survey of the European Transplant Centers . Transplantation 2000 ; 70 : 1492 – 1497 Google Scholar Crossref Search ADS PubMed WorldCat 7 Concepcion BP , Forbes RC , Schaefer HM. Older candidates for kidney transplantation: who to refer and what to expect? World J Transplant 2016 ; 6 : 650 – 657 Google Scholar Crossref Search ADS PubMed WorldCat 8 Knoll GA. Kidney transplantation in the older adult . Am J Kidney Dis 2013 ; 61 : 790 – 797 Google Scholar Crossref Search ADS PubMed WorldCat 9 Stamm LV. Syphilis: re-emergence of an old foe . Microb Cell 2016 ; 3 : 363 – 370 Google Scholar Crossref Search ADS PubMed WorldCat 10 Fischer SA , Avery RK , AST Infectious Diseases Community of Practice. Screening of donor and recipient prior to solid organ transplantation . Am J Transplant 2009 ; 9 (Suppl 4) : S7 – S18 Google Scholar Crossref Search ADS PubMed WorldCat 11 Len O , Garzoni C , Lumbreras C et al. Recommendations for screening of donor and recipient prior to solid organ transplantation and to minimize transmission of donor-derived infections . Clin Microbiol Infect 2014 ; 20 (Suppl 7) : 10 – 18 Google Scholar Crossref Search ADS PubMed WorldCat 12 Vitiello GA , Sayed BA , Wardenburg M et al. Utility of prostate cancer screening in kidney transplant candidates . J Am Soc Nephrol 2016 ; 27 : 2157 – 2163 Google Scholar Crossref Search ADS PubMed WorldCat 13 Ramos EL , Kasiske BL , Alexander SR et al. The evaluation of candidates for renal transplantation. The current practice of U.S. transplant centers . Transplantation 1994 ; 57 : 490 – 497 Google Scholar Crossref Search ADS PubMed WorldCat 14 Akolekar D , Oniscu GC , Forsythe JL. Variations in the assessment practice for renal transplantation across the United Kingdom . Transplantation 2008 ; 85 : 407 – 410 Google Scholar PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Standard work-up of the low-risk kidney transplant candidate: a European expert survey of the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States Working Group

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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10.1093/ndt/gfy391
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Abstract

Abstract Background Existing guidelines on the evaluation and preparation of recipients for kidney transplantation target the entire spectrum of patients with end-stage renal disease. Within the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States (DESCARTES) Working Group, it was proposed that in a subset of relatively young patients (<40 years) without significant comorbidities (such as diabetes or cardiovascular disease), the work-up for transplantation could be restricted to a small set of tests. Methods Aiming for agreement between transplant centres across Europe, we surveyed the opinion of 80 transplant professionals from 11 European states on the composition of a minimal work-up. Results We show that there is a wide agreement among European experts that the work-up for kidney transplantation of the low-risk candidate, as opposed to the standard risk candidate, could include a limited number of investigations. However, there is some disagreement regarding the small number of diagnostic procedures, which is related to geographical location within Europe and the professional background of respondents. Conclusions Based on the results of the survey, published guidelines and expert meetings by the DESCARTES Working Group, we have formulated a proposal for the work-up of low-risk kidney transplant candidates. age, ESRD, guidelines, kidney transplantation, pre-dialysis INTRODUCTION Patients wishing to undergo renal transplantation are subjected to screening procedures to assess their suitability for transplantation. Several guidelines for the evaluation of renal transplant candidates have been published [1–5]. Unfortunately, there is no universal agreement between these guidelines. Moreover, they usually aim to cover the entire spectrum of patients and do not necessarily provide specific recommendations for certain subsets of patients. This leaves room for different protocols, and it has indeed been demonstrated that there is significant variation in the assessment practices among various transplant centres [6]. Although many renal transplant candidates are old and have multiple comorbidities, requiring special investigations, there is also a subset of relatively young patients with end-stage renal disease, without significant comorbidities. Within the ERA-EDTA Developing Education Science and Care for Renal Transplantation in European States (DESCARTES) Working Group, it was proposed that for these low-risk renal transplant candidates, the work-up could be restricted to a small set of tests in order to reduce the ‘work-up’ time needed and to maximize the chances of pre-emptive transplantation. Moreover, it should be feasible to obtain agreement between transplant centres across Europe on what such a minimal work-up should entail. We present the results of a survey on the opinion of transplant professionals from 11 European states on the composition of a minimal work-up and confirm the variability between the different countries and between nephrologists and surgeons for certain examinations. Based on the results of this survey and on the expert meetings by the DESCARTES Working Group, we have formulated a proposal for the evaluation of a subgroup of relatively young transplant candidates (<40 years) without significant comorbidities (such as diabetes or cardiovascular disease). MATERIALS AND METHODS The process of formulating our proposal consisted of several stages. First, members of the ERA-EDTA DESCARTES Working Group agreed on the definition of a low-risk kidney transplant candidate. This was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation from a deceased or living donor, who has been on dialysis for not >5 years and does not have a diagnosis of diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. Secondly, an initial survey was developed to ask the opinion on a set of diagnostic procedures that could be part of the standard work-up. This comprised of both items on which the DESCARTES Working Group members expected broad agreement regarding their inclusion in a standard work-up (mandatory investigations—see Supplementary data, Appendix S1), as well as a set of items that were expected to be judged as unnecessary by the majority of respondents (laboratory examinations, imaging tests, functional assays and consultations with various specialists—see Question 2, Supplementary data, Appendix S1). This initial survey was sent to 37 and completed by 31 transplant physicians (nephrologists and surgeons) who were approached by members of the DESCARTES Working Group. These colleagues were transplant physicians from academic transplant centres with extensive experience (>5 years) in the work-up of kidney transplant candidates. The answers of this initial survey, including the respondent’s comments, were discussed within the DESCARTES Working Group. It appeared that some questions, especially regarding cancer screening, were misinterpreted by some respondents. This led to several minor modifications in order to improve the survey. The major modification was the inclusion of a general question regarding cancer screening (do you agree or disagree to perform ‘cancer screening according to national guidelines’) as well as a distinct set of tests/examinations regarding cancer screening (Supplementary data, Appendix S2, Question 3: cancer screening). We sent this second version (Supplementary data, Appendix S2) to a larger group of transplant professionals (others than involved in the initial survey), selected as described above, to increase the representability. The second survey was sent to 57 and completed by 49 transplant physicians, resulting in a total response rate for the two surveys of 85%. For the questions that were identical between the two versions of the survey, the answers were pooled (n = 80). Finally, the results of the survey were extensively discussed within the DESCARTES Working Group, taking data from literature and existing guidelines into account. Indeed, it was decided that an examination that was recommended (Grade 1 recommendation) for all kidney transplant candidates by one of the following groups/organizations—American Society of Transplantation (AST) [1], Canadian Society of Transplantation (CTS) [2], Renal Association endorsed by the British Transplantation Society (RA-BTS) [3], Kidney Health Australia-Caring for Australians with Renal Impairment (KH-CARI) [4] and European Best Practice Guideline (ERBP) group [5]—would also be included in the minimal work-up. This ultimately resulted in a set of examinations that were supported by all members of the Working Group. To assess the effect of nationality and profession on the physician’s attitude in including an examination in the standard work-up, we fitted multilevel logistic models by jointly examining the differences between countries (random effects) and between nephrologists and surgeons (fixed effects). From the estimates of the fitted regression models, we calculated the intra-class correlation coefficient to identify the proportion of variability in the physician’s response that was related to intrinsic differences between countries, and the predicted proportion of nephrologists and surgeons supporting the given examination. Empirical Bayes estimates—log (odds ratios)—obtained from the same models were used to express to what extent the intrinsic attitude of each country to endorse an examination deviated from the overall mean of all countries (reference value). We decided to limit our analyses to the four most supported ‘additional’ diagnostic procedures proposed by respondents (with support ranging between 30% and 55%; see Table 3), but not taken up in the final proposal. RESULTS Standard work-up of the low-risk kidney transplant candidate A completed response to the survey was obtained from 52 nephrologists and 28 transplant surgeons, distributed over 56 transplant centres in 11 European countries (Table 1). All respondents agreed on the statement that the evaluation of low-risk renal transplant candidates should include: (i) referral to a nephrologist and surgeon involved in kidney transplantation; (ii) detailed history regarding cardiovascular, urological, infectious and psychological risks; and (iii) a thorough physical examination of the cardiac, abdominal, urogenital and peripheral vascular systems. Table 1 Distribution of respondents according to country and profession for first and second survey Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) A list of all respondents is given in Supplementary data, Appendix S4. a The first figure represents the number of centres covered in this survey; the number in parentheses represents the total number of active kidney transplant centres for each country. Open in new tab Table 1 Distribution of respondents according to country and profession for first and second survey Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) Country First survey Second survey Total number of respondents Number of centresa Nephrologist Surgeon Nephrologist Surgeon Austria 1 0 2 1 4 2 (4) Belgium 2 2 0 4 8 7 (8) Czech Republic 1 0 3 2 6 4 (7) Denmark 2 1 3 1 7 3 (3) France 0 0 5 0 5 4 (32) Germany 2 1 7 4 14 9 (41) Italy 3 2 1 2 8 8 (39) The Netherlands 5 1 3 1 10 6 (8) Spain 1 1 4 0 6 4 (39) Switzerland 0 0 1 0 1 1 (6) UK 2 4 4 1 11 8 (24) Total 19 12 33 16 80 56 (211) A list of all respondents is given in Supplementary data, Appendix S4. a The first figure represents the number of centres covered in this survey; the number in parentheses represents the total number of active kidney transplant centres for each country. Open in new tab Next, respondents were asked whether they agreed with the individual diagnostic procedures for the standard work-up of a low-risk kidney transplant candidate. For each of the diagnostic procedures included in this proposal, there was agreement by >75% of respondents (Table 2). In addition, respondents had the opportunity to indicate if additional diagnostic procedures (listed in Table 3) should be included in the standard work-up of a low-risk kidney transplant candidate. Of all the items listed in Table 3, only five were thought to belong to a standard work-up by >25% of respondents: ultrasound of the abdomen (54%), echocardiography (45%), blood tests for syphilis (VDRL/TPHA; 40%), referral of female patients to a gynaecologist (33%) and an ultrasound Doppler of the iliac vessels (31%). Table 2 Percentage of respondents who agreed that a diagnostic procedure should be included in the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. HIV, human immunodeficiency virus; PTH, parathyroid hormone; ECG, electrocardiogram. Open in new tab Table 2 Percentage of respondents who agreed that a diagnostic procedure should be included in the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 Diagnostic procedure % N = 80 (total no. surveyed)  Full blood count (haemoglobin, leucocytes, thrombocytes) 100  Liver enzymes 96  INR/APTT 95  Hepatitis B serology 99  Hepatitis C serology 99  HIV serology 99  PTH 90  Urine culture 83  CMV serology 95  EBV serology 94  VZV serology 76  Chest X-ray 95  Ultrasound of kidneys 84  ECG 100 N = 49 (second survey)  Cancer screening according to national guidelines 98  Regular visit to dentist 88 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension or any abnormality of the urogenital tract. HIV, human immunodeficiency virus; PTH, parathyroid hormone; ECG, electrocardiogram. Open in new tab Table 3 Percentage of respondents (n = 80) who indicated that a diagnostic procedure should be added to the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension and any abnormality of the urogenital tract. PCR, polymerase chain reaction; ECG, electrocardiogram. Open in new tab Table 3 Percentage of respondents (n = 80) who indicated that a diagnostic procedure should be added to the standard work-up of all low-risk renal transplant candidatesa Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 Diagnostic procedure % Abdominal ultrasound 54 Echocardiography 45 Syphilis blood tests (VDRL/TPHA) 40 Ultrasound Doppler of the iliac vessels 31 In vitro tests for tuberculosis (IGRA/Quantiferon) 25 Toxoplasma serology 19 Mantoux test 16 Orthopantomogram 15 Ultrasound Doppler carotid arteries 14 Hepatitis C PCR 14 Exercise ECG 13 Lung-function test 8 Pelvic X-ray 6 Voiding cystography 6 Urodynamic test 5 Cystoscopy 3 Colonoscopy 3 Myocardial scintigraphy 3 Referral to gynaecologist 33 Referral to urologist (if urologist is not a member of surgical team) 21 Referral to psychologist 16 Referral to cardiologist 16 Referral to psychiatrist 1 a A low-risk renal transplant candidate was defined as a patient aged 18–40 years old, prepared for a first kidney transplantation with a deceased or living donor, who has been on dialysis for not >5 years and who does not have diabetes mellitus, a history of cardiovascular disease except for hypertension and any abnormality of the urogenital tract. PCR, polymerase chain reaction; ECG, electrocardiogram. Open in new tab What did we find in other guidelines? Kidney Disease: Improving Global Outcome do not address the work-up of kidney transplant candidates. Neither the CTS, KH-CARI, RA-BTS nor the ERBP group provide a list of the minimal work-up that should be undertaken in low-risk kidney transplant candidates. A summary of relevant recommendations from these guidelines for the work-up in general, including the strength and quality of evidence, is provided in Table 4. Table 4 Summary of recommendations in existing guidelines on preparation of a kidney transplant candidate Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C The guidelines of AST and CTS used the following grading system: Grade A—there is good evidence to support; Grade B—there is fair evidence to support; Grade C—the existing evidence is conflicting, but other factors may influence decision-making; Grade D—there is fair evidence to recommend against; Grade E—there is good evidence to recommend against. The guidelines of the RA, KHA-CARI and ERBP used the approach of the GRADE Working Group. The quality of evidence is graded from A (high) to D (very low) and the strength of the recommendation classified as 1 (strong) or 2 (weak). ECG, electrocardiography; LV, left ventricular; LVH, left ventricular hypertrophy; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Table 4 Summary of recommendations in existing guidelines on preparation of a kidney transplant candidate Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C Topic Guideline organization Recommendation Strength of recommendation Screening for liver disease AST Medical history, physical examination, serum total bilirubin and transaminase levels, hepatitis B and C serology Grade A CTS Medical history, physical examination, serum bilirubin and liver en zyme levels, hepatitis B and C serology Grade C RA-BTS Hepatitis B and C serology Grade 1A KHA-CARI Hepatitis B and C serology Ungraded HIV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A KHA-CARI To be assessed before transplantation Ungraded Hyperparathyroidism AST and CTS Calcium, phosphorus and PTH be measured Grade A CMV serology AST and CTS To be assessed before transplantation Grade A RA-BTS To be assessed before transplantation Grade 1A EBV serology CTS To be assessed before transplantation Grade A BTS To be assessed before transplantation Grade 1A VZV serology RA-BTS To be assessed before transplantation Grade 1A ERBP To be assessed before transplantation Grade 1D Cancer screening AST According to recommendations that apply to general population Grade A CTS According to recommendations that apply to general population Grade C ERBP According to recommendations that apply to general population Ungraded ERBP Ultrasound for presence of kidney cancer Ungraded Screening for cardiac disease AST Assess risk factors for ischaemic heart disease Grade A Perform cardiac stress test in patients at high risk Grade B Evaluate for possible LVH or myocardial dysfunction with history, physical examination, ECG and chest X-ray Grade A Echocardiography if there is evidence of LVH or myocardial dysfunction Grade B CTS History, physical examination, ECG, chest X-ray Grade A Further testing for ischaemic heart disease in symptomatic patients and patients with diabetes or multiple risk factors Grades A and B Echocardiogram in patients with evidence of LV dysfunction or in patients at high risk for LV dysfunction Grades B and C RA-BTS Only in high-risk patients Grade 2C KHA-CARI Only in patients with moderate or high clinical risk Grade 2B ERBP History, physical examination, ECG, chest X-ray Grade 1C Exercise tolerance test and echocardiography in high-risk patients Grade 1C Screening for peripheral vascular disease AST History and physical examination Grade C Mycobacterial infection AST Exposure history, chest X-ray. Mantoux test in candidates without a history of vaccination or of tuberculosis Grade A CTS Careful clinical history, chest X-ray and Mantoux test Grade C Screening for cerebral vascular disease AST Consider screening of high-risk patients with carotid ultrasound Grade C Psychosocial evaluation CTS Evaluation by an experienced competent individual Grade C The guidelines of AST and CTS used the following grading system: Grade A—there is good evidence to support; Grade B—there is fair evidence to support; Grade C—the existing evidence is conflicting, but other factors may influence decision-making; Grade D—there is fair evidence to recommend against; Grade E—there is good evidence to recommend against. The guidelines of the RA, KHA-CARI and ERBP used the approach of the GRADE Working Group. The quality of evidence is graded from A (high) to D (very low) and the strength of the recommendation classified as 1 (strong) or 2 (weak). ECG, electrocardiography; LV, left ventricular; LVH, left ventricular hypertrophy; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Consensus opinion of experts As a final step to formulate our proposal, the results of the survey were discussed within the DESCARTES Working Group. The outcome of this process was that the DESCARTES Working Group recommends limiting the examinations performed as a standard work-up of low-risk kidney transplant candidates to the items listed in Table 2. Serology for cytomegalovirus (CMV), Epstein–Barr virus (EBV) and Varicella zoster virus (VZV) was deemed useful for determining the need for CMV prophylaxis, the use of belatacept in EBV-seronegative candidates and potential vaccination for VZV in VZV-seronegative candidates. Although five further items were considered to be universally indicated by >25% of respondents (Table 3), we could not find any data in the literature to support such a policy [1, 2, 3, 4, 5]. Therefore, the DESCARTES Working Group does not recommend performing these investigations for screening purposes only. Of course, there can be valid reasons to perform these or other examinations in selected cases. Therefore, the final proposal for the work-up of young, comorbidity-free kidney transplant candidates is displayed in Table 5. None of the existing guidelines provides recommendations that contradict our present proposal. Table 5 Standard work-up of the low-risk kidney transplant candidate: a European survey and proposal of the ERA-EDTA DESCARTES Working Group Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Table 5 Standard work-up of the low-risk kidney transplant candidate: a European survey and proposal of the ERA-EDTA DESCARTES Working Group Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease Recommended to include in all patients  Detailed history and thorough physical examination  Laboratory assays   Full blood count, liver enzymes, INR/APTT, HBV, HCV, HIV, CMV, EBV, VZV serology, PTH, urine culture  Other assays/consultations   Chest X-ray, ECG, ultrasound of kidneys, cancer screening according to national guidelines, regular dentist visit To be considered as part of standard work-up  Screening for latent infection with mycobacteria  Syphilis testing  Review of native kidney biopsy  Testing for genetic cause of kidney disease HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; ECG, electrocardiogram; PTH, parathyroid hormone. Open in new tab Effect of nationality and profession on the physician’s attitude to include an examination in the standard work-up There was no general agreement on the need for several examinations as part of the standard work-up. For the four examinations not included in the standard work-up but identified as most frequently supported, we analysed whether the tendency to include them differed by country or professional background (nephrologist or surgeon) of respondents. Table 6 and the figures in Supplementary data, Appendix S3 show that the variation between respondents was in large part (74%) explained by intrinsic differences between countries; this was particularly seen in the wish to perform an abdominal ultrasound. This was far less the case for echocardiography (20%), ultrasound Doppler of the iliac vessels (13%) and VDRL/TPHA (2%). In general, respondents from UK, Denmark and The Netherlands had a more restrictive attitude towards performing screening investigations, while there was a trend by Austrian and Italian respondents to be more exhaustive (Supplementary data, Appendix S3). In addition, we found differences in attitudes between nephrologists and surgeons. In general, after adjusting for country differences, nephrologists were more likely to include examinations in the standard work-up than surgeons. This was especially the case for echocardiography and for VDRL/TPHA (Table 6). Table 6 Role of intrinsic differences between countries and of differences between nephrologists and surgeons in the attitudes of including some examinations in the normal work-up Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 The table shows findings from multilevel logistic models jointly examining the differences between countries (random effects) and the differences between nephrologists and surgeons (fixed effects) in including the examination in the standard work-up. Intra-class correlation coefficient reflects the proportion of variability in the attitude to prescribe the examination that is related to intrinsic difference between countries. Predicted means stands for the predicted proportions of nephrologists and surgeons, respectively, including the examination in the standard work-up. The proportions are estimated from the fitted multilevel logistic model (i.e. after adjusting for differences between countries). CI, confidence interval; US, ultrasound. Open in new tab Table 6 Role of intrinsic differences between countries and of differences between nephrologists and surgeons in the attitudes of including some examinations in the normal work-up Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 Diagnostic procedure Intra-class correlation coefficient (95% CI) Predicted means: nephrologists versus surgeons, %; P-value VDRL/TPHA 0.02 (0.00–1.00) 48 versus 19; 0.014 Ultrasound Doppler iliac vessels 0.13 (0.1–0.68) 38 versus 24; 0.21 US abdomen 0.74 (0.32–0.95) 54 versus 55; 0.97 Echocardiography 0.20 (0.04–0.63) 57 versus 29; 0.021 The table shows findings from multilevel logistic models jointly examining the differences between countries (random effects) and the differences between nephrologists and surgeons (fixed effects) in including the examination in the standard work-up. Intra-class correlation coefficient reflects the proportion of variability in the attitude to prescribe the examination that is related to intrinsic difference between countries. Predicted means stands for the predicted proportions of nephrologists and surgeons, respectively, including the examination in the standard work-up. The proportions are estimated from the fitted multilevel logistic model (i.e. after adjusting for differences between countries). CI, confidence interval; US, ultrasound. Open in new tab DISCUSSION Our survey shows that there is considerable agreement among experts from all over Europe that the work-up for kidney transplantation for the low-risk candidate, as opposed to the standard-risk candidate, should only include a limited number of examinations. However, there is some disagreement regarding a couple of diagnostic procedures, which is related to geographical location and the professional background of respondents. Existing guidelines on the evaluation and preparation of recipients for kidney transplantation aim to cover the entire spectrum of patients with end-stage renal disease. However, there is a large variation in age and comorbidity between kidney transplant candidates, which can result in considerable differences in the required pre-transplantation work-up. Moreover, global guidelines may be less applicable for areas with a more homogeneous healthcare system like Europe. For older transplant candidates, more specific recommendations have been published, with an emphasis on the assessment of the functional status and on the scoring of frailty [7, 8]. In contrast, no specific recommendations have been reported for low-risk kidney transplant candidates. According to the definition that we used for a low-risk candidate, about 17% of all patients wait-listed in Eurotransplant in 2015 and 2016 belonged to this category (request Eurotransplant 8 December 2017). While older age and comorbidities will induce practice variation, agreement on a uniform policy should be more easily obtained in young and relatively healthy patients. Based on these considerations, the ERA-EDTA DESCARTES Working Group took the initiative to formulate a recommendation on the minimal work-up of low-risk kidney transplant candidates. Limiting the work-up in these patients to a restricted set of examinations could reduce the burden for patients, accelerate listing for transplantation and decrease costs. All respondents agreed on the requirement of a detailed history and a physical examination at the transplant centre. The history should include information on the cause of native kidney disease since many native kidney diseases are associated with recurrence and/or increased risk of complications post-transplantation. This may require review of the native kidney biopsy or genetic testing. Since there is little to no scientific evidence supporting the value of various additional examinations as part of the standard work-up, we used a survey to collect the opinions of a sample of 80 transplant professionals from 11 European countries. Since this was comprised of a selected group of individuals with a rather high response rate, we cannot exclude some selection bias. Moreover, the opinions of these professionals do not necessarily reflect an evidence-based approach, although there was reasonable agreement between the various respondents on most of the items. We therefore feel that the resulting recommendations on a limited set of investigations (Table 5) can guide individual physicians to undertake the work-up for their low-risk patients. There were four tests that >25% of respondents indicated should be added to a standard work-up: abdominal ultrasound, echocardiography, syphilis testing and ultrasound of the iliac vessels. For some examinations, such as US abdomen, we found that geographical location accounted for most of the heterogeneity between respondents. However, the difference reached statistical significance in a limited number of countries (e.g. UK and Denmark being less inclined compared with the others). Overall, about half of respondents were in favour of performing an abdominal ultrasound in uncomplicated, low-risk candidates. The most frequently given argument was that it is a simple and cheap examination, useful for screening for gallstones and malignancies, especially of the kidney. Notably, there are no data in the literature to support this recommendation. The ERBP group guideline included an ungraded statement that suggested screening kidney transplant candidates for the presence of kidney cancer by ultrasound [5]. Other guidelines do not provide recommendations on this issue. With respect to echocardiography, all guidelines summarized in Table 4 indicate that this should only be performed by clinical indication and not routinely in low-risk patients. Although only a very small number of cases of syphilis in kidney transplant patients have been reported, the incidence of syphilis is rising worldwide [9]. Testing for latent syphilis and subsequent treatment in case of a positive test can therefore be useful before transplantation, particularly in high-risk patients, and is recommended by several guidelines although not mentioned in others [10, 11]. There are no data on the cost-effectiveness of ultrasound of the iliac vessels, and this examination is not included in any guideline. One-third of respondents indicated that referral to a gynaecologist should be part of the standard work-up. We expect that the main reason for referral was to exclude gynaecological pathology before transplantation, but the survey did not address this issue. Counselling about contraception and pregnancy post-transplantation could be an alternative reason for gynaecological consultancy. In general, we advocate a restrictive use of examinations for which there is no sound evidence. Unrestricted use of diagnostic procedures, even if they are of low cost, may result in additional investigations, delay of transplantation and decreased transplantation rates, as was shown for prostate cancer screening [12]. Nevertheless, additional tests can be indicated in patients with a specific risk profile, for example, Mantoux test or in vitro tests for exposure to mycobacteria in a patient from an area where mycobacteria are endemic. Furthermore, it should be emphasized that our proposal concerns initial testing and abnormal results may require further examination. Three earlier studies observed significant variation in the evaluation process of kidney transplant candidates in the USA, Europe and UK, respectively [6, 13, 14]. Although these studies were not limited to low-risk patients, similar findings emerged from the current survey. We found a significant effect of the country on the attitude to performing diagnostic tests. Remarkably, in the European study by Fritsche et al. [6] that was published >15 years ago, exactly the same observation was made, with the most restrictive approach by respondents from the UK and Scandinavia [6]. Evidently, cultural factors and organizational aspects of the healthcare system are important and sustained driving forces in medical practice, especially when scientific evidence is missing. Although Fritsche et al. observed limited influence from the professional background of respondents on practice variation, we observed that nephrologists were more likely to perform diagnostic procedures than surgeons. We hope that our recommendations for the standard work-up of low-risk kidney transplant candidates will lead to a timely listing for transplantation. These young patients with no or few comorbidities benefit substantially from transplantation, allowing them to lead a near-normal life in many cases. Individual physicians or transplant centres striving for cost-effective patient care will hopefully feel supported by this consensus report from a group of European opinion leaders. ACKNOWLEDGEMENTS We greatly appreciate the help of M. Pippias in providing linguistic improvements. CONFLICT OF INTEREST STATEMENT None of the authors has a conflict of interest. The results presented in this article have not been published previously. REFERENCES 1 Kasiske BL , Cangro CB , Hariharan S et al. The evaluation of renal transplantation candidates: clinical practice guidelines . Am J Transplant 2001 ; 1 (Suppl 2) : 3 – 95 Google Scholar PubMed WorldCat 2 Knoll G , Cockfield S , Blydt-Hansen T et al. Canadian Society of Transplantation: consensus guidelines on eligibility for kidney transplantation . 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Recommendations for screening of donor and recipient prior to solid organ transplantation and to minimize transmission of donor-derived infections . Clin Microbiol Infect 2014 ; 20 (Suppl 7) : 10 – 18 Google Scholar Crossref Search ADS PubMed WorldCat 12 Vitiello GA , Sayed BA , Wardenburg M et al. Utility of prostate cancer screening in kidney transplant candidates . J Am Soc Nephrol 2016 ; 27 : 2157 – 2163 Google Scholar Crossref Search ADS PubMed WorldCat 13 Ramos EL , Kasiske BL , Alexander SR et al. The evaluation of candidates for renal transplantation. The current practice of U.S. transplant centers . Transplantation 1994 ; 57 : 490 – 497 Google Scholar Crossref Search ADS PubMed WorldCat 14 Akolekar D , Oniscu GC , Forsythe JL. Variations in the assessment practice for renal transplantation across the United Kingdom . Transplantation 2008 ; 85 : 407 – 410 Google Scholar PubMed WorldCat © The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. 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Journal

Nephrology Dialysis Transplantation – Oxford University Press

Published: Sep 1, 2019

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