Publications by authors named "Michele F Eisenga"

66 Publications

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

Am J Kidney Dis 2021 Dec 3. Epub 2021 Dec 3.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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 log 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.
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http://dx.doi.org/10.1053/j.ajkd.2021.10.009DOI Listing
December 2021

Circulating DHEA-S levels and major cardiovascular outcomes in chronic Chagas cardiomyopathy: A prospective cohort study.

Int J Cardiol 2022 Feb 26;349:90-95. Epub 2021 Nov 26.

Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland. Electronic address:

Objective: To analyze the association of circulating dehydroepiandrosterone sulfate (DHEA-S) levels with cardiovascular outcomes in patients with chronic Chagas cardiomyopathy (CCM) diagnosis.

Background: DHEA-S is among the main endogenous steroid hormones. Some studies have suggested a relevant role of this hormone in infections and the setting of CCM. Nevertheless, no study has evaluated the prognostic role of DHEA-S in CCM patients.

Methods: Prospective cohort study. Patients with CCM and reduced ejection fraction were included. We explored the association of DHEA-S levels with NT-proBNP levels and echocardiographic variables using linear regression models. Next, by using Cox Proportional Hazard models, we examined whether levels of DHEA-S could predict a composite outcome (CO) including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD).

Results: Seventy-four patients were included (59% males, median age: 64 years). After adjustment for confounding factors, high DHEA-S levels were associated with better LVEF, lower left atrium volume, end-systolic volume of the left ventricle and lower NT-proBNP levels. 43% of patients experienced the CO during a median follow-up of 40 months. Increased levels of DHEA-S were associated with a lower risk of developing the CO (HR 0.43; 95%CI 0.21-0.86). Finally, adding DHEA-S to the multivariate model did not improve the prediction of the CO, but substituting NT-proBNP in the model with DHEA-S showed similar performance.

Conclusions: In patients with CCM, higher DHEA-S levels were associated with lower mortality, heart transplantation, and LVAD implantation. Further larger studies are required to confirm our results and assess causality.
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http://dx.doi.org/10.1016/j.ijcard.2021.11.054DOI Listing
February 2022

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

Clin J Am Soc Nephrol 2021 11;16(11):1686-1694

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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; =0.007) and lower physical health-related quality of life (-0.11 SDs; 95% confidence interval, -0.19 to -0.02; =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.
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http://dx.doi.org/10.2215/CJN.06600521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729428PMC
November 2021

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

Eur J Nutr 2021 Oct 22. Epub 2021 Oct 22.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen and University of Groningen, Post Box 30.001, 9700 RB, Groningen, The Netherlands.

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 (P < 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.
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http://dx.doi.org/10.1007/s00394-021-02702-0DOI Listing
October 2021

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

Diabetes Care 2021 Dec 5;44(12):2683-2690. Epub 2021 Oct 5.

Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

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 β-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 ( = 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 HbA (hazard ratio [HR] 0.31 [95% CI 0.16-0.59], < 0.001; and HR 0.32 [95% CI 0.15-0.68], = 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.
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http://dx.doi.org/10.2337/dc21-0237DOI Listing
December 2021

Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies.

Nutrients 2021 Aug 31;13(9). Epub 2021 Aug 31.

Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman's ρ 0.54, 0.60, and -0.54, respectively, < 0.001 for all), and each 10 mL/min/1.73 m increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.
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http://dx.doi.org/10.3390/nu13093069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467091PMC
August 2021

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

Transpl Int 2021 Nov 7;34(11):2305-2316. Epub 2021 Oct 7.

Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1111/tri.14110DOI Listing
November 2021

Hypoxia-inducible factor prolyl hydroxylase inhibitor, C-terminal fibroblast growth factor 23 fragments, and hepcidin.

Kidney Int 2021 09;100(3):709

Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.04.038DOI Listing
September 2021

Self-reported alcohol consumption, carbohydrate deficient transferrin and risk of cardiovascular disease: The PREVEND prospective cohort study.

Clin Chim Acta 2021 Sep 26;520:1-7. Epub 2021 May 26.

Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

Background: Self-reported alcohol consumption is an established risk factor for cardiovascular disease (CVD). Carbohydrate deficient transferrin (CDT) is an established objective marker of excessive alcohol consumption, but data on its prospective association with CVD are lacking. We aimed to evaluate the associations of self-reported alcohol consumption and CDT (expressed as %CDT, a more reliable marker than absolute CDT levels) with CVD risk.

Materials And Methods: In the PREVEND prospective study of 5,206 participants (mean age, 53 years; 47.7% males), alcohol consumption by self-reports, absolute CDT measured using the Siemens nephelometric assay and %CDT calculated as the percentage of total transferrin concentrations, were assessed at baseline. Alcohol consumption was classified into 5 categories: abstention (reference), light, light-moderate, moderate and heavy alcohol consumption.Hazard ratios (HRs) (95% confidence intervals [CI]) for first CVD events were estimated.

Results: Mean (SD) of %CDT was 1.59 (0.54) %. During a median follow-up of 8.3 years, 326 first CVD events were recorded. Compared with abstainers, the multivariable-adjusted HRs (95% CIs) of CVD for light, light-moderate, moderate and heavy alcohol consumption were 0.66 (0.46-0.95), 0.83 (0.62-1.11), 0.83 (0.61-1.14) and 0.80 (0.48-1.36), respectively. Light alcohol consumption was associated with reduced coronary heart disease risk 0.62 (0.40-0.96), whereas light-moderate alcohol consumption was associated with reduced stroke risk 0.45 (0.24-0.83). The association of %CDT with CVD risk was not significant.

Conclusions: Our findings confirm the established association between self-reported light to moderate alcohol consumption and reduced CVD risk. However, %CDT within the normal reference range may not be a risk indicator for CVD.
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http://dx.doi.org/10.1016/j.cca.2021.05.024DOI Listing
September 2021

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population.

J Am Heart Assoc 2021 06 17;10(11):e018549. Epub 2021 May 17.

Division of Nephrology Department of Internal Medicine University of GroningenUniversity Medical Center Groningen Groningen the Netherlands.

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community-dwelling individuals whether a higher plasma interleukin 6 (IL-6) level is associated with an increased risk of developing new-onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case-cohort study based on the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective general population-based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL-6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02-1.61; =0.03) after adjustment for key risk factors. Specifically, IL-6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16-2.19; =0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75-1.47; =0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL-6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04-2.06; =0.03) after adjustment for key risk factors. Conclusions IL-6 is associated with new-onset HFpEF in community-dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL-6 might be a novel treatment target to prevent HFpEF.
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http://dx.doi.org/10.1161/JAHA.120.018549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483531PMC
June 2021

Iron deficiency, with and without anaemia, across strata of kidney function in kidney transplant recipients.

Nephrol Dial Transplant 2021 12;36(12):2342-2344

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1093/ndt/gfab173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643576PMC
December 2021

Iron Deficiency Defined by Hepcidin in Critically Ill Patients.

Crit Care 2021 04 12;25(1):138. Epub 2021 Apr 12.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

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http://dx.doi.org/10.1186/s13054-021-03542-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040202PMC
April 2021

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

Kidney Int 2021 06 8;99(6):1280-1295. Epub 2021 Apr 8.

Inserm Unit 1018, Team 5, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS), Villejuif, France; Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Villejuif, France. Electronic address:

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.
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http://dx.doi.org/10.1016/j.kint.2021.03.020DOI Listing
June 2021

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

Am J Transplant 2021 04 11;21(4):1535-1544. Epub 2020 Oct 11.

Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

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.
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http://dx.doi.org/10.1111/ajt.16312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048636PMC
April 2021

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

Kidney Int 2021 05 14;99(5):1213-1224. Epub 2020 Sep 14.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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 log 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.
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http://dx.doi.org/10.1016/j.kint.2020.08.027DOI Listing
May 2021

Iron deficiency after kidney transplantation.

Nephrol Dial Transplant 2021 11;36(11):1976-1985

Department of Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1093/ndt/gfaa123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577626PMC
November 2021

Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.

Eur J Epidemiol 2020 Aug 20;35(8):763-773. Epub 2020 Aug 20.

Institute of Social and Preventive Medicine (ISPM), University of Bern, Mittelstrasse 43, 3012, Bern, Switzerland.

Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin [weighted mean difference (WMD), - 4.08 g/L (95% CI - 5.12; - 3.05)] and red blood cell count [WMD, - 0.16 × 10 /L (95% CI - 0.31; - 0.014)], and higher ferritin [WMD, - 473.25 ng/mL (95% CI 382.52; 563.98)] and red cell distribution width [WMD, 1.82% (95% CI 0.10; 3.55)]. A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.
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http://dx.doi.org/10.1007/s10654-020-00678-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438401PMC
August 2020

The association between haemoglobin concentrations and muscle mass determined from urinary creatinine excretion rate: a population-based cohort study.

Br J Haematol 2020 09 24;190(6):e349-e352. Epub 2020 Jun 24.

Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1111/bjh.16912DOI Listing
September 2020

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

PLoS Med 2020 06 15;17(6):e1003140. Epub 2020 Jun 15.

Department of Nephrology and Renal Transplantation, University Hospitals Leuven and Nephrology & Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

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.
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http://dx.doi.org/10.1371/journal.pmed.1003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295199PMC
June 2020

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

J Clin Med 2020 06 4;9(6). Epub 2020 Jun 4.

Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

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; = 0.005) and cardiovascular death (HR, 1.87; 95% CI 1.14-3.06; = 0.01). However, the associations were abrogated following adjustment for FGF23 (HR, 1.28; 95% CI 0.87-1.88; = 0.20, and HR, 1.45; 95% CI 0.84-2.48; = 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.
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http://dx.doi.org/10.3390/jcm9061737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356141PMC
June 2020

Sodium-Glucose Cotransporter 2 Inhibitors and Kidney Outcomes: True Renoprotection, Loss of Muscle Mass or Both?

J Clin Med 2020 May 25;9(5). Epub 2020 May 25.

Department of Nephrology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have emerged as practice-changing treatments for patients with type 2 diabetes, reducing both the risk of cardiovascular events and kidney events. However, regarding the latter, caution is warranted, as these kidney endpoints are defined using glomerular filtration rate estimations based on creatinine, the non-enzymatic product of creatine residing in muscles. Creatinine-based estimations of the glomerular filtration rate are only valid if the treatment has no effect on changes in muscle mass over time. Yet, circumstantial evidence suggests that treatment with SGLT2 inhibitors does result in a loss of muscle mass, rendering serum creatinine-based kidney endpoints invalid. Currently, it cannot be excluded that the described renoprotective effect of SGLT2 inhibitors is in part or in whole the consequence of a loss of muscle mass. Post-hoc analyses of existing trials or new trials based on kidney function markers independent of muscle mass can provide more definitive answers on the proposed renoprotective effects of SGLT2 inhibitors.
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http://dx.doi.org/10.3390/jcm9051603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291210PMC
May 2020

Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia.

Blood Adv 2020 04;4(8):1678-1682

Van Creveldkliniek, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias.
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http://dx.doi.org/10.1182/bloodadvances.2020001595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189297PMC
April 2020

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

Nephrol Dial Transplant 2021 01;36(1):121-128

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1093/ndt/gfz266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771975PMC
January 2021

Altered Gut Microbial Fermentation and Colonization with in Renal Transplant Recipients.

J Clin Med 2020 Feb 14;9(2). Epub 2020 Feb 14.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Renal transplant recipients (RTRs) often suffer from posttransplant diarrhea. The observed dysbiosis in RTR may influence the fermentation processes in the gut. In this study, we aimed to investigate whether fermentation differs between RTRs and healthy controls (HCs), by measuring breath H and CH concentrations. Additionally, we determined the fecal presence of the methanogen (), which plays a main role in the process of methanogenesis. Data from the TransplantLines Biobank and Cohort Study (NCT03272841) was used. A total of 142 RTRs and 77 HCs were included. Breath H concentrations in RTRs were not significantly different from HCs. Breath CH concentrations in RTRs were significantly lower compared with HCs (median [interquartile range (IQR)] 7.5 [3.9-10.6] ppm vs. 16.0 [8.0-45.5] ppm, < 0.001). was less frequently present in the feces of RTRs compared to HCs (28.6% vs. 86.4% resp., < 0.001). Our findings regarding the altered methanogenesis in the gut of RTRs show similarities with previous results in inflammatory bowel disease patients. These findings provide novel insight into the alterations of fermentation after renal transplantation, which may contribute to understanding the occurrence of posttransplant diarrhea.
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http://dx.doi.org/10.3390/jcm9020518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073595PMC
February 2020

Characteristics and Dysbiosis of the Gut Microbiome in Renal Transplant Recipients.

J Clin Med 2020 Feb 1;9(2). Epub 2020 Feb 1.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands.

Renal transplantation is life-changing in many aspects. This includes changes to the gut microbiome likely due to exposure to immunosuppressive drugs and antibiotics. As a consequence, renal transplant recipients (RTRs) might suffer from intestinal dysbiosis. We aimed to investigate the gut microbiome of RTRs and compare it with healthy controls and to identify determinants of the gut microbiome of RTRs. Therefore, RTRs and healthy controls participating in the TransplantLines Biobank and Cohort Study (NCT03272841) were included. We analyzed the gut microbiome using 16S rRNA sequencing and compared the composition of the gut microbiome of RTRs to healthy controls using multivariate association with linear models (MaAsLin). Fecal samples of 139 RTRs (50% male, mean age: 58.3 ± 12.8 years) and 105 healthy controls (57% male, mean age: 59.2 ± 10.6 years) were collected. Median time after transplantation of RTRs was 6.0 (1.5-12.5)years. The microbiome composition of RTRs was significantly different from that of healthy controls, and RTRs had a lower diversity of the gut microbiome ( < 0.01). Proton-pump inhibitors, mycophenolate mofetil, and estimated glomerular filtration rate (eGFR) are significant determinants of the gut microbiome of RTRs ( < 0.05). Use of mycophenolate mofetil correlated to a lower diversity ( < 0.01). Moreover, significant alterations were found in multiple bacterial taxa between RTRs and healthy controls. The gut microbiome of RTRs contained more Proteobacteria and less Actinobacteria, and there was a loss of butyrate-producing bacteria in the gut microbiome of RTRs. By comparing the gut microbiome of RTRs to healthy controls we have shown that RTRs suffer from dysbiosis, a disruption in the balance of the gut microbiome.
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http://dx.doi.org/10.3390/jcm9020386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074359PMC
February 2020

Pretransplant NT-proBNP, Dialysis Vintage, and Posttransplant Mortality in Kidney Transplant Recipients.

Transplantation 2020 10;104(10):2158-2165

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.

Background: End-stage kidney disease and dialysis vintage are characterized by accelerated atherosclerosis, volume overload, and progressive left ventricular hypertrophy, leading to elevated N-terminal probrain natriuretic peptide (NT-proBNP) levels. Pretransplant dialysis vintage is associated with excess mortality after transplantation. We want to study whether pretransplant NT-proBNP is associated with posttransplantation mortality and if it explains the association of dialysis vintage with posttransplantation mortality in kidney transplant recipients (KTR).

Methods: We measured plasma NT-proBNP on arrival at the hospital before kidney transplantation in 658 KTR between January 1995 and December 2005 in our center. Multivariable Cox regression analyses, adjusted for potential confounders, were used to prospectively study the associations of dialysis vintage and NT-proBNP with all-cause mortality.

Results: During median 12.7 (7.8-15.6) years of follow-up after transplantation, 248 (37.7%) KTR died. Dialysis vintage was associated with an increased risk of posttransplant mortality in the fully adjusted model (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.03-1.43; P = 0.02), independent of potential confounders. The association weakened materially and lost significance after further adjustment for NT-proBNP (HR, 1.14; 0.96-1.34; P = 0.14). NT-proBNP was independently associated with all-cause mortality in the fully adjusted model (HR, 1.34; 1.16-1.55; P < 0.001). The association remained independent of adjustment for dialysis vintage (HR, 1.31; 1.13-1.52; P < 0.001).

Conclusions: Our study shows that longer dialysis vintage is associated with a higher mortality risk in KTR, and this association might be explained for a considerable part by variation in pretransplant NT-proBNP at the time of transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003125DOI Listing
October 2020

Plasma Vitamin C and Cancer Mortality in Kidney Transplant Recipients.

J Clin Med 2019 Nov 23;8(12). Epub 2019 Nov 23.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

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 μmol/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; < 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; = 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.
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http://dx.doi.org/10.3390/jcm8122064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947225PMC
November 2019

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

Front Immunol 2019 24;10:2511. Epub 2019 Oct 24.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

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). 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. 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; = 0.008) and sC5b-9 excretion (HR, 1.34; 95% CI 1.10-1.63; = 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; < 0.001). 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.
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http://dx.doi.org/10.3389/fimmu.2019.02511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830301PMC
October 2020

Canagliflozin and Renal Outcomes in Diabetic Nephropathy.

N Engl J Med 2019 09;381(11):1089

University Medical Center Groningen, Groningen, the Netherlands

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http://dx.doi.org/10.1056/NEJMc1909687DOI Listing
September 2019
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