Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to ...potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between
genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear.
genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release.
genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of
genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.
The COVID‐19 pandemic has transformed traditional in‐person care into a new reality of virtual care for patients with complex chronic disease (CCD), but how has this transformation impacted clinical ...judgement? I argue that virtual specialist‐patient interaction challenges clinical reasoning and clinical judgement (clinical reasoning combined with statistical reasoning). However, clinical reasoning can improve by recognising the abductive, deductive, and inductive methods that the clinician employs. Abductive reasoning leading to an inference to the best explanation or invention of an explanatory hypothesis is the default response to unfamiliar or confusing situations. Deductive reasoning supports a previously established goal, but deductive accuracy requires sound premises leading to a valid conclusion. Inductive reasoning uses efficient data sorting, data interpretation, and plan creation without a previously established goal, and allows assessing inferential accuracy over time. In all cases, communication remains the backbone of the clinical encounter. Virtual care for CCD challenges clinical judgement by reducing available information, so even experienced specialists who use induction might default to deduction or abduction. The visit might shorten, decreasing narrative competence and in‐turn management quality. Clinical judgement in virtual encounters can be enhanced by allowing sufficient time, employing allied health staff, using an advance script, avoiding dogmatic commitment to either virtual or in‐person encounters, special training in virtual care, and conscious awareness of abductive, deductive, and inductive reasoning processes. Clinical judgement in virtual encounters especially calls for Gestalt cognition to assess a situational pattern irreducible to its parts and independent of its particulars, so that efficient data interpretation and self‐reflection are enabled. Gestalt cognition integrates abduction, deduction, and induction, appropriately divides the time and effort spent on each, and can compensate for reduced available information. Evaluating one's clinical judgement for those components especially vulnerable to compromise can help optimize the delivery of virtual care for patients with CCD.
Medical good luck and medical bad luck Prasad, G.V. Ramesh
Journal of evaluation in clinical practice,
April 2020, 2020-Apr, 2020-04-00, 20200401, Volume:
26, Issue:
2
Journal Article
Peer reviewed
Every individual experiences good luck and bad luck. Three features characterize medical events associated with good luck or bad luck: There is no control over the event, the event occurs through ...chance or accident, and the event is of significant interest. These characteristics can be used to develop a working definition of medical luck. Medical good luck and medical bad luck are typically assigned to either the individual or to the event, but assigning these instead to the relationship between individual and event provides the opportunity for intervention. By assigning valences to each individual‐event relationship and summating them, the total good luck or bad luck associated with the event can be determined. Intervening in the medical event by increasing the valence of the significance for each affected individual to the event will increase that event's total good luck. A total valence of zero before or after intervention does not, however, imply absent medical luck but simply a combination of medical good luck and medical bad luck because significance interest in the event persists. Therefore, there is no medical luck simpliciter, only medical good luck and medical bad luck. Medical events are especially helpful to understanding good luck and bad luck, because they are non‐fictional, often generate significant interest, and are modifiable.
A diagnosis of new-onset diabetes after transplantation（NODAT） carries with it a threat to the renal allograft,as well as the same short- and long-term implicationsof type 2 diabetes seen in the ...general population.NODAT usually occurs early after transplantation, andis usually diagnosed according to general populationguidelines. Non-modifiable risk factors for NODATinclude advancing age, African American, Hispanic, orSouth Asian ethnicity, genetic background, a positive family history for diabetes mellitus, polycystic kidney disease, and previously diagnosed glucose intolerance. Modifiable risk factors for NODAT include obesity and the metabolic syndrome, hepatitis C virus and cytomegalovirus infection, corticosteroids, calcineurin inhibitor drugs （especially tacrolimus）, and sirolimus. NODAT affects graft and patient survival, and increases the incidence of post-transplant cardiovascular disease. The incidence and impact of NODAT can be minimized through pre- and post-transplant screening to identify patients at higher risk, including by oral glucose tolerance tests, as well as multi-disciplinary care, lifestyle modification, and the use of modified immunosuppressive regimens coupled with glucose-lowering therapies including oral hypoglycemic agents and insulin. Since NODAT is a major cause of post-transplant morbidity and mortality, measures to reduce its incidence and impact have the potential to greatly improve overall transplant success.
Living donors are the preferred source of organs for kidney transplantation, which is the treatment modality of choice for end‐stage kidney disease. Health care systems widely promote living kidney ...donation. However, women are consistently overrepresented among living donors. The reasons behind the sex‐based disparity in living kidney donation remain poorly understood. Compared to women, men possess a greater amount of kidney function, and the higher deceased donation rate among men reflects their higher overall kidney quality. A plausible medical explanation for the sex‐based disparity in living kidney donation includes an uncompromising emphasis on preserving donor health, with less emphasis placed on organ quality, which is the main criterion in deceased donor selection. On the other hand, consent to deceased donation is also greater in women, indicating their greater desire to donate even though fewer women actually become deceased donors. Therefore, nonmedical reasons for the sex disparity in living donation must be sought. Increased empathic distress or emotional memory; a greater sense of responsibility, urgency, and impulsiveness with increased reaction to empathy; a different body image; and a different social status may all contribute to greater living kidney donation in women. Economic inequity may be the singular explanation when personal worth links to economic worth. To better understand the sex disparity in living kidney donation, we need better data on the reasons behind both nondonation and donor rejection after evaluation in clinical practice. Nondirected living kidney donation provides unique opportunities to minimize factors such as emotional distress, empathy, and impulsiveness. More liberal acceptance criteria for donors with isolated medical abnormalities and testing legitimate donor reimbursement strategies based on actual income levels rather than a fixed amount can assist in both ascertaining the reasons behind the sex disparity in living kidney donation and increasing overall living kidney donation rates.
Severe COVID-19 appears to disproportionately affect people who are immunocompromised, although Canadian data in this context are limited. We sought to determine factors associated with severe ...COVID-19 outcomes among recipients of organ transplants across Canada.
We performed a multicentre, prospective cohort study of all recipients of solid organ transplants from 9 transplant programs in Canada who received a diagnosis of COVID-19 from March 2020 to November 2021. Data were analyzed to determine risk factors for oxygen requirement and other metrics of disease severity. We compared outcomes by organ transplant type and examined changes in outcomes over time. We performed a multivariable analysis to determine variables associated with need for supplemental oxygen.
A total of 509 patients with solid organ transplants had confirmed COVID-19 during the study period. Risk factors associated with needing (
= 190), compared with not needing (
= 319), supplemental oxygen included age (median 62.6 yr, interquartile range IQR 52.5-69.5 yr v. median 55.5 yr, IQR 47.5-66.5;
< 0.001) and number of comorbidities (median 3, IQR 2-3 v. median 2, IQR 1-3;
< 0.001), as well as parameters associated with immunosuppression. Recipients of lung transplants (
= 48) were more likely to have severe disease with a high mortality rate (
= 15, 31.3%) compared with recipients of other organ transplants, including kidney (
= 48, 14.8%), heart (
= 1, 4.4%), liver (
= 9, 11.4%) and kidney-pancreas (
= 3, 12.0%) transplants (
= 0.02). Protective factors against needing supplemental oxygen included having had a liver transplant and receiving azathioprine. Having had 2 doses of SARS-CoV-2 vaccine did not have an appreciable influence on oxygen requirement. Multivariable analysis showed that older age (odds ratio OR 1.04, 95% confidence interval CI 1.02-1.07) and number of comorbidities (OR 1.63, 95% CI 1.30-2.04), among other factors, were associated with the need for supplemental oxygen. Over time, disease severity did not decline significantly.
Despite therapeutic advances and vaccination of recipients of solid organ transplants, evidence of increased severity of COVID-19, in particular among those with lung transplants, supports ongoing public health measures to protect these at-risk people, and early use of COVID-19 therapies for recipients of solid organ transplants.
Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti-Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances ...preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear.
We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed.
Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26-0.83, p < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39-7.90, p = 0.006).
TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.
Knowledge of the psychosocial benefits and harms faced by living kidney donors is necessary for informed consent and follow‐up. We reviewed any English language study where psychosocial function was ...assessed using questionnaires in 10 or more donors after nephrectomy. We searched MEDLINE, EMBASE, Web of Science, Psych INFO, Sociological s and CINAHL databases and reviewed reference lists from 1969 through July 2006. Independently, two reviewers ed data on study, donor and control group characteristics, psychosocial measurements and their outcomes. Fifty‐one studies examined 5139 donors who were assessed an average of 4 years after nephrectomy. The majority experienced no depression (77–95%) or anxiety (86–94%), with questionnaire scores similar to controls. The majority reported no change or an improved relationship with their recipient (86–100%), spouse (82–98%), family members (83–100%) and nonrecipient children (95–100%). Some experienced an increase in self‐esteem. A majority (83–93%) expressed no change in their attractiveness. Although many scored high on quality of life measures, some prospective studies described a decrease after donation. A small proportion of donors had adverse psychosocial outcomes. Most kidney donors experience no change or an improvement in their psychosocial health after donation. Harms may be minimized through careful selection and follow‐up.
Most kidney donors experience no change or an improvement in their psychosocial health after donation, and adversity may be minimized through careful selection and follow‐up.
Living donors may incur out-of-pocket costs during the donation process. While many jurisdictions have programs to reimburse living kidney donors for expenses, few programs have been evaluated.
The ...Program for Reimbursing Expenses of Living Organ Donors was launched in the province of Ontario, Canada in 2008 and reimburses travel, parking, accommodation, meals, and loss of income; each category has a limit and the maximum total reimbursement is $5500 CAD. We conducted a case study to compare donors' incurred costs (out-of-pocket and lost income) with amounts reimbursed by Program for Reimbursing Expenses of Living Organ Donors. Donors with complete or partial cost data from a large prospective cohort study were linked to Ontario's reimbursement program to determine the gap between incurred and reimbursed costs (n = 159).
The mean gap between costs incurred and costs reimbursed to the donors was $1313 CAD for out-of-pocket costs and $1802 CAD for lost income, representing a mean reimbursement gap of $3115 CAD. Nondirected donors had the highest mean loss for out-of-pocket costs ($2691 CAD) and kidney paired donors had the highest mean loss for lost income ($4084 CAD). There were no significant differences in the mean gap across exploratory subgroups.
Reimbursement programs minimize some of the financial loss for living kidney donors. Opportunities remain to remove the financial burden of living kidney donors.
Approximately 40% of the kidneys for transplant worldwide come from living donors. Despite advantages of living donor transplants, rates have stagnated in recent years. One possible barrier may be ...costs related to the transplant process that potential willing donors may incur for travel, parking, accommodation, and lost productivity.
To better understand and quantify the financial costs incurred by living kidney donors, we conducted a prospective cohort study, recruiting 912 living kidney donors from 12 transplant centers across Canada between 2009 and 2014; 821 of them completed all or a portion of the costing survey. We report microcosted total, out-of-pocket, and lost productivity costs (in 2016 Canadian dollars) for living kidney donors from donor evaluation start to 3 months after donation. We examined costs according to (
) the donor's relationship with their recipient, including spousal (donation to a partner), emotionally related nonspousal (friend, step-parent, in law), or genetically related; and (
) donation type (directed, paired kidney, or nondirected).
Living kidney donors incurred a median (75th percentile) of $1254 ($2589) in out-of-pocket costs and $0 ($1908) in lost productivity costs. On average, total costs were $2226 higher in spousal compared with emotionally related nonspousal donors (
=0.02) and $1664 higher in directed donors compared with nondirected donors (
<0.001). Total costs (out-of-pocket and lost productivity) exceeded $5500 for 205 (25%) donors.
Our results can be used to inform strategies to minimize the financial burden of living donation, which may help improve the donation experience and increase the number of living donor kidney transplants.
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