Change in Mortality Risk Over Time in Young Kidney Transplant Recipients

Mortality risk for kidney transplant recipients may change with increasing accumulated exposure to the “transplantation milieu.” We sought to characterize changes over time in mortality rate and in age‐, sex‐ and race‐standardized mortality ratios (SMR) relative to the general population, and to estimate the association between increasing time since first transplant and mortality risk. A total of 18 911 patients who received a first transplant at <21 years old (1983–2006), and whose data were recorded in the USRDS, were studied. There were 2713 deaths over a median follow‐up of 8.9 (interquartile range 4.0–14.5; maximum 23) years. Among those with graft function, mortality was highest in the first post transplant year; beyond the first year of the first transplant, age‐adjusted mortality rates and SMRs decreased slightly over follow‐up. Cause of death was cardiovascular for 34.6%, infection for 19.5%, malignancy for 5.8%, other for 21.4% and unknown for 18.7%. For every 1‐year time increment after the end of the first post transplant year, age‐adjusted all‐cause and cardiovascular mortality rates fell by 1% (p = 0.06) and 16% (p = 0.007), respectively; infection‐related mortality rate did not change over time (p = 0.5). These results suggest that exposure to the transplantation milieu has no cumulative negative effects on cardiovascular health over the long term.     

Major Variation across Local Transplant Centers in Probability of Kidney Transplant for Wait-Listed Patients

BackgroundGeographic disparities in access to deceased donor kidney transplantation persist in the United States under the Kidney Allocation System (KAS) introduced in 2014, and the effect of transplant center practices on the probability of transplantation for wait-listed patients remains unclear.MethodsTo compare probability of transplantation across centers nationally and within donation service areas (DSAs), we conducted a registry study that included all United States incident adult kidney transplant candidates wait listed in 2011 and 2015 (pre-KAS and post-KAS cohorts comprising 32,745 and 34,728 individuals, respectively). For each center, we calculated the probability of deceased donor kidney transplantation within 3 years of wait listing using competing risk regression, with living donor transplantation, death, and waiting list removal as competing events. We examined associations between center-level and DSA-level characteristics and the adjusted probability of transplant.ResultsCandidates received deceased donor kidney transplants within 3 years of wait listing more frequently post-KAS (22%) than pre-KAS (19%). Nationally, the probability of transplant varied 16-fold between centers, ranging from 4.0% to 64.2% in the post-KAS era. Within DSAs, we observed a median 2.3-fold variation between centers, with up to ten-fold and 57.4 percentage point differences. Probability of transplantation was correlated in the post-KAS cohort with center willingness to accept hard-to-place kidneys (r=0.55, P<0.001) and local organ supply (r=0.44, P<0.001).ConclusionsLarge differences in the adjusted probability of deceased donor kidney transplantation persist under KAS, even between centers working with the same local organ supply. Probability of transplantation is significantly associated with organ offer acceptance patterns at transplant centers, underscoring the need for greater understanding of how centers make decisions about organs offered to wait-listed patients and how they relate to disparities in access to transplantation.     

Cancer Mortality in Kidney Transplantation

Immunosuppression is associated with an increased risk of cancer in kidney transplant recipients compared to the general population. It is less clear whether standardized cancer mortality ratios (SMRs) are also increased. This study's hypothesis is that SMRs are not increased because of competing risks of death. During the median follow-up of 5.05 years (Q1–Q3: 2.36–8.62), there were 1937 cancer deaths and 36 619 noncancer deaths among 164 078 first kidney-only transplant recipients captured in the United States Renal Data System between January 1990 and December 2004. The observed cancer death rate was 206 per 100 000 patient-years compared to an expected rate of 215 per 100 000 patient-years in the general population. The overall age- and sex-adjusted SMR was only 0.96 (95% CI 0.92–1.00). However, patients <50 years had SMRs significantly greater than unity while patients >60 had SMRs lower than unity. Up to 25% of cancer-related deaths occurred after allograft failure. These findings challenge the notion that cancer is a major cause of premature death in all kidney transplant recipients and has implications for design of cancer prevention strategies in kidney transplant recipients .     

Percentage of Hypochromic Red Blood Cells is an Independent Risk Factor for Mortality in Kidney Transplant Recipients

There are no published studies on the associations between anemia or iron status parameters and important long-term outcomes in kidney transplant recipients (KTR). We prospectively studied 438 KTR from a large transplant clinic for all-cause mortality and kidney allograft loss. Hemoglobin and iron status parameters (serum iron, transferrin, transferrin saturation, ferritin, percentage of hypochromic red blood cells [%HRBC]) were assessed at baseline as were important demographic, clinical and laboratory characteristics. The Austrian Dialysis and Transplant Registry and the Eurotransplant database were used to ascertain immunological and transplantation-related parameters and to ascertain death and allograft rejection. Cox proportional hazard models were used for analyses. Over 7.8 years of follow-up, 129 deaths (29.5%) occurred and 208 grafts (47.5%) were lost. From multivariate analyses, we found that anemia (hemoglobin <10g/dL) was not associated with mortality or graft loss. Among the iron status parameters, only %HRBC was associated with greater all-cause mortality. Patients with HRBC >10% had twice the mortality risk (HR: 2.06; 95%CI: 1.12-3.79) compared to patients with HRBC <5%. Neither of the iron status parameters were associated with allograft rejection. In conclusion, we found that %HRBC was an independent risk factor for mortality in KTR, while other iron status parameters or anemia were not associated with risk. Larger studies on the association between anemia and these outcomes are warranted.     

C-Reactive Protein and Body Mass Index Independently Predict Mortality in Kidney Transplant Recipients

C-reactive protein (CRP) is a risk factor for cardiovascular outcomes and mortality in the general population. To date, there are no prospective studies of the association between CRP and mortality or allograft loss in kidney transplant recipients (KTR). In 1995, 438 consecutive KTR were enrolled in this prospective study. Important information on demographic, clinical and immunological characteristics was collected at baseline, and CRP was measured using standard methods. Patients were then followed-up for a median 7.8 years. Time-to-event analyses (univariate and multivariate Cox proportional hazards regression models) were used to study the main outcomes: all-cause mortality and kidney allograft loss, defined as the earlier of return to dialysis, re-transplantation, or death. From univariate analyses, we found that CRP >or=0.5 mg/dL was associated with a 83% greater mortality risk compared with lower levels of this inflammatory marker [hazard ratio (HR) = 1.83; 95% confidence interval (CI): 1.23-2.72; p = 0.003]. After multivariate adjustment, patients with a CRP >or=0.5 mg/dL had a 53% higher mortality risk compared with patients whose CRP was below that threshold (HR = 1.53; 95% CI: 1.01-2.31; p = 0.04). No associations between CRP and the risk of kidney allograft loss were detected. Furthermore, we were not able to detect any effect modification between CRP and body mass index on the outcomes under study. We conclude that CRP predicts all-cause mortality, but not allograft loss in stable KTR.     

Body Mass Index,Waist Circumference and Mortality in Kidney Transplant Recipients

Higher body mass index (BMI) appears paradoxically associated with better outcomes in patients with chronic kidney disease. Whereas higher BMI reflects both increased visceral and subcutaneous fat and/or muscle mass, a combined assessment of BMI and waist circumference may enable differentiation of visceral adiposity from muscle and/or nonvisceral fat mass. We examined the association of BMI and waist circumference with all‐cause mortality in a prospective cohort of 993 kidney transplant recipients. Associations were examined in Cox models with adjustment for demographic and comorbid conditions and for inflammatory markers. Unadjusted death hazard ratios (95%CI) associated with one standard deviation higher BMI and waist circumference were 0.94 (0.78, 1.13), p = 0.5 and 1.20 (1.00, 1.45), p = 0.05, respectively. Higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], p < 0.001), and higher waist circumference was more strongly associated with higher mortality after adjustment for BMI (2.18 [1.55–3.08], p < 0.001). The associations of waist circumference with mortality remained significant after additional multivariable adjustments. Higher BMI and waist circumference display opposite associations with mortality in kidney transplant recipients. Waist circumference appears to be a better prognostic marker for obesity than BMI.     

Kidney Function and Risk of Cardiovascular Disease and Mortality in Kidney Transplant Recipients: The FAVORIT Trial

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all‐cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49±18 mL/min/1.73 m². In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m² higher eGFR at levels below 45 mL/min/1.73 m² was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m². In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.     

Pre‐Kidney Transplant Lower Extremity Impairment and Post‐Kidney Transplant Mortality

Prediction models for post‐kidney transplantation mortality have had limited success (C‐statistics ≤0.70). Adding objective measures of potentially modifiable factors may improve prediction and, consequently, kidney transplant (KT) survival through intervention. The Short Physical Performance Battery (SPPB) is an easily administered objective test of lower extremity function consisting of three parts (balance, walking speed, chair stands), each with scores of 0–4, for a composite score of 0–12, with higher scores indicating better function. SPPB performance and frailty (Fried frailty phenotype) were assessed at admission for KT in a prospective cohort of 719 KT recipients at Johns Hopkins Hospital (8/2009 to 6/2016) and University of Michigan (2/2013 to 12/2016). The independent associations between SPPB impairment (SPPB composite score ≤10) and composite score with post‐KT mortality were tested using adjusted competing risks models treating graft failure as a competing risk. The 5‐year posttransplantation mortality for impaired recipients was 20.6% compared to 4.5% for unimpaired recipients (p < 0.001). Impaired recipients had a 2.30‐fold (adjusted hazard ratio [aHR] 2.30, 95% confidence interval [CI] 1.12–4.74, p = 0.02) increased risk of postkidney transplantation mortality compared to unimpaired recipients. Each one‐point decrease in SPPB score was independently associated with a 1.19‐fold (95% CI 1.09–1.30, p < 0.001) higher risk of post‐KT mortality. SPPB‐derived lower extremity function is a potentially highly useful and modifiable objective measure for pre‐KT risk prediction.     

Spermatocele Following Kidney Transplant

Lymphocele following kidney transplant is a common occurrence, but on occasion, what appears to be a lymphocele is not. We present an unusual case of a kidney transplant recipient whose presumed lymphocele was actually a spermatocele. Our patient is a 60‐year‐old man who is 11 years status post his second deceased donor kidney transplant. The original cause of his renal failure was poststreptococcal glomerulonephritis. He was followed with this nonobstructing lymphocele for years, but wished to have it addressed at the time of sigmoidectomy for recurrent diverticulitis. Preoperative imaging included CT scan, which showed a 12 cm × 6 cm collection, of greater density than simple fluid, adjacent to the bladder, and causing mass effect on the bladder. Intraoperatively, the collection was somewhat atypical for a lymphocele, and located posterior to the bladder. Cultures were negative, but evaluation of the fluid revealed it to be a spermatocele. Postoperative ultrasound demonstrated full resolution of the collection.     

Kidney Transplant from the Same Donor without Maintenance Immunosuppression after Previous Hematopoietic Stem Cell Transplant

In January 2005, an 18‐year‐old male patient with acute myeloid leukemia (AML) received a haploidentical hematopoietic stem cell transplantation (HSCT) from his father. He developed hemolytic uremic syndrome and end‐stage renal disease (ESRD) requiring hemodialysis on day 357 after HSCT. On day 1020 after HSCT, a living kidney donation from the stem cell donor was carried out. The creatinine before kidney transplantation (KT) was ≈450 μmol/L, 268 μmol/L on day 2 after KT, 88 μM on day 38 and 89 μmol/L on day 960 (day 1980 after HSCT). Immunosuppression was gradually discontinued: cortisone on day 28, tacrolimus on day 32 and MMF on day 100 after KT (day 1120 after HSCT). As of June 2010, 66 months after HSCT and 32 months after KT, the patient has had neither rejection episodes nor clinical manifestations of transplantation‐related complications. The patient reached 100% hematopoietic donor chimerism prekidney transplant and retained this state postkidney transplant. This unique case is the first report of a successful kidney transplant without immunosuppression after HSCT from the same haploidentical donor.     

Humoral and Cellular Immune Responses after Influenza Vaccination in Kidney Transplant Recipients

It has been speculated that influenza vaccination of renal allograft recipients could be associated with de novo production and/or increased titers of anti-HLA antibodies (HLA-Ab). To directly address this issue, we recruited 66 stable renal transplant recipients and 19 healthy volunteers during the 2005–2006 vaccination campaign. At day 0 and day 30 following vaccination, HLA-Ab were screened and in parallel influenza-specific antibody and T-cell responses were assessed. Humoral postvaccinal responses to A/H1N1 and A/H3N2 strains, but not B strain, were less frequent in transplanted patients than in control subjects. Significant expansion of influenza-specific IFN-γ-producing T cells was observed at similar frequencies in patients and controls. There was no correlation between cellular and humoral postvaccinal responses. No impact of sex, age or immunosuppressive regimen could be evidenced. Vaccination was not associated with any significant change in preexisting or de novo anti-HLA sensitization. No episode of allograft rejection was recorded in any of the patients. Our results suggest that flu vaccination is safe in stable renal transplanted patients. Larger studies are needed for definitive statistical proof of the safety and effectiveness, with regard to the quality of the immune response, of yearly influenza vaccination in immunosuppressed patients.     

Inhibitors of mTOR and Risks of Allograft Failure and Mortality in Kidney Transplantation

Data on long‐term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139 370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years posttransplantation, primary use of mTORIs without CNIs (N = 3237) was associated with greater risks of allograft failure and death compared with a CNI‐based regimen (N = 125 623); the hazard ratio (HR) of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12–4.32) after discharge to 1.40 (95% CI 1.26–1.57) by year 2. During years 2–8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95% CI, 1.11–1.41) and the composite (HR 1.17; 95%CI, 1.08–1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity‐score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95% CI, 1.05–1.39) and the composite (HR 1.18; 95% CI, 1.08–1.30) in years 2–8. Compared with CNI‐based regimens, use of an mTORI‐based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival.     

Predictors of Having a Potential Live Donor: A Prospective Cohort Study of Kidney Transplant Candidates

The barriers to live donor transplantation are poorly understood. We performed a prospective cohort study of individuals undergoing renal transplant evaluation. Participants completed a questionnaire that assessed clinical characteristics as well as knowledge and beliefs about transplantation. A participant satisfied the primary outcome if anyone contacted the transplant center to be considered as a live donor for that participant. The final cohort comprised 203 transplant candidates, among whom 80 (39.4%) had a potential donor contact the center and 19 (9.4%) underwent live donor transplantation. In multivariable logistic regression, younger candidates (OR 1.65 per 10 fewer years, p < 0.01) and those with annual income ≥US$ 15 000 (OR 4.22, p = 0.03) were more likely to attract a potential live donor. Greater self‐efficacy, a measure of the participant's belief in his or her ability to attract a donor, was a predictor of having a potential live donor contact the center (OR 2.73 per point, p < 0.01), while knowledge was not (p = 0.56). The lack of association between knowledge and having a potential donor suggests that more intensive education of transplant candidates will not increase live donor transplantation. On the other hand, self‐efficacy may be an important target in designing interventions to help candidates find live donors.     

Data-Driven Kidney Transplant Phenotyping as a Histology-Independent Framework for Biomarker Discovery

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Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients

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Kidney transplantation

Renal transplantation is well established as the treatment of choice for selected patients with end-stage renal failure. A renal transplant recipient can enjoy an improved quality of life while benefiting from a reduction in the mortality compared with long-term dialysis. However, the success of transplantation is limited by the disparity between an ever growing demand and an insufficient supply of organs. Expansion of the organ donor pool has been achieved through increased utilization of living donor kidneys, transplantation across HLA and ABO boundaries, as well as a greater acceptance and consideration of more marginal kidneys from deceased donors. While 1-year graft survival rates are significantly higher than a decade ago, the rate of chronic graft loss after the first year remains substantial. Although the surgical procedure has changed little over many years, recipients have certainly become more complex with increasing age, obesity, comorbidity and repeat transplants.