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.</p

Proeftuin Food Valley : de kwaliteit van de leefomgeving

Het agrarische gebruik heeft gevolgen voor de kwaliteit van de leefomgeving. Schaalvergroting is ook voor veel agrarische bedrijven in FoodValley een toekomststrategie. Een ander deel van de bedrijven is relatief klein, een aanzienlijk deel daarvan heeft geen opvolger. Functieverandering van agrarische bedrijven neemt een hoge vlucht en verandert het aanzien van het landschap. Bovendien ontstaan nieuwe en soms ongewenste soorten van bedrijvigheid in vrijkomende agrarische gebouwen en boerderijen. Ondanks het overwegend intensieve agrarisch gebruik, kent de Vallei ook veel "trage gebieden". Dit zijn delen van de Vallei waar het grootgrondbezit van oudsher van belang was en is. Hier liggen waardevolle oude cultuurlandschappen, die zich kenmerken door een sterke verweving van landbouw en natuu

Erythropoietin, Fibroblast Growth Factor 23, and Death After Kidney Transplantation

Elevated levels of erythropoietin (EPO) are associated with an increased risk of death in renal transplant recipients (RTRs), but the underlying mechanisms remain unclear. Emerging data suggest that EPO stimulates production of the phosphaturic hormone fibroblast growth factor 23 (FGF23), another strong risk factor for death in RTRs. We hypothesized that the hitherto unexplained association between EPO levels and adverse outcomes may be attributable to increased levels of FGF23. We included 579 RTRs (age 51 ± 12 years, 55% males) from the TransplantLines Insulin Resistance and Inflammation Cohort study (NCT03272854). During a follow-up of 7.0 years, 121 RTRs died, of which 62 were due to cardiovascular cause. In multivariable Cox regression analysis, EPO was independently associated with all-cause (HR, 1.66; 95% CI 1.16-2.36; P = 0.005) and cardiovascular death (HR, 1.87; 95% CI 1.14-3.06; P = 0.01). However, the associations were abrogated following adjustment for FGF23 (HR, 1.28; 95% CI 0.87-1.88; P = 0.20, and HR, 1.45; 95% CI 0.84-2.48; P = 0.18, respectively). In subsequent mediation analysis, FGF23 mediated 72% and 50% of the association between EPO and all-cause and cardiovascular death, respectively. Our results underline the strong relationship between EPO and FGF23 physiology, and provide a potential mechanism underlying the relationship between increased EPO levels and adverse outcomes in RTRs

Association of Hepcidin-25 with survival after kidney transplantation

Background Hepcidin is considered the master regulator of iron homoeostasis. Novel hepcidin antagonists have recently been introduced as potential treatment for iron-restricted anaemia. Meanwhile, serum hepcidin has been shown to be positively associated with cardiovascular disease and inversely with acute kidney injury. These properties may lead to contrasting effects, especially in renal transplant recipients (RTR), which are prone to cardiovascular diseases and graft failure. To date, the role of serum hepcidin in RTR is unknown. We, therefore, prospectively determined the association of serum hepcidin with risk of graft failure, cardiovascular mortality and all-cause mortality in RTR. Materials and methods Serum hepcidin was assessed in an extensively phenotyped RTR cohort by dual-monoclonal sandwich ELISA specific immunoassay. Statistical analyses were performed using univariate linear regression followed by stepwise backward linear regression. Cox proportional hazard regression models were performed to determine prospective associations. Results We included 561 RTR (age 51 +/- 12 years). Mean haemoglobin (Hb) was 8.6 +/- 1.0 mM. Median [IQR] serum hepcidin was 7.2 [3.2-13.4] ng/mL. Mean estimated glomerular filtration rate was 47 +/- 16 mL/min/ 1.73 m(2). In univariate Cox regression analyses, serum hepcidin was not associated with risk of graft failure, cardiovascular mortality or all-cause mortality. Notably, after adjustment for high sensitivity C-reactive protein and ferritin, serum hepcidin became negatively associated with all-cause mortality (hazard ratio 0.89; 95% confidence interval 0.80-0.99, P = 0.3). Conclusions In this study, we did not find an association between serum hepcidin and outcomes, that is graft failure, cardiovascular mortality or all-cause mortality. Based on our results, it is questionable whether serum hepcidin may be used to predict a beneficial effect of hepcidin antagonists

Urinary Properdin and sC5b-9 Are Independently Associated With Increased Risk for Graft Failure in Renal Transplant Recipients

The pathophysiology of late kidney-allograft failure remains complex and poorly understood. Activation of filtered or locally produced complement may contribute to the progression of renal failure through tubular C5b-9 formation. This study aimed to determine urinary properdin and sC5b-9 excretion and assess their association with long-term outcome in renal transplant recipients (RTR). Methods: We measured urinary properdin and soluble C5b-9 in a well-defined cross-sectional cohort of RTR. Urinary specimens were taken from a morning urine portion, and properdin and sC5b-9 were measured using an enzyme-linked-immunosorbent assay (ELISA). Cox proportional hazard regression analyses were used to investigate prospective associations with death-censored graft failure. Results: We included 639 stable RTR at a median [interquartile range] 5.3 (1.8-12.2) years after transplantation. Urinary properdin and sC5b-9 excretion were detectable in 161 (27%) and 102 (17%) RTR, respectively, with a median properdin level of 27.6 (8.6-68.1) ng/mL and a median sC5b-9 level of 5.1 (2.8-12.8) ng/mL. In multivariable-adjusted Cox regression analyses, including adjustment for proteinuria, urinary properdin (HR, 1.12; 95% CI 1.02-1.28; P = 0.008) and sC5b-9 excretion (HR, 1.34; 95% CI 1.10-1.63; P = 0.003) were associated with an increased risk of graft failure. If both urinary properdin and sC5b-9 were detectable, the risk of graft failure was further increased (HR, 3.12; 95% CI 1.69-5.77; P < 0.001). Conclusions: Our findings point toward a potential role for urinary complement activation in the pathogenesis of chronic allograft failure. Urinary properdin and sC5b-9 might be useful biomarkers for complement activation and chronic kidney allograft deterioration, suggesting a potential role for an alternative pathway blockade in RTR

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 β = 0.39, p &lt; 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized β = 0.29, p &lt; 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 &lt; 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 &lt; 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p &lt; 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

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 β = 0.39, p &lt; 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized β = 0.29, p &lt; 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 &lt; 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 &lt; 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p &lt; 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

Plasma Vitamin C and Cancer Mortality in Kidney Transplant Recipients

There is a changing trend in mortality causes in kidney transplant recipients (KTR), with a decline in deaths due to cardiovascular causes along with a relative increase in cancer mortality rates. Vitamin C, a well-known antioxidant with anti-inflammatory and immune system enhancement properties, could offer protection against cancer. We aimed to investigate the association of plasma vitamin C with long-term cancer mortality in a cohort of stable outpatient KTR without history of malignancies other than cured skin cancer. Primary and secondary endpoints were cancer and cardiovascular mortality, respectively. We included 598 KTR (mean age 51 +/- 12 years old, 55% male). Mean (SD) plasma vitamin C was 44 +/- 20 mu mol/L. At a median follow-up of 7.0 (IQR, 6.2-7.5) years, 131 patients died, of which 24% deaths were due to cancer. In Cox proportional hazards regression analyses, vitamin C was inversely associated with cancer mortality (HR 0.50; 95%CI 0.34-0.74; p <0.001), independent of potential confounders, including age, smoking status and immunosuppressive therapy. In secondary analyses, vitamin C was not associated with cardiovascular mortality (HR 1.16; 95%CI 0.83-1.62; p = 0.40). In conclusion, plasma vitamin C is inversely associated with cancer mortality risk in KTR. These findings underscore that relatively low circulating plasma vitamin C may be a meaningful as yet overlooked modifiable risk factor of cancer mortality in KTR

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 β = 0.39, p &lt; 0.001), and urinary copper excretion was positively associated with u-LFABP (standardized β = 0.29, p &lt; 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 &lt; 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 &lt; 0.001). u-LFABP was a significant mediator of this association (74% of indirect effect, p &lt; 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