Iron deficiency, anemia, and patient-reported outcomes in kidney transplant recipients.

Kidney transplant recipients (KTRs) experience more fatigue, anxiety, and depressive symptoms and lower concentration and health-related quality of life (HRQoL) compared with the general population. Anemia is a potential cause that is well-recognized and treated. Iron deficiency, however, is often unrecognized, despite its potential detrimental effects related to and unrelated to anemia. We investigated the interplay of anemia, iron deficiency, and patient-reported outcomes in 814 outpatient KTRs (62% male, age 56 ± 13 years) enrolled in the TransplantLines Biobank and Cohort Study (Groningen, The Netherlands). In total, 28% had iron deficiency (ie, transferrin saturation < 20% and ferritin < 100 µg/L), and 29% had anemia (World Health Organization criteria). In linear regression analyses, iron deficiency, but not anemia, was associated with more fatigue, worse concentration, lower wellbeing, more anxiety, more depressive symptoms, and lower HRQoL, independent of age, sex, estimated glomerular filtration rate, anemia, and other potential confounders. In the fully adjusted logistic regression models, iron deficiency was associated with an estimated 53% higher risk of severe fatigue, a 100% higher risk of major depressive symptoms, and a 51% higher chance of being at risk for sick leave/work disability. Clinical trials are needed to investigate the effect of iron deficiency correction on patient-reported outcomes and HRQoL in KTRs.

Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.

BACKGROUND: The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status. METHOD: Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC). RESULTS: After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p < 0.05). No association was observed between CVD-RFs and TSAT (p > 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [ß = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [ß = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04]. CONCLUSION: In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses.

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.

Urinary Copper Excretion Is Associated with Long-Term Graft Failure in Kidney Transplant Recipients.

INTRODUCTION: In chronic kidney disease, proteinuria increases urinary copper excretion, inducing oxidative tubular damage and worsening kidney function. We investigated whether this phenomenon occurred in kidney transplant recipients (KTRs). In addition, we studied the associations of urinary copper excretion with the biomarker of oxidative tubular damage urinary liver-type fatty-acid binding protein (u-LFABP) and death-censored graft failure. METHODS: This prospective cohort study was performed in the Netherlands between 2008 and 2017, including outpatient KTR with a functioning graft for longer than 1 year, who were extensively phenotyped at baseline. Twenty-four-hour urinary copper excretion was measured by inductively coupled plasma mass spectrometry. Multivariable linear and Cox regression analyses were performed. RESULTS: In 693 KTR (57% men, 53 ± 13 years, estimated glomerular filtration rate [eGFR] 52 ± 20 mL/min/1.73 m2), baseline median urinary copper excretion was 23.6 (interquartile range 11.3-15.9) µg/24 h. Urinary protein excretion was positively associated with urinary copper excretion (standardized ß = 0.39, p < 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized ß = 0.29, p < 0.001). During a median follow-up of 8 years, 109 (16%) KTR developed graft failure. KTR with relatively high copper excretion were at higher risk of long-term graft failure (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.32-1.86 per log2, p < 0.001), independent of multiple potential confounders like eGFR, urinary protein excretion, and time after transplantation. A dose-response relationship was observed over increasing tertiles of copper excretion (HR: 5.03, 95% CI: 2.75-9.19, tertile 3 vs. 1, p < 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p < 0.001). CONCLUSION: In KTR, urinary protein excretion is positively correlated with urinary copper excretion. In turn, higher urinary copper excretion is associated with an independent increased risk of kidney graft failure, with a substantial mediating effect through oxidative tubular damage. Further studies are warranted to investigate whether copper excretion-targeted interventions could improve kidney graft survival.

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.

Sleep quality, fatigue, societal participation and health-related quality of life in kidney transplant recipients: a cross-sectional and longitudinal cohort study.

BACKGROUND: Fatigue and impaired health-related quality of life (HRQoL) are common among kidney transplant recipients (KTR). We hypothesized that both may partially be attributable to poor sleep. METHODS: Cross-sectional and longitudinal data of KTR enrolled in the TransplantLines Biobank and Cohort Study were used. Sleep quality was assessed using the Pittsburgh Sleep Quality Index questionnaire. Individual strength (i.e. a composite of fatigue, concentration, motivation and physical activity), societal participation and HRQoL were assessed using validated questionnaires. RESULTS: We included 872 KTR (39% female, age 56 ± 13 years) and 335 healthy controls. In total, 33% of male KTR and 49% of female KTR reported poor sleep quality, which was higher compared with male and female healthy controls (19% and 28%, respectively, P < .001 for both). In logistic regression analyses, female sex, anxiety, active smoking, low protein intake, physically inactive lifestyle, low plasma magnesium concentration, using calcineurin inhibitors, not using mTOR inhibitors and using benzodiazepine agonists were associated with poor sleep quality. In adjusted linear regression analyses, poor sleep was strongly and independently associated with lower individual strength [standardized ß (st.ß) = 0.59, 95% confidence interval (CI) 0.45 to 0.74, P < .001], poorer societal participation (frequency: st.ß = -0.17, 95% CI -0.32 to -0.01, P = .04; restrictions: st.ß = -0.36, 95% CI -0.51 to -0.21, P < .001; satisfaction: st.ß = -0.44, 95% CI -0.59 to -0.28, P < .001) and lower HRQoL (physical: st.ß = -0.53, 95% CI -0.68 to -0.38, P < .001; mental: st.ß = -0.64, 95% CI -0.78 to -0.50, P < .001). The associations with poorer societal participation and lower HRQoL were strongly mediated by individual strength (P < .001 for all), yet the suggested direct effects of poor sleep quality on HRQoL remained significant (Pphysical = .03, Pmental = .002). Longitudinal data of 292 KTR showed that sleep quality improves after kidney transplantation in males (P < .001), but not in females (P = .9). CONCLUSIONS: Poor sleep quality is common among KTR, and may be a potential target to improve fatigue, societal participation and HRQoL among KTR.

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.

Low selenium intake is associated with risk of all-cause mortality in kidney transplant recipients.

BACKGROUND: Deficiency of the essential trace element selenium is common in kidney transplant recipients (KTR), potentially hampering antioxidant and anti-inflammatory defence. Whether this impacts the long-term outcomes of KTR remains unknown. We investigated the association of urinary selenium excretion, a biomarker of selenium intake, with all-cause mortality; and its dietary determinants. METHODS: In this cohort study, outpatient KTR with a functioning graft for longer than 1 year were recruited (2008-11). Baseline 24-h urinary selenium excretion was measured by mass spectrometry. Diet was assessed by a 177-item food frequency questionnaire, and protein intake was calculated by the Maroni equation. Multivariable linear and Cox regression analyses were performed. RESULTS: In 693 KTR (43% men, 52 ± 12 years), baseline urinary selenium excretion was 18.8 (interquartile range 15.1-23.4) µg/24-h. During a median follow-up of 8 years, 229 (33%) KTR died. KTR in the first tertile of urinary selenium excretion, compared with those in the third, had over a 2-fold risk of all-cause mortality [hazard ratio 2.36 (95% confidence interval 1.70-3.28); P < .001], independent of multiple potential confounders including time since transplantation and plasma albumin concentration. The most important dietary determinant of urinary selenium excretion was protein intake (Standardized ß 0.49, P < .001). CONCLUSIONS: Relatively low selenium intake is associated with a higher risk of all-cause mortality in KTR. Dietary protein intake is its most important determinant. Further research is required to evaluate the potential benefit of accounting for selenium intake in the care of KTR, particularly among those with low protein intake.

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.

Iron Deficiency and Nephrotoxic Heavy Metals: A Dangerous Interplay?

Heavy metals are common in our environment, and all individuals are exposed to them to some extent. These toxic metals have several harmful effects on the body, including the kidney, which is a very sensitive organ. Indeed, heavy metal exposure has been linked to an increased risk of chronic kidney disease (CKD) and its progression, which may be explained by the well-established nephrotoxic effects of these metals. In this hypothesis and narrative literature review, we will shed light on the potential role that another highly common problem in patients with CKD, iron deficiency, may play in the damaging effects of heavy metal exposure in this patient group. Iron deficiency has previously been linked with an increased uptake of heavy metals in the intestine due to the upregulation of iron receptors that also take up other metals. Furthermore, recent research suggests a role of iron deficiency in the retention of heavy metals in the kidney. Therefore, we hypothesize that iron deficiency plays a crucial role in the damaging effects of heavy metal exposure in patients with CKD and that iron supplementation might be a strategy to combat these detrimental processes.

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.

Plasma cadmium is associated with increased risk of long-term kidney graft failure.

The kidney is one of the most sensitive organs to cadmium-induced toxicity, particularly in conditions of long-term oxidative stress. We hypothesized that, in kidney transplant recipients, nephrotoxic exposure to cadmium represents an overlooked hazard for optimal graft function. To test this, we performed a prospective cohort study and included 672 outpatient kidney transplant recipients with a functioning graft of beyond one year. The median plasma cadmium was 58 ng/L. During a median 4.9 years of follow-up, 78 kidney transplant recipients developed graft failure with a significantly different distribution across tertiles of plasma cadmium (13, 26, and 39 events, respectively). Plasma cadmium was associated with an increased risk of graft failure (hazard ratio 1.96, 95% confidence interval 1.56‒2.47 per log2 ng/L). Similarly, a dose-response relationship was observed over increasing tertiles of plasma cadmium, after adjustments for potential confounders (donor, recipient, transplant and lifestyle characteristics), robust in both competing risk and sensitivity analyses. These findings were also consistent for kidney function decline (graft failure or doubling of serum creatinine). Thus, plasma cadmium is independently associated with an increased risk of long-term kidney graft failure and decline in kidney function. Further studies are needed to investigate whether exposure to cadmium represents an otherwise overlooked modifiable risk factor for adverse long-term graft outcomes in different populations.

Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.

In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research.

Urinary liver-type fatty acid-binding protein is independently associated with graft failure in outpatient kidney transplant recipients.

Urinary liver-type fatty acid-binding protein (uL-FABP) is a biomarker of kidney hypoxia and ischemia, and thus offers a novel approach to identify early kidney insults associated with increased risk of graft failure in outpatient kidney transplant recipients (KTR). We investigated whether uL-FABP is associated with graft failure and whether it improves risk prediction. We studied a cohort of 638 outpatient KTR with a functional graft ≥1-year. During a median follow-up of 5.3 years, 80 KTR developed graft failure. uL-FABP (median 2.11, interquartile range 0.93-7.37 µg/24"/>h) was prospectively associated with the risk of graft failure (hazard ratio 1.75; 95% confidence interval 1.27-2.41 per 1-SD increment; P = .001), independent of potential confounders including estimated glomerular filtration rate and proteinuria. uL-FABP showed excellent discrimination ability for graft failure (c-statistic of 0.83) and its addition to a prediction model composed by established clinical predictors of graft failure significantly improved the c-statistic to 0.89 (P for F-test <.001). These results were robust to several sensitivity analyses. Further validation studies are warranted to evaluate the potential use of a risk-prediction model including uL-FABP to improve identification of outpatient KTR at high risk of graft failure in clinical care.

Iron deficiency after kidney transplantation.

Iron deficiency (ID) is highly prevalent in kidney transplant recipients (KTRs) and has been independently associated with an excess mortality risk in this population. Several causes lead to ID in KTRs, including inflammation, medication and an increased iron need after transplantation. Although many studies in other populations indicate a pivotal role for iron as a regulator of the immune system, little is known about the impact of ID on the immune system in KTRs. Moreover, clinical trials in patients with chronic kidney disease or heart failure have shown that correction of ID, with or without anaemia, improves exercise capacity and quality of life, and may improve survival. ID could therefore be a modifiable risk factor to improve graft and patient outcomes in KTRs; prospective studies are warranted to substantiate this hypothesis.

Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

BACKGROUND: Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone that increases early in the course of chronic kidney disease (CKD), is associated with disease progression in patients with established CKD. Here we aimed to investigate the association between plasma FGF23 and new-onset CKD in the general population. METHODS: We included 5253 individuals without CKD who participated in the Prevention of Renal and Vascular Endstage Disease study, a prospective, population-based cohort. Multi-variable Cox regression was used to study the association of plasma C-terminal FGF23 with new-onset CKD, defined as a combined endpoint of estimated glomerular filtration rate (eGFR) <60 mL/min/ 1.73 m2, urinary 24-h albumin excretion (UAE) >30 mg/24 h or both, or with all-cause mortality. RESULTS: The median baseline FGF23 was 68 [interquartile range (IQR) 56-85] RU/mL, eGFR was 95 ± 13 mL/min/1.73 m2 and UAE was 7.8 (IQR 5.8-11.5) mg/24 h. After follow-up of 7.5 (IQR 7.2-8.0) years, 586 participants developed CKD and 214 participants died. A higher FGF23 level was associated with new-onset CKD, independent of risk factors for kidney disease and parameters of bone and mineral homoeostasis {fully adjusted hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.10-1.44] per doubling of FGF23; P = 0.001}. In secondary analyses, FGF23 was independently associated with new-onset eGFR <60 mL/min/1.73 m2 [adjusted HR 1.28 (95% CI 1.00-1.62); P = 0.048] or with UAE >30 mg/24 h [adjusted HR 1.24 (95% CI 1.06-1.45); P = 0.01] individually. A higher FGF23 level was also associated with an increased risk of all-cause mortality [fully adjusted HR 1.30 (95% CI 1.03-1.63); P = 0.03]. CONCLUSIONS: High FGF23 levels are associated with an increased risk of new-onset CKD and all-cause mortality in this prospective population-based cohort, independent of established CKD risk factors.

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.

The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study.

BACKGROUND: Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs. METHODS AND FINDINGS: We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7-9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38-2.52, P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality (HR 1.68, 95% CI 1.21-2.33, P = 0.002). Moreover, the HR for mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48-3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23-2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation. CONCLUSIONS: We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02811835, NCT01331668.