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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 (Pb) with late graft failure in kidney transplant recipients (KTR) remains unknown.STUDY DESIGN: Prospective cohort study in the Netherlands.SETTING & PARTICIPANTS: We studied outpatient KTR (n=670) with a functioning graft for ≥1 year recruited at a university setting (2008-2011, NCT02811835) and followed, on average, for 4.9 (IQR, 3.4‒5.5) years. Additionally, end-stage kidney disease patients (n=46) enrolled in the ongoing TransplantLines Cohort and Biobank Study (2016-2017, NCT03272841) were studied at admission for transplantation and at 3, 6, 12, and 24 months after transplantation.EXPOSURE: Plasma Pb was log2 transformed to estimate the association with outcomes per doubling of plasma Pb concentration and also considered categorically as tertiles of the Pb distribution.OUTCOME: Kidney graft failure (restart of dialysis or re-transplantation) with the competing event of death with a functioning graft.ANALYTICAL APPROACH: Multivariable-adjusted cause-specific hazards models where follow-up of KTR who died with a functioning graft was censored.RESULTS: Median baseline plasma Pb was 0.31 (IQR, 0.22─0.45) μg/L among all KTRs. During follow-up, 78 (12%) KTR developed graft failure. Higher plasma Pb was associated with increased risk of graft failure (HR 1.59, 95% CI 1.14‒2.21 per doubling; P=0.006) independent of age, sex, transplant characteristics, eGFR, 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 Pb categorically. In serial measurements, plasma Pb was significantly higher at admission for transplantation than at 3-months post-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 Pb concentrations, which fall after transplantation, 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 Pb may represent novel risk-management strategies to decrease the rate of kidney allograft failure.

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.