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- Materials and Methods
The study examines selection for kidney transplantation and determines who are referred, how many had contraindications and whether comorbidity indices predict transplant status. Of 113 consecutive adult incident end-stage renal disease (ESRD) patients at this single center 47 (41.6%) were referred. Using published guidelines, 48 (42.5%) had a specific contraindication. However 26 (23%) were neither referred nor had contraindications. An ESRD mortality score, acute renal failure status and albumin were independent predictors of referral but only the mortality score was predictive of contraindication status. The Charlson and ESRD comorbidity indices were less predictive of contraindication or referral status. In a comparison of patients who were Candidates (referred and no contraindication, n = 39) compared to those who were Neither (not referred and no contraindications, n = 26), age was the most discriminating factor (c = 0.99, 95% CI 0.97–1.00). Comorbidity and mortality indices were inferior. Neither patients were older (75 ± 7 years) and had comorbidity scores that were higher than Candidates but similar to those with contraindications (ESRD index; Neither 3.3 ± 2.5, Candidate 1.4 ± 1.8, and contraindication 4.1 ± 3.4). Comorbitity indices do not help explain selection practices whereas age is an important discriminator. How many Neither patients would benefit from transplantation is not known.
- Top of page
- Materials and Methods
Kidney transplantation is considered to be the best form of end-stage renal disease (ESRD) therapy. Evidence suggests that kidney transplantation results in superior length and quality of life at less cost (1,2). However, a considerable percentage of patients are never considered for transplantation. Determining who is a candidate for a transplant is one of the most important activities of the nephrologist.
There are national guidelines on the evaluation of patients for transplantation but most do not explicitly state absolute contraindications to transplantation (3–5). The recently published Canadian Transplant Society consensus report looked more closely at eligibility criteria (5). There have been several studies examining selection and center practice (6–9). The study by Holley et al. examined the characteristics of patients accepted or denied access to the wait list (6). However, these patients were referred to a transplant center and were already preselected. A large study of incident hemodialysis patients from several countries reported on demographic and comorbidity with regards to transplant status (7). However patients over the age of 65, patients starting peritoneal dialysis, or preemptive transplanted patients were excluded. Epstein et al. looked at appropriateness of patient selection but did not include patients >54 years of age (8). A European survey of center practice has data relevant to selection practice, however the specifics on numbers declined are not available (9).
There is also recent evidence that comorbidity indices, such as the Charlson index, predict patient survival after a kidney transplant (10,11). There are several studies that show these indices predict patient survival on dialysis (12–14). However, there have been no studies to determine whether these indices predict or assist in patient selection for the transplant wait list.
Our center has a policy that states all patients with ESRD should be considered for transplantation. However, we have never examined compliance to this policy. The overall aim of this study was to examine compliance to the policy. To exclude some of the biases in previous studies we examined all incident adult patients starting ESRD therapy over a 1 year period not simply those age <55 or <65 (7,8).
We set out to answer three specific questions and to test one or more hypotheses for each of these three overriding questions on this cohort of individuals: the first explored referral status. Since the percentage of patients on dialysis that are currently on the list is about 15% in our region, we asked whether a similar percentage of the incident patients would be candidates (15). We also hypothesised that there were a number of demographic, clinical and laboratory variables that would predict referral. Specifically we wanted to test whether comorbidity indices predicted referral status. We also predicted that referral to the transplant coordinator would be late for most patients.
The second separate question asked what percentage of the cohort had a specific medical or surgical contraindication to transplantation at the time of ESRD initiation (contraindication status). We postulated that only a minority of patients would have an absolute contraindication. This was an opportunity to utilize the recently published Canadian consensus guidelines on eligibility (5). We also wanted to test the ability of comorbidity indices to predict contraindication status.
The third inquiry more specifically tested compliance to the policy. After excluding patients with contraindications, we asked whether there would be some remaining individuals, who were neither referred nor had contraindications to transplantation. We also considered that this might be a sizable group, given the older age and comorbidity of incident ESRD patients. We wanted to compare this group to those who were candidates (both referred and no contraindications). Our hypothesis was that comorbidity indices and possibly other variables would predict potential candidacy status.
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- Materials and Methods
Of the 113 incident patients the etiology of the ESRD was diabetes mellitus 30 (27%), glomerulonephritis 21 (19%), renal vascular disease 19 (17%), adult polycystic kidney disease 17 (15%) and other 26 (23%). ESRD therapy was preemptive transplantation 8 (7%), peritoneal dialysis 13 (12%) and hemodialysis 92 (81%). The demographic and comorbidities for the entire cohort are shown in Table 1. At the end of the study period the center presently has 499 on dialysis and 71 (14%) are on the transplant list. Of these 71, 5 are not yet on dialysis.
Table 1. Referred versus unreferred
| ||Referred N = 47||Unreferred N = 66||Total cohort N = 113||Prob|
|Age in years (range)||51 ± 12 (25–72)||69 ± 12 (37–85)||62 ± 15||0.000|
|Sex (male)||34 (68%)||45 (72%)||79 (70%)|| |
|Acute disease||3 (6.4%)||23 (35%)||26 (23%)||0.000|
|Diabetes mellitus||13 (28%)||27 (41%)||40 (35%)|| |
|Cancer||5 (10%)||18 (27%)||23 (20%)||0.031|
|IHD||12 (26%)||28 (42%)||40 (35%)|| |
|CHF||7 (15%)||31 (47%)||38 (34%)||0.001|
|Stroke||5 (11%)||11 (17%)||16 (14%)|| |
|PVD||3 (6.4%)||14 (21%)||17 (15%)||0.034|
|COLD||0 (0%)||14 (21%)||14 (12%)||0.000|
|Current smoker||10 (21%)||6 (9.2%)||16 (14%)|| |
|GFR (mL/min/1.73 m2)||8.1 ± 5.0||7.8 ± 3.6||8.0 ± 4.2|| |
|Albumin (g/L)||36 ± 5||30 ± 7||32 ± 7||0.000|
|Hemoglobin (g/L)||106 ± 19||100 ± 14||103 ± 17||0.000|
|Weight (kg)||86 ± 18||78 ± 21||82 ± 20|| |
|BMI (kg/m2)||30.7 ± 7.8||29.1 ± 6.3||29.8 ± 7.0|| |
|Charlson index||3.4 ± 1.7||5.5 ± 2.6||4.6 ± 2.4||0.000|
|ESRD index||1.6 ± 2.0||4.0 ± 3.2||3.0 ± 3.0||0.000|
Of the 113 patients 47 (42%) were referred to the transplant center for consideration. Most of the patients were referred prior to initiation of ESRD (85%, 40/47) with a median of 296 days prior to ESRD start (1001 pre- to 145 days post-ESRD). However only 21 of the 47 (45%) were referred >365 days prior to dialysis start. Of the 47 referred only 31 have been listed to date with a median of 211 days (17 to 1410 days) from referral to listing. Table 1 also shows the differences between referred and unreferred patients. Referred were in general younger and had less comorbidity (less cancer, CHF, PVD and COLD). Figure 1A shows the ROC curves for the Charlson (c = 0.74, 95% CI 0.65–0.83), ESRD (c = 0.73, 95% CI 0.64–0.82), and Barrett's mortality (c = 0.86, 95% CI 0.79–0.93) indices for predicting referral. Both comorbidity indices were moderately good predictors of referral however there was a significant overlap in scores between groups (Table 1). The correlation between the Charlson and ESRD indices was very high (r= 0.962). The mortality score was significantly better than the comorbidity indices but not better than age alone (c = 0.87, 95% CI 0.81–0.94). The multivariable logistic regression model (Table 2) found that in addition to age, acute status and serum albumin were also independently predictive of referral. Neither comorbidity indices nor individual comorbidities were significant in the model. In a rerunning of the model with the mortality index (without age), serum albumin was also predictive. None of the patients referred have died compared to 12 of the nonreferred.
Table 2. Logistic regression models
|Variable||Exp(B)||95% CI||p Value||Model R2*|
|Model 1 (age, sex, acute status, laboratory data, comorbidity indices)|
| Referred versus unreferred|
| Age (per year)||0.827||0.766–0.894||0.000|| |
| Acute status||0.075||0.006–0.867||0.038|| |
| Albumin (g/L)||1.23||1.08–1.39||0.001||0.544|
| With contraindication versus without contraindication|
| Acute||4.74||1.49–15.1||0.003|| |
| ESRD index||1.23||1.07–1.41||0.009||0.210|
| Neither versus candidate|
| Age (per year)||1.79||1.18–2.70||0.006||0.672|
|Model 2 (sex, mortality index and laboratory data)|
| Referred versus unreferred|
| Mortality index||0.31||0.20–0.504||0.000|| |
| Albumin (g/L)||1.17||1.043–1.31||0.007|| |
| Acute status||0.20||0.03–1.28||0.09||0.500|
| With contraindication versus without contraindication|
| Mortality index||1.647||1.271–2.134||0.000|| |
| Acute status||3.40||1.019–11.4||0.043||0.269|
| Neither versus candidate|
| Mortality index||8.33||2.35–29.5||0.000||0.538|
Table 3 shows the characteristics of the 48 (42%) patients who had a contraindication to transplantation at the time of ESRD start. Reasons included malignancy within the recommended wait period (13), recent cardiovascular event (15), active disease (infection (6), scleroderma (1), calciphlaxis (1), rapidly progressive glomerulonephritis (6), PVD (5)) and pregnancy (1). In fact eight of the referred patients had a contraindication to transplantation. Patients with contraindications had more comorbidity (more IHD, COLD and PVD). Despite statistically significant differences by ANOVA, the comorbidity indices (Charlson c = 0.66, 95% CI 0.56–0.76 and ESRD, c = 0.67, 95% CI 0.56–0.76)) were not highly predictive (Figure 1B) of whether a patient had a defined contraindication to transplantation. The mortality index was a better predictor (c = 0.72, 95% CI 0.62–0.81) whereas age was not significant (c = 0.59, 95% CI 0.49–0.70). The logistic regression model (Table 2) found acute kidney disease status and comorbidity index or mortality index were predictive of contraindication status. Only two of the patients without a contraindication have died compared to 10 with a contraindication.
Table 3. Without versus with contraindication
| ||Without contraindication N = 65||With contraindication N = 48||Prob|
|Age in years (range)||69 ± 16 (25–84)||65 ± 11 (37–85)||0.045|
|Sex (male)||48 (74%)||31 (65%)|| |
|Acute Disease||6 (9.2%)||20 (42%)||0.000|
|Diabetes mellitus||25 (38%)||15 (31%)|| |
|Cancer||9 (14%)||14 (29%)|| |
|IHD||16 (25%)||24 (50%)||0.009|
|CHF||17 (26%)||21 (44%)|| |
|Stroke||10 (15%)||6 (13%)|| |
|PVD||5 (7.7%)||12 (25%)||0.016|
|COLD||4 (6.2%)||10 (21%)||0.023|
|Current smoker||13 (20%)||3 (6.4%)||0.053|
|GFR (mL/min/1.73 m2)||8.4 ± 4.6||7.4 ± 3.5|| |
|Albumin (g/L)||34 ± 6||30 ± 7||0.001|
|Hemoglobin (g/L)||106 ± 19||97 ± 13||0.008|
|Charlson index||4.0 ± 2.1||5.5 ± 2.7||0.002|
|ESRD index||2.2 ± 2.4||4.1 ± 3.4||0.001|
|Mortality score||3.1 ± 1.7||4.7 ± 2.1||0.000|
After excluding patients with a contraindication, Table 4 shows the breakdown into potential candidates (referred and no contraindications) and Neither (not referred and no contraindications). These Neither individuals were older with a mean age of 75 (range 60–84) with a greater level of comorbidity (more DM, CHF, PVD and COLD) and higher mortality risk score. The mortality index had a very high concordance score (c = 0.92, 95% CI 0.86–0.99), however age alone was best (c = 0.99, 95% CI 0.97–1.00). In comparison the other comorbidity indices (Charlson c = 0.76, 95% CI 0.61–0.89) and ESRD (c = 0.75, 95% CI 0.62–0.87) (Figure 1C) were less predictive. In the logistic regression model age was the best discriminator (Table 2).
Table 4. Candidate (referred and no contraindication) versus neither (not referred and no contraindication)
| ||Candidate* N = 39||Neither N = 26||Prob|
|Age in years (range)||50 ± 12 (25–69)||75 ± 7 (60–84)||0.000|
|Sex (male)||28 (72%)||20 (77%)|| |
|Acute disease||2 (5.1%)||4 (15%)||0.000|
|Diabetes mellitus||12 (31%)||13 (50%)|| |
|Cancer||3 (7.7%)||6 (23%)|| |
|IHD||7 (21%)||9 (35%)|| |
|CHF||6 (12%)||11 (42%)||0.16|
|Stroke||5 (15%)||5 (19%)|| |
|PVD||1 (2.9%)||4 (13%)|| |
|COLD||0 (0%)||4 (15%)||0.02|
|Current smoker||10 (26%)||3 (12%)|| |
|GFR (mL/min/1.73m2)||8.4 ± 5.1||8.2 ± 3.8|| |
|Albumin (g/L)||35 ± 5||32 ± 6||0.049|
|Hemoglobin (g/L)||108 ± 20||105 ± 13|| |
|Charlson index||3.3 ± 1.6||5.1 ± 2.1||0.000|
|ESRD index||1.4 ± 1.8||3.3 ± 2.5||0.001|
|Mortality score||2.1 ± 1.2||4.6 ± 1.2||0.000|
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- Materials and Methods
Despite a center wait list to dialysis ratio of only 14%, a considerably greater proportion (42%) of incident patients have been referred for a transplant. However, slightly less than half had been referred more than a year pre-ESRD start. Almost half (42%) of the cohort had a defined contraindication to transplantation at ESRD start. A significant minority (23%) had no real contraindication to dialysis and were not referred. Not surprisingly this last group has a high degree of comorbidity and were considerably older. Age remains the most important determinant of referral, with almost no referrals over the age of 70 years.
As expected referral status is more likely to occur in the younger patient and less likely to occur in patients with acute disease or low serum albumin. Patients with acute disease or debilitated (low serum albumin) likely will require a period of stability before referral. Although comorbidity scores were significant predictors of referral in a univariate analysis, these indices were not when both age and laboratory variables were included. It is possible that with larger sample sizes or in a different center comorbidity indices would be more predictive of referral status. The concordance statistics (ROC curve analysis) shows that the predictive ability would be modest at best.
The second inquiry concerned contraindication status. Surprisingly age was not a predictor of contraindication status. Acute disease status (i.e. rapidly progressive glomerulonephritis) and high comorbidity index scores were predictive of contraindication status in the multivariate analysis. However, the index scores were only weakly predictive (low concordance (c) statistic of only 0.66) since the timing and severity of the comorbid event play a role in determining whether a patient has a significant contraindication.
In the final inquiry, patients with medical and surgical contraindications were excluded. The remaining without contraindications were divided into those referred (potential Candidates) and those not referred (Neither). Only 23% of patients from the overall cohort fall into this Neither category. Although comorbidity indices were significant predictors by univariate analysis, age was the best overall discriminator. Comorbidity indices are less predictive than age since nearly all age <65 (one exception) without contraindications were referred even with very high comorbidity scores whereas some older patients were not referred despite little or modest comorbidity. Many of these patients were ‘considered’ for transplantation by the attending nephrologists (compliance with the policy). However reason for not referral was age, comorbidity or both. Our program has transplanted patients up to and including age 72, so that there appears to be an age ceiling on acceptance. It is possible that comorbidity scores might be most helpful within an age window between 65 and 75+.
The limitations of our study should be addressed. Our population was somewhat different to the Canadian incident ESRD population of 2002 (15). The etiology of ESRD in the nation (vs. our cohort) was diabetes mellitus 32% (vs. 27%), renal vascular disease/hypertension 18.4% (vs. 17%), adult polycystic kidney disease PCKD 4% (vs. 15%), and glomerulonephritis 12.8% (vs. 19%). The comorbidities were also slightly different in the Canadian incident ESRD population compared to our cohort (CHF 31.4% vs. 34%, PVD 26.6% vs. 15%, cancer 13.3% vs. 20%, and diabetes mellitus 37.6% vs. 35%, respectively). Our crude ratio of patients on the wait list compared to dialysis patients is relatively low at 13.8%, however the national average is similar at 16.6% (2845/17 116) dialysis population (15). Despite these small differences our cohort appears to be a reasonable representation of the Canadian incident ESRD population. We suspect that the discrepancy between the relatively low percentage on the list (14%) and the relatively higher percentage that are candidates (>30%) is that noncandidates accumulate on dialysis and some candidates are transplanted preemptively. A change in acceptance rates is less likely the explanation. Transplant rates have been relatively stable and wait list numbers in our region have not increased (15). Despite the above it is quite possible that other centers in Canada or elsewhere have different practices.
We did not explore other comorbidity indices such as the Davis or Khan indices. These do not appear to have additional predictive value over the Charlson index in the ESRD population (13). We did not perform an analysis of the Index of Coexistent Disease largely because the instrument was time consuming, required trained observers and is not greatly superior to the others tested (19,20). Although, the mortality index reported by Barrett had better discrimination for referral and contraindication status, it does include age (18). Age clearly is the important discriminator in the analysis. Barrett's index was developed to predict mortality in incident dialysis patients with the intention that patients with extremely high mortality rates might not be initiated on treatment (18). Barrett's study also found that the clinician's independent prediction was correlated to the score and marginally better than the predictive model, suggesting that a physician's gestalt for likelihood of survival may be a key factor in selection. Since there is only limited follow-up, the ability of the score to predict mortality, its intended use, was not evaluated in this study. Although, the guidelines expressly state that age is not a reason for nonreferral, it appears to be incorporated into the decision-making process. It is quite possible that some of the elderly patients in the Neither group would benefit from transplantation, but this study was not designed to test this.
The study does also not take into account that some patients within the contraindication group might also become eligible at a later time. It is also possible that some Candidates may develop critical contraindications prior to transplantation or during the evaluation process. At the present time 31 of the 39 Candidates have been listed or transplanted. Of these remaining, four have refused to continue their work-up and deferred transplantation at this time, three remain under evaluation, and one underwent nephrectomy for an incidental renal cell cancer (<6 cm) detected during the transplant evaluation and will be reconsidered. We felt that the analysis could only be done if a consistent easily identifiable time point was used. Time of initiation of ESRD was therefore chosen as the most appropriate time to determine eligibility. It was reassuring to see that most of the individuals were referred prior to the initiation of dialysis. One of the limitations for transplant referral is that some of the patients had an acute disease process or were referred late for their kidney disease to a nephrologist. The seemingly long time from referral to listing can be explained in part because some were referred very early. Actual listing does not occur in our center unless a patient has progressive disease and two consecutive calculated GFRs <15 mL/min.
Low rates of listing the elderly have also been described in the United States. Less than 3% of patients over 70 are listed for transplantation (21). Although, the elderly transplanted do appear to have a survival advantage with transplantation over dialysis, the advantage in absolute years is much less than younger recipients (1,22). Mortality rates even for those elderly listed are extremely high, increase with waiting time and many die on the wait list (22,23). The use of expanded criteria donors to reduce wait times may be of particular benefit to the elderly (24,25). It is not known to what extent age or comorbidity play a role in patient selection in the United States, but there is evidence that it does impact allocation while on the list (26). It is of interest to note that in a survey of deceased organ kidney allocation policy most respondents from the United Kingdom do not feel that age should be used (27). However the subset of elderly (>70 age) in the survey tended to select the younger recipient in preference to the older recipient and only 32.6% felt that age should not be a criteria for allocation. To what extent current selection practices are appropriate remains a challenge to the transplant community at large.
In summary, we found the Canadian guidelines identify a substantial number of incident patients with contraindications at the time of ESRD start. However about 20% have neither contraindication nor are referred. This group is elderly and the majority has comorbidities that impact on life expectancy. Clinicians are probably incorporating these factors into their decision-making process when considering referral. Nonetheless age appears to be the most important factor for determining referral in patients without obvious contraindications to transplantation. The findings do show that referral to the transplant coordinator is late in more than half of potential candidates. Although, the comorbidity indices predict survival in dialysis and transplant recipients, it remains to be determined whether these indices will be of added value in the selection process. It must be stressed that this single center experience cannot be used to infer practice at other centers. We hope our analysis motivates other to examine their selection practice. Selection for the wait list is one of the most important areas of nephrology practice that to date has received limited attention.