Prevalence of Frailty in Patients Referred to the Kidney Transplant Waitlist.

Background: Comparisons between frailty assessment tools for waitlist candidates are a recognized priority area for kidney transplantation. We compared the prevalence of frailty using three established tools in a cohort of waitlist candidates. Methods: Waitlist candidates were prospectively enrolled from 2016 to 2020 across five centers. Frailty was measured using the Frailty Phenotype (FP), a 37-variable frailty index (FI), and the Clinical Frailty Scale (CFS). The FI and CFS were dichotomized using established cutoffs. Agreement was compared using κ coefficients. Area under the receiver operating characteristic (ROC) curves were generated to compare the FI and CFS (treated as continuous measures) with the FP. Unadjusted associations between each frailty measure and time to death or waitlist withdrawal were determined using an unadjusted Cox proportional hazards model. Results: Of 542 enrolled patients, 64% were male, 80% were White, and the mean age was 54±14 years. The prevalence of frailty by the FP was 16%. The mean FI score was 0.23±0.14, and the prevalence of frailty was 38% (score of ≥0.25). The median CFS score was three (IQR, 2-3), and the prevalence was 15% (score of ≥4). The κ values comparing the FP with the FI (0.44) and CFS (0.27) showed fair to moderate agreement. The area under the ROC curves for the FP and FI/CFS were 0.86 (good) and 0.69 (poor), respectively. Frailty by the CFS (HR, 2.10; 95% CI, 1.04 to 4.24) and FI (HR, 1.79; 95% CI, 1.00 to 3.21) was associated with death or permanent withdrawal. The association between frailty by the FP and death/withdrawal was not statistically significant (HR, 1.78; 95% CI, 0.79 to 3.71). Conclusion: Frailty prevalence varies by the measurement tool used, and agreement between these measurements is fair to moderate. This has implications for determining the optimal frailty screening tool for use in those being evaluated for kidney transplant.

Frailty and the Kidney Transplant Wait List: Protocol for a Multicenter Prospective Study.

BACKGROUND: Understanding how frailty affects patients listed for transplantation has been identified as a priority research need. Frailty may be associated with a high risk of death or wait-list withdrawal, but this has not been evaluated in a large multicenter cohort of Canadian wait-listed patients. OBJECTIVE: The primary objective is to evaluate whether frailty is associated with death or permanent withdrawal from the transplant wait list. Secondary objectives include assessing whether frailty is associated with hospitalization, quality of life, and the probability of being accepted to the wait list. DESIGN: Prospective cohort study. SETTING: Seven sites with established renal transplant programs that evaluate patients for the kidney transplant wait list. PATIENTS: Individuals who are being considered for the kidney transplant wait list. MEASUREMENTS: We will assess frailty using the Fried Phenotype, a frailty index, the Short Physical Performance Battery, and the Clinical Frailty Scale at the time of listing for transplantation. We will also assess frailty at the time of referral to the wait list and annually after listing in a subgroup of patients. METHODS: The primary outcome of the composite of time to death or permanent wait-list withdrawal will be compared between patients who are frail and those who are not frail and will account for the competing risks of deceased and live donor transplantation. Secondary outcomes will include number of hospitalizations and length of stay, and in a subset, changes in frailty severity over time, change in quality of life, and the probability of being listed. Recruitment of 1165 patients will provide >80% power to identify a relative hazard of ≥1.7 comparing patients who are frail to those who are not frail for the primary outcome (2-sided α = .05), whereas a more conservative recruitment target of 624 patients will provide >80% power to identify a relative hazard of ≥2.0. RESULTS: Through December 2019, 665 assessments of frailty (inclusive of those for the primary outcome and all secondary outcomes including repeated measures) have been completed. LIMITATIONS: There may be variation across sites in the processes of referral and listing for transplantation that will require consideration in the analysis and results. CONCLUSIONS: This study will provide a detailed understanding of the association between frailty and outcomes for wait-listed patients. Understanding this association is necessary before routinely measuring frailty as part of the wait-list eligibility assessment and prior to ascertaining the need for interventions that may modify frailty. TRIAL REGISTRATION: Not applicable as this is a protocol for a prospective observational study.

CONTEXTE: La compréhension de l'incidence de la fragilité sur les patients en attente d'une greffe rénale a été désignée comme un besoin prioritaire de recherche. La fragilité pourrait être associée à un risque élevé de mortalité ou de se voir retiré de la liste d'attente pour une transplantation, mais elle n'a jamais été évaluée dans une vaste cohorte multicentrique de patients canadiens en attente d'une greffe. OBJECTIFS: Le principal objectif consiste à déterminer si la fragilité d'un patient l'expose à un plus grand risque de décès ou de retrait permanent de la liste d'attente pour une greffe. Nous souhaitons également vérifier s'il existe un lien entre la fragilité et le nombre d'hospitalisations, la qualité de vie et la probabilité d'être accepté sur la liste d'attente. TYPE D'ÉTUDE: Étude de cohorte prospective. CADRE: Sept sites disposant d'un programme de transplantation rénale évaluant les patients en vue de leur inscription sur la liste d'attente pour une greffe. SUJETS: Des candidats à la liste d'attente pour une transplantation rénale. MESURES: La fragilité sera évaluée à l'aide du Phénotype de Fried (un indice de la fragilité), du test SPPB (Short Physical Performance Battery) et de l'échelle Clinical Frailty Scale au moment de l'inscription sur la liste d'attente pour une transplantation. Nous mesurerons la fragilité des patients de leur orientation vers le programme jusqu'à leur inscription sur la liste, puis sur une base annuelle après leur inclusion dans un sous-groupe de patients. MÉTHODOLOGIE: Le résultat principal, soit un composite du délai avant le décès ou le retrait permanent de la liste, sera comparé entre les patients fragiles et non fragiles, et tiendra compte des risques concurrents découlant de la transplantation selon que l'organe provient d'un donneur vivant ou décédé. Les résultats secondaires comprendront le nombre d'hospitalisations et leur durée, les variations de la fragilité et de la qualité de vie au fil du temps (pour un sous-groupe de patients), de même que les probabilités d'être inscrit sur la liste d'attente. Le recrutement de 1 165 patients nous permettrait d'obtenir un risque relatif d'au moins 1,7 dans plus de 80 % des cas lors de la comparaison des patients fragiles à ceux qui ne le sont pas pour le résultat principal (double erreur alpha = 0,05), alors que ce risque relatif serait de 2,0 avec un objectif de recrutement plus conservateur de 624 patients. RÉSULTATS: Un total de 665 évaluations de la fragilité (tant pour le résultat primaire que pour les résultats secondaires, y compris les mesures répétitives) a été complété en décembre 2019. LIMITES: Les résultats et leur analyse devront tenir compte des possibles variations entre les différents sites en ce qui concerne les processus d'aiguillage et d'inscription sur les listes d'attente pour une greffe. CONCLUSION: Cette étude fournira une compréhension détaillée de l'association entre la fragilité et les résultats cliniques pour les patients en attente d'une greffe. La compréhension de cette association est nécessaire avant d'inclure systématiquement la mesure de la fragilité au processus d'évaluation de l'admissibilité à la liste d'attente et avant d'établir le besoin de procéder à des interventions susceptibles de modifier la fragilité du patient.

Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

Similar outcomes for Canadian renal transplant recipients followed up in transplant centers and satellite clinics.

BACKGROUND: A significant proportion of long-term care for renal transplant recipients (RTRs) in Canada is provided by community nephrologists in satellite clinics (SCs). The outcomes of RTRs followed up in SCs have not been formally compared with those followed up in transplant centers (TCs). METHODS: This multicenter retrospective study from 13 TCs and SCs across Canada compared patient and graft outcomes in RTRs with a functioning graft more than or equal to 18 months. Data were abstracted at 6 to 18 months posttransplantation, and at last visit (if >18 months). Patients were stratified in a 1:1 ratio between TCs and SCs, and by a 3:1 ratio between cyclosporine A and tacrolimus. The primary outcome was change (Δ) in Modification of Diet in Renal Disease estimated glomerular filtration rate (eGFR) from 6 to 18 months posttransplantation (ΔeGFRM18-6). Secondary outcomes included the prevalence of hyperlipidemia, diabetes, and hypertension. RESULTS: A total of 264 RTRs followed at TCs and SCs demonstrated broad similarity in baseline recipient and donor characteristics. ΔeGFRM18-6 were similar for TCs versus SCs and better for tacrolimus versus cyclosporine A (P=0.022). There was no difference in lipid levels between TCs and SCs during 6 to 18 months, although low-density lipoprotein cholesterol was lower in SCs versus TCs at most recent visit (2.6 vs. 2.3 mmol/L; P=0.003). Fasting blood glucose levels were similar in TCs and SCs. Comparable target blood pressure levels were achieved, and the prevalence of hypertension was similar for both TCs and SCs at all time points. CONCLUSION: Short-term graft and patient outcomes are similar in TC and SC RTRs, supporting the feasibility of follow-up patient care outside major TCs.

A quality of life comparison in cyclosporine- and tacrolimus-treated renal transplant recipients across Canada.

BACKGROUND: Many Canadian renal transplant recipients receive either cyclosporine or tacrolimus as a long-term immunosuppressive agent. We investigated the effect of these drugs on quality of life (QoL) in Canadian transplant recipients. METHODS: We included adult single-organ recipients undergoing a transplant between July 1997 and March 2005, whose graft function was =18 months, recruited across 13 Canadian sites including 5 transplant centers (TCs) and 8 satellite centers (SCs). Patients were stratified 3:1 by cyclosporine vs. tacrolimus based on calcineurin inhibitor(s) (CNIs) received at 6 months posttransplant and matched 1:1 by TC vs. SC. Physical (PCS) and mental component summary (MCS) scores measured by the SF-12 scale for cyclosporine- and tacrolimus-treated recipients were compared. Patient opinions about their perceived CNI-related side effects captured by categorical questions or a numerical Likert scale (1-10) were compared by chi-square test or ANOVA, respectively. RESULTS: There were 231 participants (124 cyclosporine, 43 tacrolimus and 64 with dual experience) who responded to both questionnaires. Their SF-12-measured PCS and MCS scores were similar (PCS 42.0, 43.0 and 41.4, p=0.705; MCS 50.3, 47.8 and 47.1, p=0.115; respectively). However, patients receiving tacrolimus more strongly preferred to continue on this CNI than those receiving cyclosporine (67.4% vs. 44.4%, p=0.009), while more patients on cyclosporine wished to stop taking it (23.4 vs. 2.3%, p=0.004). Patient preference for CNI did not differ by center type. CONCLUSION: QoL among Canadian renal transplant recipients receiving cyclosporine or tacrolimus is similar. Although Canadian recipients prefer tacrolimus, CNI type does not significantly affect their QoL.

Development of end stage renal disease following an acute cardiac event.

We determined the rate and risk factors for end-stage renal disease (ESRD) in consecutive patients discharged after a cardiac event in a large, unbiased Canadian cohort that receives universal health coverage. A total of 8236 adults hospitalized over a 2 year period were followed for up to 7.5 years and the incidence of ESRD and mortality determined. Of these, 113 reached ESRD (stage 5). Patients with moderate (stage 3) and severe (stage 4) renal insufficiency were more likely to develop ESRD than those patients at stage 1 or 2. However, patients with moderate renal insufficiency were 78.6 times more likely to die than to develop ESRD. Absolute rates of progression to ESRD per 100-patient years were 0.08 at stages 1 and 2, 0.17 at stage 3 and 4.27 at stage 4. Age, diabetes, hypertension and congestive heart failure also predicted ESRD. We found that patients with stage 4 disease are at high risk of ESRD after a cardiac admission while those at stage 3 are far more likely to die than to develop ESRD.

Outcomes of acute coronary syndrome in a large Canadian cohort: impact of chronic renal insufficiency, cardiac interventions, and anemia.

BACKGROUND: Chronic renal insufficiency (CRI) has been identified as an important risk factor for cardiac events. Studies in the United States reported decreased survival and decreased use of surgical and medical interventions after myocardial infarction in patients with CRI. METHODS: We studied the impact of renal function on health outcomes in a Canadian cohort of consecutive patients admitted with acute coronary syndrome (ACS) between October 1997 and October 1999. The study design is an observational cohort of 5,549 adult patients who survived to discharge with a discharge diagnosis of ACS. Renal function is classified into 4 levels: (1) normal, glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m2 (>1.33 mL/s); (2) mild CRI, GFR of 60 to 80 mL/min/1.73 m2 (1.00 to 1.33 mL/s); (3) moderate CRI, GFR of 30 to 59 mL/min/1.73 m2 (0.50 to 0.98 mL/s); and (4) severe CRI, GFR less than 30 mL/min/1.73 m2 (<0.50 mL/s). The primary outcome is death. RESULTS: Advanced and moderate CRI independently predicted death (hazard ratio, 1.06; 95% confidence interval [CI], 1.01 to 1.12; and hazard ratio, 1.23; 95% CI, 1.18 to 1.29). Severe anemia (hemoglobin level < 9.0 g/dL [<90 g/L]) also was an independent risk factor for death (hazard ratio, 1.38; 95% CI, 1.18 to 1.61). Use of beta-blockers (hazard ratio, 0.91; 95% CI, 0.86 to 0.97), acetylsalicylic acid (hazard ratio, 0.90; 95% CI, 0.84 to 0.97), lipid-lowering therapy (hazard ratio, 0.84; 95% CI, 0.78 to 0.89), and medical thrombolysis (hazard ratio, 0.89; 95% CI, 0.81 to 0.97) were associated with reduced risk for death. Medical interventions with beta-blockers, acetylsalicylic acid, lipid-lowering therapy, and thrombolysis and surgical intervention were significantly less likely to be used in patients with CRI. CONCLUSION: Despite universal access to health care, Canadian patients with CRI are more likely to die after a cardiac event and less likely to receive important interventions.

Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation.

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant population. We prospectively evaluated 94 first solitary kidney transplant patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was also given to 72 recipients. MPA exposure was measured by HPLC using a limited sampling estimate of 12 h area under the curve (AUC [0-12]) within the first week. Efficacy was determined by the occurrence of acute rejection and toxicity by the need to reduce MMF doses within the first 3 months post-transplantation. Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver operator curve analysis shows that MPA AUC [0-12] on day 3 was predictive of efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate analysis of only patients on basiliximab shows that the MPA AUC [0-12] on day 3 was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate exposure to MPA by day 3 is associated with low acute rejection but cannot predict toxicity. Adequate MPA exposure is also important with basiliximab induction therapy.

Cardiovascular disease reduction in the outpatient kidney transplant clinic.

Cardiovascular disease (CVD) is an important cause of death in kidney transplant recipients. Future CVD mortality was estimated by a risk calculator in all patients (n = 439) with a functioning transplant (>6 months), followed at our center. In addition to CURRENT mortality rates, an OPTIMAL rate (adding anti-hypertensive and lipid-lowering therapy in uncontrolled patients) and an HISTORIC rate (higher systolic blood pressures and the absence of statin use in our population 5 years ago) were also calculated. Overall, the predicted CURRENT CVD mortality rates are 0.82 (95% CI 0.81-0.83) of HISTORIC rates. Predicted OPTIMAL CVD mortality rates are 0.90 (95% CI 0.87-0.92) of CURRENT rates. To achieve OPTIMAL rates, a 27% increase in blood pressure and lipid-lowering drug use is required. There were few contraindications to these medications, implying that physician prescribing was the major barrier to minimizing risk. Despite OPTIMAL rates, the transplant population's relative risk is 2.3 (median, 95% CI 2.1-2.5) times higher than that in the general population. Therefore, targeted therapy to reduce CVD risk can have substantial benefit, but CVD mortality may continue to exceed that in the general population.

Screening for prostate, breast and colorectal cancer in renal transplant recipients.

American Society of Transplantation guidelines recommend screening renal transplant recipients for breast, colorectal and prostate cancer. However there is a lack of evidence to support this practice. Computer simulation modeling was used to estimate the years of life lost as a result of these cancers in 50-year-old renal transplant recipients and subjects in the general population. Renal transplant recipients lost fewer years of life to cancer than people in the general population largely because of reduced life expectancy. In nondiabetic transplant recipients, loss of life as a result of these cancers was comparable with that in the general population only under assumptions of increased cancer incidence and cancer-specific mortality risks. Even with two-fold higher cancer incidence and disease-specific mortality risks, diabetic transplant recipients lost considerably fewer life years to cancer than those in the general population. Recommended cancer screening for the general population may not yield the expected benefits in the average renal transplant recipient but the benefits will be considerably higher than for patients on dialysis. Transplanted patients at above-average cancer risk in good health may achieve the benefits of screening that are seen in the general population.

Studies of prognostic factors in end-stage renal disease: an epidemiological and statistical critique.

We reviewed prognostic studies for patients treated with renal replacement therapy by using an electronic database and bibliographic review for 1990 to 1998. Using the inclusion criteria of English language, adult patients, primary article, minimum 50 patients, primary focus on prognostic factors, and mortality outcome, 104 articles were identified. The 104 articles were reviewed for eight epidemiological and seven statistical criteria that addressed the scientific validity and interpretability of results. The following percentages of the 104 articles satisfied each of the eight epidemiological criteria: (1) a priori hypothesis, 6%; (2) zero time specified, 49%; (3) prognostic factors collected before zero time, 69%; (4) inception cohort, 59%; (5) control for treatment, 74%; (6) operational criteria, 82%; (7) missing variables reported, 12%; and (8) loss to follow-up reported, 42%. Summary analysis showed that 76% of studies satisfied four or fewer of the eight identified criteria. In the 77 articles (74%) that used the Cox proportional hazards model, the following percentages of articles met each of the seven statistical criteria: (1) proportional hazards verified, 26%; (2) censoring explained, 57%; (3) multivariate analysis performed, 91%; (4) significance levels given, 99%; (5) age adjusted, 95%; (6) diabetes adjusted, 66%; and (7) cardiac adjusted, 44%. Summary analysis found that 47% of the 77 studies satisfied four or fewer of the seven identified criteria. Superficially, results appear to show that when the Cox proportional hazards model was used, statistical analysis was better than the epidemiological design. However, studies we examined had serious defects in both epidemiological design and statistical analysis. The consequent validity of results for the quantification of prognostic factors is questionable.