Comparison of 2 Immunosuppression Minimization Strategies in Kidney Transplantation: The ALLEGRO Trial.

BACKGROUND: Evidence on the optimal maintenance of immunosuppressive regimen in kidney transplantation recipients is limited. METHODS: The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in de novo kidney transplant recipients, in which 2 immunosuppression minimization strategies were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. In the minimization groups, either steroids were withdrawn from day 3, or tacrolimus exposure was reduced from 6 mo after transplantation. The primary endpoint was kidney transplant function at 24 mo. RESULTS: A total of 295 participants were included in the intention-to-treat analysis. Noninferiority was shown for the primary endpoint; estimated glomerular filtration rate at 24 mo was 45.3 mL/min/1.73 m 2 in the early steroid withdrawal group, 49.0 mL/min/1.73 m 2 in the standard immunosuppression group, and 44.7 mL/min/1.73 m 2 in the tacrolimus minimization group. Participants in the early steroid withdrawal group were significantly more often treated for rejection ( P = 0.04). However, in this group, the number of participants with diabetes mellitus during follow-up and total cholesterol at 24 mo were significantly lower. CONCLUSIONS: Tacrolimus minimization can be considered in kidney transplant recipients who do not have an increased immunological risk. Before withdrawing steroids the risk of rejection should be weighed against the potential metabolic advantages.

Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients.

Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1-9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21, p = 0.019). Furthermore, in linear regression analyses, severe tremor was strongly and independently associated with lower physical and mental HRQoL (ß = -16.10, 95% CI: -22.23 to -9.98, p < 0.001 and ß = -12.68, 95% CI: -18.23 to -7.14, p < 0.001 resp.). SOTR frequently report tremor-related impairment of activities of daily living. Tacrolimus trough concentrations appeared as a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT03272841.

Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients: Results From the TransplantLines Biobank and Cohort Study.

RATIONALE & OBJECTIVE: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. EXPOSURE: PPI use, PPI type, PPI dosage, and duration of PPI use. OUTCOME: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. ANALYTICAL APPROACH: Logistic and linear regression. RESULTS: We included 937 kidney transplant recipients (mean age 56±13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P<0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P<0.001), lower physical HRQoL (regression coefficient-8.54, 95% CI, -11.54 to-5.54, P<0.001), and lower mental HRQoL (regression coefficient-4.66, 95% CI, -7.15 to-2.17, P<0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. LIMITATIONS: Residual confounding and inability to assess causal relationships. CONCLUSIONS: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted. PLAIN-LANGUAGE SUMMARY: In this observational study, we investigated the association of proton pump inhibitors with fatigue and health-related quality of life among kidney transplant recipients. Our data showed that proton pump inhibitors were independently associated with fatigue severity, severe fatigue, and lower physical and mental health-related quality of life. These associations were present among all individually assessed proton pump inhibitor types and were dose dependent. While we await future studies on this topic, proton pump inhibitor use might be an easily accessible target for alleviating fatigue and improving health-related quality of life among kidney transplant recipients.

Iron deficiency and cognitive functioning in kidney transplant recipients: findings of the TransplantLines biobank and cohort study.

BACKGROUND: Neurocognitive impairment is common in kidney transplant recipients (KTRs). Adequate brain functioning requires energy and neurotransmitter activity, for which iron is essential. We aimed to investigate iron deficiency (ID) as a potentially modifiable risk factor for cognitive impairment in KTRs. METHODS: We analyzed stable KTRs participating in the TransplantLines Biobank and Cohort study. Participants underwent neuropsychological tests for memory, mental speed, and attention and executive functioning. ID was defined as ferritin <100 µg/mL or 100-299 µg/mL with transferrin saturation (TSAT) ≤20%. Associations between iron status and norm scores of neurocognitive outcomes, corrected for age, sex and education, were assessed using multivariable linear regression analyses adjusted for potential confounders including hemoglobin. RESULTS: We included 166 KTRs [median (IQR) age 57 (45-65) years, 59% male, estimated glomerular filtration rate 51±18 mL/min/1.73 m2]. Time since transplantation was 5.8 (1.0-12.0) years. Prevalence of ID was 65%. ID was independently associated with lower scores for mental speed (std.ß = -0.19, P = .02) and attention and executive functioning (std.ß = -0.19, P = .02), and tended to be associated with worse memory (std.ß = -0.16, P = .07). Lower plasma ferritin levels were associated with worse memory (std.ß = 0.23, P = .007), mental speed (std.ß = 0.34, P < .001), and attention and executive functioning (std.ß = 0.30, P = .001). Lower TSAT was associated with worse memory (std.ß = 0.19, P = .04) and mental speed (std.ß = 0.27, P = .003), and tended to be associated with worse attention and executive functioning (std.ß = 0.16, P = .08). CONCLUSIONS: Iron-deficient KTRs performed worse on neurocognitive tasks measuring memory, mental speed, and attention and executive functioning. These findings set the stage for prospective studies addressing whether ID correction restores cognitive function after kidney transplantation.

Long-term cognitive impairments in kidney transplant recipients: impact on participation and quality of life.

BACKGROUND: Cognitive impairment is often present shortly after transplantation in kidney transplant recipients (KTR). To date, it is unknown whether these impairments persist in thelong term, to what extent they are associated with disease-related variables and whether they affect societal participation and quality of life (QoL) of KTR. METHOD: This study was part of the TransplantLines Biobank & Cohort Study in the University Medical Center Groningen. A total of 131 KTR, with a mean age of 53.6 years (SD = 13.5) transplanted ≥1 year ago (M = 11.2 years, range 1-41.7 years), were included and compared with 306 healthy controls (HC). KTR and HC were well matched; there were no significant differences regarding age, sex and education. All participants were assessed with neuropsychological tests measuring memory, mental speed, attention and executive functioning, and with questionnaires examining societal participation and QoL. RESULTS: Compared with HC, KTR performed significantly worse on memory, mental speed and measures of executive functioning (all P-values <0.05). Moreover, 16% of KTR met the criteria for mild cognitive impairment (MCI), compared with 2.6% of the HC. MCI in KTR was not significantly correlated with age- and disease-related variables. Poorer cognitive functioning was significantly related to lower levels of societal participation and to lower QoL (all P-values <0.01). CONCLUSIONS: This study shows long-term cognitive impairments in KTR, which are not related to disease-related variables. Neuropsychological assessment is important to timely signal these impairments, given their serious negative impact on societal participation and QoL.

Gut microbiome dysbiosis is associated with increased mortality after solid organ transplantation.

Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival rates after transplantation vary considerably. There is now increasing evidence that the gut microbiome is linked to the survival of patients undergoing hematopoietic cell transplant, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1370 fecal samples from 415 liver and 672 renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes, and virulence factors. To quantify taxonomic and metabolic dysbiosis, we also analyzed 1183 age-, sex-, and body mass index-matched controls from the same population. In addition, a subset of 78 renal transplant recipients was followed longitudinally from pretransplantation to 24 months after transplantation. Our data showed that both liver and kidney transplant recipients suffered from gut dysbiosis, including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistance genes and virulence factors. These changes were found to persist up to 20 years after transplantation. Last, we demonstrated that the use of immunosuppressive drugs was associated with the observed dysbiosis and that the extent of dysbiosis was associated with increased mortality after transplantation. This study represents a step toward potential microbiome-targeted interventions that might influence the outcomes of recipients of solid organ transplantation.

Decreased haemoglobin levels are associated with lower muscle mass and strength in kidney transplant recipients.

BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs. METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength. RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. ß = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. ß = 0.22, P < 0.001), handgrip strength (std. ß = 0.15, P < 0.001), and worse FTSTS test scores (std. ß = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001). CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

Renal Endothelial Cytotoxicity Assay to Diagnose and Monitor Renal Transplant Recipients for Anti-Endothelial Antibodies.

Tissue-specific nonhuman leukocyte antigen (HLA) antigens can play crucial roles in allograft immunity and have been shown to trigger humoral responses leading to rejection of HLA-matched kidney allografts. Interest in the role of endothelial-specific antigens has grown over the past years, and several case reports have been described in which antibodies reacting with endothelial cells (ECs) are associated with rejection. Such antibodies escape the detection in conventional crossmatch tests as they do not react with lymphocytes. However, due to the heterogeneity of endothelial cells from different vascular beds, it remains difficult to draw organ-specific conclusions from studies describing endothelial crossmatch assays. We present a case of a 69-year-old male patient whose kidney allograft was rejected as hyperacute, despite the absence of pretransplant HLA-specific antibodies. To place findings from previous studies in a kidney-related context, we performed crossmatch assays with primary renal endothelial cells. The patient's serum was reactive with primary renal ECs, demonstrated by antibody binding and complement-dependent cytotoxicity. Antibodies from this patient did not react with lymphocytes nor were HLA donor-specific antibodies (DSAs) found. Two years later, the patient successfully received a second kidney transplant after treatment with rituximab and plasmapheresis before and after transplantation. We demonstrated that the removal of antibodies against non-HLA EC-specific molecules can be monitored using a primary renal EC crossmatch test, possibly contributing to a successful transplantation outcome.

Ultra-processed foods and risk of all-cause mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTRs) have a 6-fold higher risk of mortality than age- and sex-matched controls. Whether high consumption of ultra-processed foods is associated with survival in RTRs is unknown. OBJECTIVES: We aimed to study the association between high consumption of ultra-processed foods and all-cause mortality in stable RTRs. METHODS: We conducted a prospective cohort study in adult RTRs with a stable graft. Dietary intake was assessed using a validated 177-item FFQ. Food items were categorized according to the NOVA classification system and the proportion ultra-processed foods comprised of total food weight per day was calculated. RESULTS: We included 632 stable RTRs (mean ± SD age: 53.0 ± 12.7 y, 57% men). Mean ± SD consumption of ultra-processed foods was 721 ± 341 g/d (28% of total weight of food intake), whereas the intake of unprocessed and minimally processed foods, processed culinary ingredients, and processed foods accounted for 57%, 1%, and 14%, respectively. During median follow-up of 5.4 y [IQR: 4.9-6.0 y], 129 (20%) RTRs died. In Cox regression analyses, ultra-processed foods were associated with all-cause mortality (HR per doubling of percentage of total weight: 2.13; 95% CI: 1.46, 3.10; P < 0.001), independently of potential confounders. This association was independent from the quality of the overall dietary pattern, expressed by the Mediterranean Diet Score (MDS) or Dietary Approaches to Stop Hypertension (DASH) score. When analyzing ultra-processed foods by groups, only sugar-sweetened beverages (HR: 1.21; 95% CI: 1.05, 1.39; P = 0.007), desserts (HR: 1.24; 95% CI: 1.02, 1.49; P = 0.03), and processed meats (HR: 1.87; 95% CI: 1.22, 2.86; P = 0.004) were associated with all-cause mortality. CONCLUSIONS: Consumption of ultra-processed foods, in particular sugar-sweetened beverages, desserts, and processed meats, is associated with a higher risk of all-cause mortality after renal transplantation, independently of low adherence to high-quality dietary patterns, such as the Mediterranean diet and the DASH diet.This trial was registered at clinicaltrials.gov as NCT02811835.

Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients: results of the TransplantLines Biobank and cohort Studies.

BACKGROUND: New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. METHODS: This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1-5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). RESULTS: Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5-1.2] mmol/L vs. 0.6 [0.4-0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64-3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). CONCLUSIONS: This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors.

Plasma neutrophil gelatinase-associated lipocalin and kidney graft outcome.

BACKGROUND: Plasma neutrophil gelatinase-associated lipocalin (pNGAL) has been investigated extensively in acute kidney injury. This study investigated its pathophysiological significance and utility as marker for graft failure and mortality in stable kidney transplant recipients (KTR). METHODS: Baseline pNGAL was measured in 698 KTR (58% male, age 53 ± 13 years, estimated glomerular filtration rate 52.4 ± 20.4 mL/min/1.73 m2) at median 5.4 (interquartile range 1.8-12.0) years after transplantation, enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study. RESULTS: pNGAL concentrations were higher in males, younger patients, patients with a deceased-donor kidney and higher serum creatinine. Independent of these, pNGAL was positively associated with urinary protein excretion, systemic inflammation parameters and calcineurin inhibitor use. During median follow-up of 5.3 (4.5-6.0) years, death-censored graft failure rates were 3.9%, 7.3% and 25.0% across increasing tertiles of pNGAL (Plog-rank < 0.001). Cox-regression analyses showed no independent associations of pNGAL with mortality, but strong associations with graft failure (hazard ratio, per doubling 4.16; 95% confidence interval 3.03-5.71; P < 0.001), which remained independent of adjustment for confounders. These associations were present only in patients with pre-existent proteinuria and poor kidney function. CONCLUSIONS: pNGAL is associated with parameters of kidney graft damage and with graft failure. The latter association is particularly present in KTR with pre-existent poor kidney function and proteinuria. Trial Registration: ClinicalTrials.gov NCT02811835.

Plasma Lead Concentration and Risk of Late Kidney Allograft Failure: Findings From the TransplantLines Biobank and Cohort Studies.

RATIONALE & OBJECTIVE: Heavy metals are known to induce kidney damage, and recent studies have linked minor exposures to cadmium and arsenic with increased risk of kidney allograft failure, yet the potential association of lead with late graft failure in kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Prospective cohort study in The Netherlands. SETTING & PARTICIPANTS: We studied outpatient KTRs (n = 670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011) and followed for a median of 4.9 (interquartile range, 3.4-5.5) years. Additionally, patients with chronic kidney disease (n = 46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, ClinicalTrials.gov identifier NCT03272841) were studied at admission for transplant and at 3, 6, 12, and 24 months after transplant. EXPOSURE: Plasma lead concentration was log2-transformed to estimate the association with outcomes per doubling of plasma lead concentration and also considered categorically as tertiles of lead distribution. OUTCOME: Kidney graft failure (restart of dialysis or repeat transplant) with the competing event of death with a functioning graft. ANALYTICAL APPROACH: Multivariable-adjusted cause-specific hazards models in which follow-up of KTRs who died with a functioning graft was censored. RESULTS: Median baseline plasma lead concentration was 0.31 (interquartile range, 0.22-0.45) µg/L among all KTRs. During follow-up, 78 (12%) KTRs experienced graft failure. Higher plasma lead concentration was associated with increased risk of graft failure (hazard ratio, 1.59 [95% CI, 1.14-2.21] per doubling; P = 0.006) independent of age, sex, transplant characteristics, estimated glomerular filtration rate, proteinuria, smoking status, alcohol intake, and plasma concentrations of cadmium and arsenic. These findings remained materially unchanged after additional adjustment for dietary intake and were consistent with those of analyses examining lead categorically. In serial measurements, plasma lead concentration was significantly higher at admission for transplant than at 3 months after transplant (P = 0.001), after which it remained stable over 2 years of follow-up (P = 0.2). LIMITATIONS: Observational study design. CONCLUSIONS: Pretransplant plasma lead concentrations, which decrease after transplant, are associated with increased risk of late kidney allograft failure. These findings warrant further studies to evaluate whether preventive or therapeutic interventions to decrease plasma lead concentration may represent novel risk-management strategies to decrease the rate of kidney allograft failure.

Boron Intake and decreased risk of mortality in kidney transplant recipients.

PURPOSE: In a search for potentially modifiable factors to improve long-term outcome among kidney transplant recipients (KTR), we hypothesized that boron exposure is associated with improved long-term outcome in KTR. METHODS: We determined 24 h urinary boron excretion using inductively coupled plasma mass spectrometry as a measure of boron exposure in 693 stable KTR (57% male, mean age 53y), enrolled in the TransplantLines Food and Nutrition Biobank and Cohort Study. Dietary intake was assessed using validated food-frequency questionnaires. RESULTS: Linear regression analyses showed that dietary intake of fruit, wine and nuts were key determinants of boron excretion. In addition, boron excretion was negatively correlated with homocysteine and inflammatory parameters. In total, 73 (32%), 47 (20%) and 30 (13%) KTR died among the lowest, middle and highest tertiles of 24 h urinary boron excretion, respectively (Plog-rank < 0.001). Cox regression analyses showed that high boron excretion was strongly associated with lower risk of mortality, independent of age, sex, estimated glomerular filtration rate and history of cardiovascular disease (HR per doubling: 0.51, 95% CI: 0.40 to 0.66, P < 0.001). CONCLUSION: Boron may be an overlooked target to improve long-term survival among KTR and potentially other patients, likely through pathways other than inflammation or the methionine-homocysteine cycle that were previously suggested. Interventional trials are warranted to confirm the potential of dietary boron supplementation in KTR and other patient populations.

Airflow Limitation, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Many kidney transplant recipients suffer from fatigue and poor health-related quality of life. Airflow limitation may be an underappreciated comorbidity among kidney transplant recipients, which could contribute to fatigue and lower health-related quality of life in this population. In this study, we compared the prevalence of airflow limitation between kidney transplant recipients and healthy controls and investigated associations of airflow limitation with fatigue and health-related quality of life in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the ongoing TransplantLines Biobank and Cohort study were used. Airflow limitation was defined as forced exhaled volume in 1 second less than the fifth percentile of the general population. Fatigue and health-related quality of life were assessed using checklist individual strength 20 revised (CIS20-R) and Short Form-36 (SF-36) questionnaires. RESULTS: A total of 539 kidney transplant recipients (58% men; mean age 56±13 years) and 244 healthy controls (45% men; mean age 57±10 years) were included. Prevalence of airflow limitation was higher in kidney transplant recipients than in healthy controls (133 [25%] versus 25 [10%]). In multinomial regression models, airflow limitation was independently associated with fatigue severity (odds ratio moderate fatigue, 1.68; 95% confidence interval, 0.92 to 3.09 and odds ratio severe fatigue, 2.51; 95% confidence interval, 1.39 to 4.55; P=0.007) and lower physical health-related quality of life (-0.11 SDs; 95% confidence interval, -0.19 to -0.02; P=0.01) in kidney transplant recipients. In exploratory mediation analyses, fatigue accounted for 79% of the association of airflow limitation with physical health-related quality of life. CONCLUSIONS: Airflow limitation is common among kidney transplant recipients. Its occurrence is associated with more than two times higher risk of severe fatigue, and it is associated with lower physical health-related quality of life. Mediation analyses suggest that airflow limitation causes fatigue, which in turn, decreases physical health-related quality of life. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: TransplantLines: The Transplantation Biobank, NCT03272841 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN06600521.mp3.

Low Circulating Concentrations of Very Long Chain Saturated Fatty Acids Are Associated with High Risk of Mortality in Kidney Transplant Recipients.

Kidney transplant recipients (KTR) are at increased risk of mortality, particularly from infectious diseases, due to lifelong immunosuppression. Although very long chain saturated fatty acids (VLSFA) have been identified as crucial for phagocytosis and clearance of infections, their association with mortality in immunocompromised patient groups has not been studied. In this prospective cohort study we included 680 outpatient KTR with a functional graft ≥1 year and 193 healthy controls. Plasma VLSFA (arachidonic acid (C20:0), behenic acid (C22:0) and lignoceric acid (C24:0)) were measured by gas chromatography coupled with a flame ionization detector. Cox regression analyses was used to prospectively study the associations of VLSFA with all-cause and cause-specific mortality. All studied VLSFA were significantly lower in KTR compared to healthy controls (all p < 0.001). During a median (interquartile range) follow-up of 5.6 (5.2-6.3) years, 146 (21%) KTR died, of which 41 (28%) died due to infectious diseases. In KTR, C22:0 was inversely associated with risk of all-cause mortality, with a HR (95% CI) per 1-SD-increment of 0.79 (0.64-0.99), independent of adjustment for potential confounders. All studied VLSFA were particularly strongly associated with mortality from infectious causes, with respective HRs for C20:0, C22:0 and C24:0 of 0.53 (0.35-0.82), 0.48 (0.30-0.75), and 0.51 (0.33-0.80), independent of potential confounders. VLSFA are inversely associated with infectious disease mortality in KTR after adjustment, including HDL-cholesterol. Further studies are needed to assess the effect of VLSFA-containing foods on the risk of infectious diseases in immunocompromised patient groups.

Malnutrition Universal Screening Tool and Patient-Generated Subjective Global Assessment Short Form and their predictive validity in hospitalized patients.

BACKGROUND AND AIMS: Malnutrition screening is a first step in the nutrition care process for hospitalized patients, to identify those at risk of malnutrition and associated worse outcome, preceding further assessment and intervention. Frequently used malnutrition screening tools including the Malnutrition Universal Screening Tool (MUST) mainly screen for characteristics of malnutrition, while the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) additionally includes risk factors for development of malnutrition, yielding a higher percentage of patients at risk. To investigate whether this translates into higher risk of worse outcome, we aimed to determine the predictive validity of MUST and PG-SGA SF for prolonged hospitalization >8 days, readmission, and mortality <6 months after hospital discharge. METHODS: In this observational study, MUST was performed according to university hospital protocol. Additional screening using PG-SGA SF was performed within 24 h of hospital admission (high risk: MUST ≥ 2, PG_SGA SF ≥ 9). Associations of MUST and PG-SGA SF with outcomes were analyzed by logistic- and Cox PH-regression. RESULTS: Of 430 patients analyzed (age 58 ± 16 years, 53% male, BMI 26.9 ± 5.5 kg/m2), MUST and PG-SGA SF identified 32 and 80 at high risk, respectively. One-hundred-eight patients had prolonged hospitalization, 109 were readmitted and 20 died. High risk by MUST was associated with mortality (HR = 3.9; 95% CI 1.3-12.2, P = 0.02), but not with other endpoints. High risk by PG-SGA SF was associated with prolonged hospitalization (OR = 2.5; 95% CI 1.3-5.0, P = 0.009), readmission (HR = 1.9; 95% CI 1.1-3.2, P = 0.03), and mortality (HR = 34.8; 95% CI 4.2-289.3, P = 0.001), independent of age, sex, hospital ward and previous hospitalization <6 months. In the 363/430 patients classified as low risk by MUST, high risk by PG-SGA SF was independently associated with higher risk of readmission (HR = 1.9; 95% CI 1.0-3.5, P = 0.04) and mortality (HR = 19.5; 95% CI 2.0-189.4, P = 0.01). CONCLUSIONS: Whereas high malnutrition risk by MUST was only associated with mortality, PG-SGA SF was associated with higher risk of prolonged hospitalization, readmission, and mortality. In patients considered as low risk by MUST, high malnutrition risk by PG-SGA SF was also predictive of worse outcome. Our findings support the use of PG-SGA SF in routine care to identify patients at risk of malnutrition and worse outcome, and enable proactive interventions.

Comparative survival of elderly renal transplant recipients with a living donor versus a deceased donor: A retrospective single center observational study.

Increasing numbers of elderly (≥65 years) patients are listed for kidney transplantation. This study compares the survival outcome between living (LDK), regularly allocated (ETKAS), and Eurotransplant Senior Program (ESP) donor kidneys in elderly recipients. This is a single-center retrospective cohort study of elderly kidney transplant recipients transplanted between 2005 and 2017. Primary outcome measures were nondeath-censored graft, death-censored graft, and patient survival. In total, 348 patients were transplanted, 109 recipients (31.3%) received an LDK, 100 (28.7%) an ETKAS, and 139 (40%) an ESP kidney. 62.5% were male, and median age was 68 years. LDK recipients had significantly better 5-year nondeath-censored graft survival compared with ETKAS and ESP (resp. 71.0% vs. 66.1% vs. 55.6%, P = 0.047). Death-censored graft survival after 1 year was significantly better in LDK recipients (99.1%) (ETKAS 90.8%; ESP 87.7%, P < 0.001). After 5 years, the difference remained significant (P < 0.001) with little additional graft loss (97.7% vs. 88.1% vs. 85.6). There was no significant difference in patient survival after 5 years (71.7% vs. 67.4% vs 61.9%, P = 0.480). In elderly recipients, the patient survival benefits of an LDK are limited, but there is decreased death-censored graft loss for LDK recipients. Nevertheless, graft survival in ETKAS and ESP remains satisfactory.

Androgens and Development of Posttransplantation Diabetes Mellitus in Male Kidney Transplant Recipients: A Post Hoc Analysis of a Prospective Study.

OBJECTIVE: Posttransplantation diabetes mellitus (PTDM) effects up to 30% of all kidney transplant recipients (KTR). Recent studies in mice found that sufficient androgen levels are necessary for ß-cell health and adequate insulin secretion. This raises the question whether a similar relationship might be present in KTR. Hence, we hypothesized that dihydrotestosterone and testosterone are associated with the development of PTDM in male KTR. RESEARCH DESIGN AND METHODS: We conducted a post hoc analyses of a prospective single-center cohort study including adult male KTR with a functioning graft ≥1 year posttransplantation. Androgen levels were assessed by liquid chromatography-tandem mass spectrometry. Development of PTDM was defined according to the American Diabetes Association's criteria. RESULTS: We included 243 male KTR (aged 51 ± 14 years), with a median dihydrotestosterone 0.9 (0.7-1.3) nmol/L and testosterone of 12.1 (9.4-15.8) nmol/L. During 5.3 (3.7-5.8) years of follow-up, 28 KTR (11.5%) developed PTDM. A clear association was observed, as 15 (19%), 10 (12%), and 3 (4%) male KTR developed PTDM in the respective tertiles of dihydrotestosterone (P = 0.008). In Cox regression analyses, both dihydrotestosterone and testosterone as continuous variables were inversely associated with the risk to development PTDM, independent of glucose and HbA1c (hazard ratio [HR] 0.31 [95% CI 0.16-0.59], P < 0.001; and HR 0.32 [95% CI 0.15-0.68], P = 0.003, respectively). CONCLUSIONS: Our results suggest that low androgen levels are a novel potential modifiable risk factor for the development of PTDM in male KTR.

Type of proton-pump inhibitor and risk of iron deficiency in kidney transplant recipients - results from the TransplantLines Biobank and Cohort Study.

Proton-pump inhibitors (PPIs) have been associated with iron deficiency (ID) in kidney transplant recipients (KTRs). Gastric acid plays a pivotal role in the intestinal absorption of non-heme iron, but the pharmacodynamics of PPIs differs in potency of acid suppression. We hypothesized that the risk of ID might be lower in KTRs using a less potent PPI. In a cohort of 724 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841), PPI use was associated with ID [odds ratio (OR) 2.02; 95% CI 1.36-2.98]. Compared with no PPI use, the point estimate of the odds ratio for risk of ID for pantoprazole (OR 1.55; 95%CI 0.78-3.10) was lower than for esomeprazole and omeprazole (3.58; 95%CI 1.73-7.40 and 1.96; 95%CI 1.31-2.94, respectively). When comparing pantoprazole users with omeprazole users on an equipotent dose (≤20 omeprazole equivalents (OE)/day) omeprazole, but not pantoprazole was associated with ID, although the lack of a significant effect of pantoprazole on the risk of ID could be caused by a lack of power. Furthermore, risk of ID was higher among users of a high PPI dose (≥ 20 OE/day) and OE as continuous variable was also independently associated with ID, indicating that risk of ID is higher while using a more potent PPI. Further investigation seems warranted to confirm whether pantoprazole leads to less ID in KTRs.

Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study.

Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4-33.3] µmol/24 h versus 34.8 [IQR 25.6-46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06-1.45]; p = 0.007). During median follow-up for 5.3 [4.5-6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44-2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.