Challenges in the management of the kidney allograft: from decline to failure: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In March 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a virtual Controversies Conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of a failing allograft, 4 broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure trajectory; immunosuppression strategies; management of medical and psychological complications, and patient factors; and choice of kidney replacement therapy or supportive care following graft loss. Identifying and paying special attention to individuals with failing allografts was felt to be important in order to prepare patients psychologically, manage immunosuppression, address complications, prepare for dialysis and/or retransplantation, and transition to supportive care. Accurate prognostication tools, although not yet widely available, were embraced as necessary to define allograft survival trajectories and the likelihood of allograft failure. The decision of whether to withdraw or continue immunosuppression after allograft failure was deemed to be based most appropriately on risk-benefit analysis and likelihood of retransplantation within a few months. Psychological preparation and support was identified as a critical factor in patient adjustment to graft failure, as was early communication. Several models of care were noted that enabled a medically supportive transition back to dialysis or retransplantation. Emphasis was placed on the importance of dialysis-access readiness before initiation of dialysis, in order to avoid use of central venous catheters. The centrality of the patient to all management decisions and discussions was deemed to be paramount. Patient "activation," which can be defined as engaged agency, was seen as the most effective way to achieve success. Unresolved controversies, gaps in knowledge, and areas for research were also stressed in the conference deliberations.

The windows of opportunity.

Models to predict survival after kidney transplantation have been developed, which have assisted clinicians in the selection of patients suitable for kidney transplant wait-listing. However, these models have ignored the competing problem of delisting and wait-list mortality, which are equally important in the decision-making process for determining transplant suitability. This commentary focuses on a newly introduced concept that integrates and quantifies the probability of wait-list survival versus receiving a deceased donor kidney transplant.

A contemporary description of patients' estimated blood losses from diagnostic phlebotomy in a census of hospital episodes from a Canadian tertiary care center.

BACKGROUND: Phlebotomy for diagnostic testing is among the commonest hospital procedures, but hospital-wide surveys of all inpatients characterizing blood draw volumes have not been published. The objectives were to characterize the daily blood volumes drawn for diagnostic testing from patients discharged from a Canadian tertiary care center, describe the daily distributions of phlebotomy volumes across service locations, and describe changes in hemoglobin (Hb) and transfusion across service locations. STUDY DESIGN AND METHODS: Data were obtained on all patients discharged between 2012 and 2014 using linked discharge abstract and laboratory data. Cumulative daily blood volume and draw frequency were reported by service and days since admission. Changes in Hb and red blood cell (RBC) transfusion rates were reported for nontransfused and transfused patients. RESULTS: Data were included on 59,715 subjects. Mean daily estimated blood loss varied from 8.5 ± 6.5 mL/day onward to 27.2 ± 20.0 mL/day in the intensive care unit (ICU; p < 0.001). Phlebotomy volumes were highest on the first day of admission and declined thereafter (p < 0.001). For nontransfused individuals in the first week of admission, Hb levels decreased by the highest percentage in the ICU. The rate of RBC unit transfusion was highest in the ICU (232.4 units/1000 patient-days; 95% confidence interval, 225.8-239.2; p < 0.0001 compared with all other locations). CONCLUSION: Considerable variation was observed in estimated blood loss due to diagnostic phlebotomy across different services within one teaching hospital. Thi information is foundational for planning interventions to minimize estimated blood loss from phlebotomy.

Frailty in end-stage renal disease: comparing patient, caregiver, and clinician perspectives.

BACKGROUND: Frailty is associated with poor outcomes for patients on dialysis and is traditionally measured using tools that assess physical impairment. Alternate measurement tools highlight cognitive and functional domains, requiring clinician, patient, and/or caregiver input. In this study, we compared frailty measures for incident dialysis patients that incorporate patient, clinician, and caregiver perspectives with an aim to contrast the measured prevalence of frailty using tools derived from different conceptual frameworks. METHODS: A prospective cohort study of incident dialysis patients was conducted between February 2014 and June 2015. Frailty was assessed at dialysis onset using: 1) modified definition of Fried Phenotype (Dialysis Morbidity Mortality Study definition, DMMS); 2) Clinical Frailty Scale (CFS); 3) Frailty Assessment Care Planning Tool (provides CFS grading, FACT-CFS); and 4) Frailty Index (FI). Measures were compared via correlation and sensitivity/specificity analyses. RESULTS: A total of 98 patients participated (mean age of 61 ± 14 years). Participants were primarily Caucasian (91%), male (58%), and the majority started on hemodialysis (83%). The median score for both the CFS and FACT-CFS was 4 (interquartile range of 3-5). The mean FI score was 0.31 (standard deviation ± 0.16). The DMMS identified 78% of patients as frail. The FACT-CFS demonstrated highest correlation (r = 0.71) with the FI, while the DMMS was most sensitive (97%, 100%) and a CFS ≥ 5 most specific (100%, 77%) at corresponding FI cutoff values (>0.21, >0.45). CONCLUSIONS: Frailty assessments of incident dialysis patients that include clinician, caregiver and patient perspectives have moderate to strong correlation with the FI. At specified FI cutoff values, the FACT-CFS and DMMS are highly sensitive measures of frailty. The CFS and FACT-CFS may represent viable alternative screening tools in dialysis patients.

Prolonged warm ischemia time is associated with graft failure and mortality after kidney transplantation.

Warm ischemia time is a potentially modifiable insult to transplanted kidneys, but little is known about its effect on long-term outcomes. Here we conducted a study of United States kidney transplant recipients (years 2000-2013) to determine the association between warm ischemia time (the time from organ removal from cold storage to reperfusion with warm blood) and death/graft failure. Times under 10 minutes were potentially attributed to coding error. Therefore, the 10-to-under-20-minute interval was chosen as the reference group. The primary outcome was mortality and graft failure (return to chronic dialysis or preemptive retransplantation) adjusted for recipient, donor, immunologic, and surgical factors. The study included 131,677 patients with 35,901 events. Relative to the reference patients, times of 10 to under 20, 20 to under 30, 30 to under 40, 40 to under 50, 50 to under 60, and 60 and more minutes were associated with hazard ratios of 1.07 (95% confidence interval, 0.99-1.15), 1.13 (1.06-1.22), 1.17 (1.09-1.26), 1.20 (1.12-1.30), and 1.23 (1.15-1.33) for the composite event, respectively. Association between prolonged warm ischemia time and death/graft failure persisted after stratification by donor type (living vs. deceased donor) and delayed graft function status. Thus, warm ischemia time is associated with adverse long-term patient and graft survival after kidney transplantation. Identifying strategies to reduce warm ischemia time is an important consideration for future study.

Incidence, etiology, and significance of acute kidney injury in the early post-kidney transplant period.

Little is known about the incidence, causes, and significance of acute kidney injury (AKI) in the early transplant period. This study used a definition as >26 µmol/L increase in creatinine within 48 h or >50% increase over a period >48 h. In 326 adult consecutive recipients of a solitary kidney transplant from 2006 to 2014 followed at this center, 21% developed AKI within the first six months. Most etiologies were CNI toxicity (33%) or unknown (26%), whereas acute rejection accounted for 17% and urinary tract obstruction for 10%. Those with AKI had a significantly lower glomerular filtration rate (GFR) at one-yr post-transplant (adjusted beta coefficient -5.5 mL/min/1.73 m(2) , 95% CI: -10.4, -0.7, p = 0.025) in a multivariable linear regression model. However, the AKI definition missed 6 of 19 episodes of acute rejection and 4 of 10 episodes of urinary tract obstruction. When acute rejection (including those that did not satisfy AKI criteria) was included in the model, other causes of AKI were not significantly associated with GFR at year 1. Although AKI, using current criteria, is likely to be a significant predictor of later outcomes, important causes are missed and the criteria are not sensitive for clinical decision-making.

The Impact of Combined Warm and Cold Ischemia Time on Post-transplant Outcomes.

Background: Prolonged warm ischemia time (WIT) and cold ischemia time (CIT) are independently associated with post-transplant graft failure; their combined impact has not been previously studied. We explored the effect of combined WIT/CIT on all-cause graft failure following kidney transplantation. Methods: The Scientific Registry of Transplant Recipients was used to identify kidney transplant recipients from January 2000 to March 2015 (after which WIT was no longer separately reported), and patients were followed until September 2017. A combined WIT/CIT variable (excluding extreme values) was separately derived for live and deceased donor recipients using cubic splines; for live donor recipients, the reference group was WIT 10 to <23 minutes and CIT >0 to <0.42 hours, and for deceased donor recipients the WIT was 10 to <25 minutes and CIT 1 to <7.75 hours. The adjusted association between combined WIT/CIT and all-cause graft failure (including death) was analyzed using Cox regression. Secondary outcomes included delayed graft function (DGF). Results: A total of 137 125 recipients were included. For live donor recipients, patients with prolonged WIT/CIT (60 to ≤120 minutes/3.04 to ≤24 hours) had the highest adjusted hazard ratio (HR) for graft failure (HR = 1.61, 95% confidence interval [CI] = 1.14-2.29 relative to the reference group). For deceased donor recipients, a WIT/CIT of 63 to ≤120 minutes/28 to ≤48 hours was associated with an adjusted HR of 1.35 (95% CI = 1.16-1.58). Prolonged WIT/CIT was also associated with DGF for both groups although the impact was more driven by CIT. Conclusions: Combined WIT/CIT is associated with graft loss following transplantation. Acknowledging that these are separate variables with different determinants, we emphasize the importance of capturing WIT and CIT independently. Furthermore, efforts to reduce WIT and CIT should be prioritized.

Contexte: La période prolongée d'ischémie à chaud (WIT­warm ischemia time) et la période prolongée d'ischémie à froid (CIT­cold ischemia time) ont été associées de façon indépendante à une défaillance du greffon post-transplantation, mais leur effet combiné n'a jamais été étudié. Nous avons examiné l'effet combiné WIT/CIT sur la défaillance du greffon toutes causes confondues après une transplantation rénale. Méthodologie: Le Scientific Registry of Transplant Recipients a été utilisé pour identifier les receveurs d'une greffe de rein entre janvier 2000 et mars 2015 (date après laquelle la WIT n'a plus été rapportée séparément). Les patients ont été suivis jusqu'en septembre 2017. Une variable combinée WIT/CIT (excluant les valeurs extrêmes) a été dérivée de façon isolée pour les donneurs vivants et les donneurs décédés à l'aide d'une fonction spline cubique. La WIT du groupe référence pour les donneurs vivants se situait entre 10 et <23 minutes, et la CIT entre 0 et <0,42 heure; pour les donneurs décédés, la WIT se situait entre 10 et <25 minutes, et la CIT entre 1 et <7,75 heures. L'association corrigée entre une combinaison WIT/CIT et la défaillance du greffon toutes causes confondues (y compris le décès) a été analysée à l'aide de la régression de Cox. Les résultats secondaires incluaient une reprise retardée de la fonction du greffon (RRFG). Résultats: Un total de 137 125 receveurs d'un rein a été inclus. Dans le groupe des receveurs d'un organe provenant d'un donneur vivant, les patients avec une WIT/CIT prolongée (60 à ≤120 minutes/3,04 à ≤24 heures) présentaient un risque relatif corrigé plus élevé de défaillance du greffon (RRc: 1,61; IC 95 %: 1,14-2,29) par rapport au groupe de référence. Dans le groupe des receveurs d'un organe provenant d'un donneur décédé, une combinaison WIT/CIT de 63 à ≤120 minutes/28 à ≤48 heures a été associée à un RRc de 1,35 (IC 95 %: 1,16-1,58). La WIT/CIT prolongée a également été associée à une RRFG pour les deux groupes, bien que cet effet ait été davantage influencé par la CIT. Conclusion: La combinaison WIT/CIT est associée à la perte du greffon après la transplantation. Sachant qu'il s'agit de variables distinctes avec des déterminants différents, nous soulignons l'importance de rapporter la WIT et la CIT de façon indépendante. Qui plus est, les efforts visant à réduire la WIT et la CIT devraient être prioritaires.

Limits to intensified mycophenolate mofetil dosing in kidney transplantation.

BACKGROUND: Studies have shown that achieving adequate exposure of mycophenolic acid (MPA) early post transplant is associated with less acute rejection in kidney recipients. Intensified dosing with the equivalent of mycophenolate mofetil (MMF) 3 g daily in tacrolimus-treated patients has been shown to increase exposure however about 15% remain below the lower therapeutic threshold of MPA area under the curve (AUC) of 30 mg · hr⁻¹ · L⁻¹ early post transplant. A post hoc analysis of this study showed that a target MPA AUC >40 mg · hr⁻¹ · L⁻¹ was most effective. The primary objective of this study was to determine whether 4 g daily of MMF would result in a greater proportion achieving adequate MPA exposure. MATERIALS AND METHODS: MMF 4 g daily was used in tacrolimus treated de novo kidney transplant recipients. A 3-point limited sample strategy was used to measure MPA AUC on days 5 and 14. Doses were adjusted at day 5 if exposure was high. RESULTS: In 30 patients, the mean AUC was 63 ± 28 mg · hr⁻¹ · L⁻¹ on day 5, with 13% (4/30) ≤ 30 mg · hr⁻¹ · L⁻¹ and 57% (17/30) >60 mg · hr⁻¹ · L⁻¹. The target MPA AUC was <40 mg · hr⁻¹ · L⁻¹ in 23% (7/30). Three patients developed gastrointestinal toxicity and required dose changes. Acute rejection occurred in only 2 patients (grade 1A and 2B) within 3 months (day 5 MPA AUCs were 29.9 and 33 mg · hr⁻¹ · L⁻¹. On day 14 the mean AUC was 46 ± 17 mg · hr⁻¹ · L⁻¹. Many were on MMF doses >2 g daily (8 on 3 g and 9 on 4 g daily). CONCLUSION: Compared to MMF 3 g daily, 4 g daily dose not result in a greater proportion adequately exposed. Rejections were few and occurred in the lower MPA exposed recipients. More than 50% of patients needed doses of MMF >2 g daily for 2 weeks to avoid underexposure. If intensified MPA dosing is considered, exceeding 3 g daily in tacrolimus-treated patients provides no added benefit.

The impact of an "acute dialysis start" on the mortality attributed to the use of central venous catheters: a retrospective cohort study.

BACKGROUND: Central venous catheters (CVCs) are associated with early mortality in dialysis patients. However, some patients progress to end stage renal disease after an acute illness, prior to reaching an estimated glomerular filtration rate (eGFR) at which one would expect to establish alternative access (fistula/peritoneal dialysis catheter). The purpose of this study was to determine if exclusion of this "acute start" patient group alters the association between CVCs and mortality. METHODS: We conducted a retrospective cohort study of 406 incident dialysis patients from 1 Jan 2006 to 31 Dec 2009. Patients were classified as acute starts if 1) the eGFR was >25 ml/min/1.73 m2, ≤ 3 months prior to dialysis initiation and declined after an acute event (n = 45), or 2) in those without prior eGFR measurements, there was no supporting evidence of chronic kidney disease on history or imaging (n = 12). Remaining patients were classified as chronic start (n = 349). RESULTS: 98 % and 52 % of acute and chronic starts initiated dialysis with a CVC. There were 148 deaths. The adjusted mortality hazard ratio (HR) for acute vs. chronic start patients was 1.84, (95 % CI [1.19-2.85]). The adjusted mortality HR for patients dialyzing with a CVC compared to alternative access was 1.19 (95 % CI [0.80-1.77]). After excluding acute start patients, the adjusted HR fell to 1.03 (95 % CI [0.67-1.57]). CONCLUSIONS: A significant proportion of early dialysis mortality occurs after an acute start. Exclusion of this population attenuates the mortality risk associated with CVCs.

Comparing the Net Benefits of Adult Deceased Donor Kidney Transplantation for a Patient on the Preemptive Waiting List vs a Patient Receiving Dialysis.

Importance: Preemptive kidney transplantation is the preferred treatment for end-stage kidney disease. However, deceased donor (DD) kidneys are limited, and the net benefit of allocating kidneys to a preemptively waitlisted patient rather than to a patient receiving dialysis is unclear. Objective: To estimate the net benefit and costs of allocating kidneys to preemptively waitlisted patients vs those receiving dialysis. Design, Setting, and Participants: This medical decision analytical model used data from the 2020 US Renal Data System to calculate patient survival among waitlisted patients who received a DD kidney transplant. Four patients were simulated, with similar characteristics: (1) a patient on the preemptive waiting list receiving a DD transplant, (2) a patient on the preemptive waiting list never receiving a transplant, (3) a waitlisted patient already receiving dialysis (dialysis vintage <1 year) receiving a transplant, and (4) a waitlisted patient already receiving dialysis (dialysis vintage <1 year) never receiving a transplant. Annual probability of initiating dialysis (for patients 1 and 2) and duration of dialysis (for patients 3 and 4) were varied in sensitivity analyses. Exposures: Allocating a DD kidney to a patient on the preemptive waiting list vs the same kidney to a patient receiving dialysis for less than 1 year, with similar recipient characteristics. Main Outcomes and Measures: Differences in projected quality-adjusted life-years (QALYs) and total costs. Results: In a simulated patient with a mean start age of 50 years (range, 30-64 years), the patient receiving a preemptive DD transplantation experienced 10.58 (95% CI, 10.36-10.80) QALYs, and the patient on the preemptive waiting list never transplanted experienced 6.83 (95% CI, 6.67-6.99) QALYs. The patient receiving DD transplantation after less than 1 year of dialysis experienced 10.33 (95% CI, 10.21-10.55) QALYs, and the patient receiving dialysis who remained on the waiting list experienced 6.20 (95% CI, 6.04-6.36) QALYs; allocating a DD kidney to the preemptive patient added 3.75 (95% CI, 3.57-3.93) QALYs, whereas allocating the kidney to the patient already receiving dialysis added 4.13 (95% CI, 3.92-4.31) QALYs. While the estimated posttransplant survival was longest for the preemptive transplant recipient, preferentially allocating the kidney to the preemptive patient results in 0.39 (95% CI, 0.49-0.29) fewer QALYs. The net cost of preemptive transplantation was $54 100 (95% CI, $44 100-$64 100) more than transplantation to a waitlisted patient. If the rate of transitioning to dialysis was 20 (rather than 33) events per 100 patient waiting list-years, the net QALYs were -0.67 (95% CI, -0.78 to -0.56). If the patient was receiving dialysis for 3 to 4 years (vs <1 year) the net benefit was not significantly different; however, net costs were considerably higher for the preemptive option. Conclusions and Relevance: In this decision analytic model study, although allocating DD kidneys to patients preemptively was the best option from a patient perspective, allocating DD kidneys to patients receiving dialysis was a better use of a scare resource from a societal perspective.

Optimal Sequencing of Deceased Donor and Live Donor Kidney Transplant Among Pediatric Patients With Kidney Failure.

Importance: In the US, live donor (LD) kidney transplant rates have decreased in pediatric recipients. Pediatric patients with kidney failure will likely need more than 1 kidney transplant during their lifetime, but the optimal sequence of transplant (ie, deceased donor [DD] followed by LD or vice versa) is not known. Objective: To determine whether pediatric recipients should first receive a DD allograft followed by an LD allograft (DD-LD sequence) or an LD allograft followed by a DD allograft (LD-DD sequence). Design, Setting, and Participants: This decision analytical model examined US pediatric patients with kidney failure included in the US Renal Data System 2019 Report who were waiting for a kidney transplant, received a transplant, or experienced graft failure. Interventions: Kidney transplant sequences of LD-DD vs DD-LD. Main Outcomes and Measures: Difference in projected life-years between the 2 sequence options. Results: Among patients included in the analysis, the LD-DD sequence provided more net life-years in those 5 years of age (1.82 [95% CI, 0.87-2.77]) and 20 years of age (2.23 [95% CI, 1.31-3.15]) compared with the DD-LD sequence. The net outcomes in patients 10 years of age (0.36 [95% CI, -0.51 to 1.23] additional life-years) and 15 years of age (0.64 [95% CI, -0.15 to 1.39] additional life-years) were not significantly different. However, for those aged 10 years, an LD-DD sequence was favored if eligibility for a second transplant was low (2.09 [95% CI, 1.20-2.98] additional life-years) or if the LD was no longer available (2.32 [95% CI, 1.52-3.12] additional life-years). For those aged 15 years, the LD-DD sequence was favored if the eligibility for a second transplant was low (1.84 [95% CI, 0.96-2.72] additional life-years) or if the LD was no longer available (2.49 [95% CI, 1.77-3.27] additional life-years). Access to multiple DD transplants did not compensate for missing the LD opportunity. Conclusions and Relevance: These findings suggest that the decreased use of LD kidney transplants in pediatric recipients during the past 2 decades should be scrutinized. Given the uncertainty of future recipient eligibility for retransplant and future availability of an LD transplant, the LD-DD sequence is likely the better option. This strategy of an LD transplant first would not only benefit pediatric recipients but allow DD kidneys to be used by others who do not have an LD option.

Disparities in Access to Preemptive Repeat Kidney Transplant: Still Missing the Mark?

Background: The need for repeat transplant due to failing kidney allografts is increasing over time. The benefit of preemptive kidney retransplant (PKre-T) is controversial. Marginalized populations are less likely to undergo their first transplant preemptively; however, whether inequities exist for those undergoing PKre-T is unknown. Methods: We performed a cohort study of adult patients undergoing live and deceased kidney transplant in the United States from 2000 to 2018 identified using the Scientific Registry of Transplant Recipients, and we identified patients with first preemptive kidney transplant (PKT) and PKre-T. In the primary analysis, a multivariable logistic regression was used to identify independent predictors of PKre-T. In secondary analyses, multivariable Cox models were used to determine the association of PKre-T with death-censored and all-cause graft loss. Results: In total, 4910 (15.5%) patients underwent PKre-T, and 43,293 (19.1%) underwent first PKT. Inequities in access to PKre-T persisted (OR, 0.49; 95% CI, 0.44 to 0.55 for unemployed versus full time; OR, 1.61; 95% CI, 1.14 to 2.25 for graduate school versus not completing high school; OR, 0.61; 95% CI, 0.52 to 0.70 for Black versus White race); 7.1% of all transplanted Black patients received PKre-T versus 17.4% of White patients. Women were more likely to undergo PKre-T than men (OR, 1.42; 95% CI, 1.29 to 1.57). PKre-T was associated with superior graft survival relative to retransplant after a period of dialysis (HR, 0.73; 95% CI, 0.67 to 0.80 for all-cause graft failure; HR, 0.72; 95% CI, 0.65 to 0.81 for death-censored graft loss). Conclusions: Despite improved patient and graft survival, inequities in access to PKre-T persist. Patients with lower education, patients with reduced employment status, patients of Black race, and men are less likely to receive PKre-T.

The Association of Pre-Transplant C-Peptide Level with the Development of Post-Transplant Diabetes: A Cohort Study.

Background: Post-transplant diabetes mellitus (PTDM) is an important complication after kidney transplantation that results in reduced patient and allograft survival. Although there are established risk factors for PTDM, whether pretransplant C-peptide levels associate with PTDM is unknown. Therefore, in this study, we aimed to examine the association of pretransplant C-peptide levels with PTDM. Methods: This was a cohort study of nondiabetic adult patients who underwent kidney transplant in Nova Scotia, Canada, between January 1, 2016, and March 31, 2021, with fasting C-peptide levels measured before transplant. Multivariable logistic regression was used to determine the association of pretransplant C-peptide (dichotomized around the median) with PTDM at 1 year post transplant. Given the known association between pretransplant obesity and PTDM, we repeated our primary analysis in a cohort restricted to a BMI of 20-35 kg/m2. Results: The median C-peptide value was 3251 (Q1 2480, Q3 4724); pretransplant C-peptide level was dichotomized at 3000 pmol/L. PTDM occurred in 25 (19%) individuals. Thirty percent of patients in the high and only 2% of patients in the low C-peptide groups developed PTDM (P<0.001). A C-peptide level ≥3000 pmol/L was strongly associated with PTDM in multivariable analysis (OR=18.9, 95% CI, 2.06 to 174.2). In a restricted cohort with a BMI of 20-35 kg/m2, an elevated pretransplant C-peptide remained independently associated with the risk of PTDM (OR=15.7, 95% CI, 1.64 to 150.3). C-peptide was the only factor independently associated with PTDM in this restricted BMI cohort. Conclusions: A pretransplant C-peptide level ≥3000 pmol/L was associated with a nearly 20-fold increased odds of PTDM at 1 year post kidney transplantation. Identifying patients with high pretransplant C-peptide levels may therefore help identify those at risk for PTDM who may benefit from focused preventative and therapeutic interventions and support.

Screening for proteinuria in kidney transplant recipients.

BACKGROUND: Proteinuria is a predictor of graft loss and death in kidney transplant recipients. This study examines the clinical significance of albumin-to-creatinine (ACR) and protein-to-creatinine (PCR) ratios compared with conventional dipstick measures of proteinuria. METHODS: At this single centre, 500 adult patients with a functioning kidney transplant > 4 months provided a urine sample for dipstick, ACR and PCR. The primary end point was defined as death-censored graft loss. Associations between proteinuria and graft loss were examined by concordance statistics and multivariate Cox models. RESULTS: There were 32 graft losses over a mean 2.98 years follow-up. PCR (c = 0.82, P < 0.001) and ACR (c = 0.83, P < 0.001) demonstrated similar concordance with events, and both scored higher than dipstick (c = 0.76, P < 0.001). ACR cut points of 30 and 300 mg/g for grading albuminuria were equivalent to 130 and 490 mg/g for PCR. Moderate grades of proteinuria by ACR and PCR were predicted of adverse events in a multivariate analysis. CONCLUSIONS: ACR and PCR are probably equivalent in predicting adverse events. Conventional dipstick is also predictive but does not appear to be as sensitive.

The role of proton pump inhibitors on early mycophenolic acid exposure in kidney transplantation: evidence from the CLEAR study.

INTRODUCTION: Proton pump inhibitors (PPIs) are often prescribed posttransplantation to prevent gastrointestinal complications. A series of recent studies have reported a relationship between PPI comedication and decreased mycophenolic acid (MPA) exposure. The objective of this subanalysis of the CLEAR data set was to determine the impact of PPI therapy on full MPA area under the curve exposures at Day 5 post kidney transplant. MATERIAL AND METHODS: Patients were randomized to receive either intensified dosing of mycophenolate mofetil (1.5 g twice daily on Days 1-5, then 1.0 g twice daily, n = 68) or standard dosing (1.0 g twice daily, n = 67). All recipients received tacrolimus and prednisone. RESULTS: In the modified intention-to-treat population, 57.9% of patients (73 of 126) received PPI therapy. The most frequently administered therapies were pantoprazole and omeprazole. There was no significant difference in mean MPA area under the curve at Day 5 for patients receiving PPI therapy as compared with those not receiving PPI therapy (51.3 versus 55.8 mg.h/L, P = 0.265). However, the MPA concentration-time curve analysis demonstrated a significant decrease in MPA concentrations at 2 hours and 12 hours postdose in patients receiving PPI therapy (P = 0.0009 and P = 0.034). No significant differences were identified in the 3-g arm specifically. In the multivariate model, only serum creatinine and albumin significantly predicted MPA area under the curve less than 30 mg.h/L at Day 5. DISCUSSION AND CONCLUSION: PPI therapy in combination with mycophenolate mofetil does not appear to have a significant impact on full MPA exposure. Because MPA pharmacokinetics were not significantly impacted when a 3-g, 5-day loading dose of mycophenolate mofetil was used in combination with PPI therapy, this strategy may be required for adequate MPA exposure whether or not a patient receives PPI comedication.

Kidney transplant survival in pediatric and young adults.

BACKGROUND: There is a perception that kidney transplant recipients transferred from pediatric centers to adult care have an increased risk of graft loss. It is not clear whether young adults transplanted in adult centers also suffer from high graft loss rates. METHODS: We examined death censored graft survival in 3 cohorts of young patients transplanted at a single center. Pediatric (PED) patients transplanted at the pediatric center were compared to a cohort of young adults (YAD; age 18- < 25) and a cohort of adults (ADL; age 25-35). RESULTS: In a multivariate Cox model for death-censored graft survival, PED survival was statistically similar to the YAD (HR 0.86, 95% CI 0.44, 1.7, p = 0.66), however the ADL cohort (HR 0.45, 95% CI 0.25, 0.82, p = 0.009) demonstrated better survival. Admitted non-adherence rates were not different among cohorts. Patients were transferred within a narrow age window (18.6 ± 1.0 age in years) but at a wide range of times from the date of transplantation (5.1 ± 3.5 years) and with a wide range of graft function (serum creatinine 182 ± 81 µmol/L). CONCLUSIONS: The perception that pediatric transfers do poorly reflects advanced graft dysfunction in some at the time of transfer. The evidence also suggests that it is not the transfer of care that is the critical issue but rather recipients, somewhere between the ages of 11-14 and 25, are a unique and vulnerable cohort. Effective strategies to improve outcomes across this age group need to be identified and applied consistently.

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study.

BACKGROUND: Macrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients. METHODS: We conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl. RESULTS: The mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035). CONCLUSIONS: Macrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.

In Search of a Better Outcome: Opting Into the Live Donor Paired Kidney Exchange Program.

BACKGROUND: Live donor (LD) kidney transplantation is the best option for patients with end-stage kidney disease (ESKD). However, this may not be the best option if a patient's donor is older and considerably smaller in weight. Patient (A) with a less than ideal donor (Donor A) might enter into a live donor paired exchange (LDPE) program with the hopes of swapping for a better-quality organ. A second patient (B) who is in the LDPE may or may not benefit from this exchange with Donor A. METHODS: This medical decision analysis examines the conditions that favor Patient A entering into the LDPE compared to directly accepting a kidney from their intended donor, as well as the circumstances where Patient B also benefits by accepting a lower-quality organ. RESULTS: Under select circumstances, a paired exchange could benefit both Patients A and B. For example, a 30-year-old Patient A with a lower-quality donor might gain 1.201.521.84 quality adjusted life years (QALYs) by entering into a LDPE for a better-quality kidney, whereas a 60-year-old Patient B might gain 0.931.031.13 QALYs by accepting Donor A's kidney rather than waiting longer in the LDPE. The net benefit (or loss) of entering the LDPE differs by recipient age, donor organ quality, likelihood of Patient B being transplanted in LDPE, and likelihood of Patient A finding an ideal donor in the LDPE. CONCLUSION: This study shows there are ways to increase live donor utilization and effectiveness that require further research and potentially changes to the LDPE process.

CONTEXTE: La transplantation d'un rein provenant d'un donneur vivant (DV) est la meilleure option pour les patients atteints d'insuffisance rénale terminale (IRT). Il est toutefois possible que ce ne soit pas la meilleure option lorsque le donneur est plus âgé et de beaucoup plus faible poids que le patient. Un patient (A) jumelé à un donneur moins qu'idéal (donneur A) pourrait être inscrit à un programme de dons croisés avec donneurs vivants (DCDV) dans l'espoir d'obtenir un organe plus approprié. Un deuxième patient (B), déjà inscrit au programme de DCDV, pourrait quant à lui bénéficier ou non de cet échange avec le donneur A. MÉTHODOLOGIE: Cette analyse des décisions médicales examine les conditions favorisant l'entrée du patient A dans le programme de DCDV comparativement à l'acceptation directe d'un rein du donneur prévu. On souhaitait également examiner les circonstances où un patient B bénéficie lui aussi de l'acceptation d'un organe de moindre qualité. RÉSULTATS: Dans certaines circonstances, un don croisé pourrait bénéficier aux deux patients. Par exemple, un patient de 30 ans (A) jumelé à un donneur de moins bonne qualité pourrait gagner 1,201,521,84 années de vie pondérée par la qualité (AVPQ) en entrant dans un programme de DCDV pour obtenir un rein de meilleure qualité, tandis qu'un patient de 60 ans (B) pourrait gagner 0, 931,031,13 AVPQ en acceptant le rein du donneur A plutôt que d'attendre plus longtemps dans le programme. Le bénéfice net (perte) d'une participation à un programme de DCDV diffère selon l'âge du receveur, la qualité de l'organe du donneur, la probabilité que le patient B soit transplanté dans le programme et la probabilité que le patient A trouve un donneur idéal dans le programme. CONCLUSION: Cette étude montre qu'il existe des moyens d'accroître l'utilisation et l'efficacité des donneurs vivants. Ces moyens nécessitent cependant des recherches plus poussées et de possibles changements dans le processus de dons croisés avec donneurs vivants.

Panic in the Pandemic: When Should Kidney Transplant Programs Close?

BACKGROUND: Pandemics greatly interfere with overall health care delivery as resources are diverted to combat the crisis. Kidney transplantation programs were closed temporarily during the COVID-19 pandemic. Given the critical shortage of organs, their short shelf life, and their overall importance to improving length and quality of life for those with kidney disease, this analysis examines the impact of discarding deceased donor organs. METHODS: The net benefit (or harm) of discarding deceased donor organs was measured in projected life years from a societal and individual perspective using a Markov model. A wide range of infection rates, pandemic durations, and case fatality rates associated with infection in wait listed and transplant recipients were examined. RESULTS: Overall, patient life expectancy fell for both wait listed and transplant recipients as the pandemic conditions became more unfavorable. However, the overall net benefit of a transplant during the pandemic was preserved. For example, prior to the pandemic, the net benefit of a kidney transplant over dialysis was calculated to be 6.25 life years (LYs) or 8.24 quality-adjusted life years (QALYs) in a 40-year old recipient. This fell to 5.86 LYs (7.78 QALYs) during the pandemic. Even assuming plausible but higher relative case fatality rates and risks of nosocomial and donor transmission in transplant recipients compared to wait listed patients, the net benefit remained >4 years for most deceased donor organs. CONCLUSION: As long as hospitals have adequate resources to deal with the pandemic and can limit nosocomial infection, kidney transplantation should not be curtailed.