Publications by authors named "Stefan P Berger"

126 Publications

A systematic review and meta-analysis of COVID-19 in kidney transplant recipients: Lessons to be learned.

Am J Transplant 2021 Jul 1. Epub 2021 Jul 1.

Department of Nephrology and Hypertension, UMC Utrecht, Utrecht, The Netherlands.

Kidney transplant recipients (KTR) may be at increased risk of adverse COVID-19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID-19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID-19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID-19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID-19. Random-effects meta-analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID-19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%-27%), and AKI, 50% (95% CI: 44%-56%), is high among KTR with COVID-19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR.
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http://dx.doi.org/10.1111/ajt.16742DOI Listing
July 2021

Hypothermic Machine Perfusion as a National Standard Preservation Method for Deceased Donor Kidneys.

Transplantation 2021 Jun 23. Epub 2021 Jun 23.

Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands Dutch Transplant Foundation, Leiden, The Netherlands Department of Surgery, Amsterdam Medical Center, Amsterdam, The Netherlands Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.

Background: Recently, continuous nonoxygenated hypothermic machine perfusion (HMP) has been implemented as standard preservation method for deceased donor kidneys in the Netherlands. This study was designed to assess the effect of the implementation of HMP on early outcomes after transplantation.

Methods: Kidneys donated in the Netherlands from 2016 to 2017 were intended to be preserved by HMP. A historical cohort (2010-2014) preserved by static cold storage (CS) was chosen as control group. Primary outcome was delayed graft function (DGF). Additional analyses were performed on safety, graft function and survival up until 2 years after transplantation.

Results: Data was collected on 2493 kidneys. Analyses showed significantly more DCD, pre-emptive and retransplants in the project cohort. Of the 681 kidneys that were transplanted during the project, 81% was preserved by HMP. No kidneys were discarded due to HMP related complications. DGF occurred in 38.2% of the project cohort versus 43.7% of the historical cohort (p <0.001), with a significantly shorter duration within the project cohort (7 versus 9 days, p = 0.003). Multivariate regression analysis showed an odds ratio of 0.69 (95% CI 0.553 - 0.855) for the risk of DGF when using HMP compared to CS (p = 0.001). There was no significant difference in kidney function, graft and recipient survival up until 2 years post transplantation.

Conclusions: This study showed that HMP as standard preservation method for deceased donor kidneys is safe and feasible. HMP was associated with a significant reduction of DGF.
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http://dx.doi.org/10.1097/TP.0000000000003845DOI Listing
June 2021

Ganciclovir therapeutic drug monitoring in transplant recipients.

J Antimicrob Chemother 2021 Jun 23. Epub 2021 Jun 23.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.

Background: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance.

Objectives: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population.

Methods: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1-2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2-4 mg/L and an AUC24h of 80-120 mg·h/L were aimed for.

Results: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2-6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline.

Conclusions: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.
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http://dx.doi.org/10.1093/jac/dkab195DOI Listing
June 2021

Comparison of renal histopathology and gene expression profiles between severe COVID-19 and bacterial sepsis in critically ill patients.

Crit Care 2021 06 10;25(1):202. Epub 2021 Jun 10.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.

Methods: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients.

Results: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19.

Conclusions: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.
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http://dx.doi.org/10.1186/s13054-021-03631-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190989PMC
June 2021

Plasma Vitamin C and Risk of Late Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Biobank and Cohort Study.

Antioxidants (Basel) 2021 Apr 21;10(5). Epub 2021 Apr 21.

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

Recent studies have shown that depletion of vitamin C is frequent in outpatient kidney transplant recipients (KTR) and that vitamin C is inversely associated with risk of death. Whether plasma vitamin C is associated with death-censored kidney graft failure remains unknown. We investigated KTR who participated in the TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study. The primary outcome was graft failure (restart of dialysis or re-transplantation). Overall and stratified ( < 0.1) multivariable-adjusted Cox regression analyses are presented here. Among 598 KTR (age 51 ± 12 years-old; 55% males), baseline median (IQR) plasma vitamin C was 44.0 (31.0-55.3) µmol/L. Through a median follow-up of 9.5 (IQR, 6.3‒10.2) years, 75 KTR developed graft failure (34, 26, and 15 events over increasing tertiles of vitamin C, log-rank < 0.001). Plasma vitamin C was inversely associated with risk of graft failure (HR per 1-SD increment, 0.69; 95% CI 0.54-0.89; = 0.004), particularly among KTR with triglycerides ≥1.9 mmol/L (HR 0.46; 95% CI 0.30-0.70; < 0.001; = 0.01) and among KTR with HDL cholesterol ≥0.91 mmol/L (HR 0.56; 95% CI 0.38-0.84; = 0.01; = 0.04). These findings remained materially unchanged in multivariable-adjusted analyses (donor, recipient, and transplant characteristics, including estimated glomerular filtration rate and proteinuria), were consistent in categorical analyses according to tertiles of plasma vitamin C, and robust after exclusion of outliers. Plasma vitamin C in outpatient KTR is inversely associated with risk of late graft failure. Whether plasma vitamin C‒targeted therapeutic strategies represent novel opportunities to ease important burden of graft failure necessitates further studies.
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http://dx.doi.org/10.3390/antiox10050631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143099PMC
April 2021

Temporal Trends in the Quality of Deceased Donor Kidneys and Kidney Transplant Outcomes in Europe: an analysis by the ERA-EDTA Registry.

Nephrol Dial Transplant 2021 Apr 12. Epub 2021 Apr 12.

Kitty J. Jager Professor, : ERA, -EDTA Registry, Department of Medical Informatics, Amsterdam, UMC-location, AMC, Amsterdam Public Health Research Institute, University of Amsterdam, Amsterdam, the, Netherlands.

Background: We investigated ten-year trends in deceased donor kidney quality expressed as the kidney donor risk index (KDRI) and subsequent effects on survival outcomes in a European transplant population.

Methods: Time trends in the crude and standardised KDRI between 2005-2015, by recipient age, sex, diabetic status, and country were examined in 24,177 adult kidney transplant recipients in seven European countries. We determined five-year patient and graft survival probabilities and the risk of death and graft loss by transplant cohort (cohort 1: 2005-2006, cohort 2: 2007-2008, cohort 3: 2009-2010) and KDRI quintile.

Results: The median crude KDRI increased by 1.3% annually from 1.31 (interquartile range, IQR: 1.08-1.63) in 2005 to 1.47 (IQR: 1.16-1.90) in 2015. This increase i.e., lower kidney quality, was driven predominantly by increases in donor age, hypertension and donation after circulatory death. With time, the gap between the median standardised KDRI in the youngest (18-44 years) and eldest (>65 years) recipients widened. There was no difference in the median standardised KDRI by recipient sex. The median standardised KDRI was highest in Austria, the Netherlands, and Basque Country (Spain). Within each transplant cohort, the 5-year patient and graft survival probability were higher for the lowest KDRIs. There was no difference in the patient and graft survival outcomes across transplant cohorts, however over time the survival probabilities for the highest KDRIs improved.

Conclusions: The overall quality of deceased donor kidneys transplanted between 2005-2015 has decreased and varies between age groups and countries. Overall patient and graft outcomes remain unchanged.
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http://dx.doi.org/10.1093/ndt/gfab156DOI Listing
April 2021

Machine-perfused donor kidneys as a source of human renal endothelial cells.

Am J Physiol Renal Physiol 2021 05 15;320(5):F947-F962. Epub 2021 Mar 15.

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

Renal endothelial cells (ECs) play crucial roles in vasorelaxation, ultrafiltration, and selective transport of electrolytes and water, but also in leakage of the glomerular filtration barrier and inflammatory processes like complement activation and leukocyte recruitment. In addition, they are target cells for both cellular and antibody-mediated rejection in the transplanted kidney. To study the molecular and cellular processes underlying EC behavior in renal disease, well-characterized primary renal ECs are indispensible. In this report, we describe a straightforward procedure to isolate ECs from the perfusion fluid of human donor kidneys by a combination of negative selection of monocytes/macrophages, positive selection by CD31 Dynabeads, and propagation in endothelium-specific culture medium. Thus, we isolated and propagated renal ECs from 102 donor kidneys, representative of all blood groups and major human leukocyte antigen (HLA) class I and II antigens. The obtained ECs were positive for CD31 and von Willebrand factor, expressed other endothelial markers such as CD34, VEGF receptor-2, TIE2, and plasmalemmal vesicle associated protein-1 to a variable extent, and were negative for the monocyte marker CD14 and lymphatic endothelial marker podoplanin. HLA class II was either constitutively expressed or could be induced by interferon-γ. Furthermore, as a proof of principle, we showed the diagnostic value of this renal endothelial biobank in renal endothelium-specific cross-matching tests for HLA antibodies. We describe a new and widely accessible approach to obtain human primary renal endothelial cells in a standardized fashion, by isolating from the perfusate of machine-perfused donor kidneys. Characterization of the cells showed a mixed population originating from different compartments of the kidney. As a proof of principle, we demonstrated a possible diagnostic application in an endothelium-specific cross-match. Next to transplantation, we foresee further applications in the field renal endothelial research.
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http://dx.doi.org/10.1152/ajprenal.00541.2020DOI Listing
May 2021

Metabolomics data complemented drug use information in epidemiological databases: pilot study of potential kidney donors.

J Clin Epidemiol 2021 Jul 9;135:10-16. Epub 2021 Feb 9.

Life Sciences Mass Spectrometry, Department of Inorganic and Analytical Chemistry, University of Geneva, Quai Ernest Ansermet 24, 1211 Geneva, Switzerland. Electronic address:

Objective: The objective of this study was to investigate whether clinical metabolomics, which is increasingly applied in population-based and epidemiological studies, can be used to provide analytical evidence of exposures, and whether such information can be useful to strengthen and/or complement corresponding clinical database entries, taking drug use as an example.

Study Design And Setting: Liquid chromatography-mass spectrometry (LC-MS) metabolomics analyses were performed on urine from 100 randomly-selected control subjects (50% females) from the TransplantLines Food and Nutrition Biobank and Cohort Study (NCT identifier 'NCT02811835'), and drugs were identified through spectral library searching and targeted signal extraction.

Results: In 83 subjects for whom drug use information was available, 22 expected and 26 unexpected prescription-only drugs were identified, while 28 expected prescription-only drugs remained undetected. In addition, 7 prescription-only drugs were found in 17 subjects for whom drug use information was unavailable, and 58 over-the-counter drugs were identified in all 100 subjects.

Conclusion: Molecular evidence for many drugs could be retrieved from LC-MS metabolomics data, which could be useful to complement and strengthen epidemiological databases given that considerable discrepancies were found between analytically-identified drugs and drugs listed in the available clinical database.
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http://dx.doi.org/10.1016/j.jclinepi.2021.02.008DOI Listing
July 2021

Aorto-Iliac Artery Calcification and Graft Outcomes in Kidney Transplant Recipients.

J Clin Med 2021 Jan 17;10(2). Epub 2021 Jan 17.

Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

While the association of vascular calcification with inferior patient outcomes in kidney transplant recipients is well-established, the association with graft outcomes has received less attention. With this dual-centre cohort study, we aimed to determine the clinical impact of recipient pre-transplant aorto-iliac calcification, measured on non-contrast enhanced computed tomography (CT)-imaging within three years prior to transplantation (2005-2018). We included 547 patients (61.4% male, age 60 (interquartile range 51-68) years), with a median follow-up of 3.1 (1.4-5.2) years after transplantation. The aorto-iliac calcification score (CaScore) was inversely associated with one-year estimated-glomerular filtration rate (eGFR) in univariate linear regression analysis (standard β -3.3 (95% CI -5.1 to -1.5, < 0.0001), but not after adjustment for potential confounders, including donor and recipient age ( = 0.077). In multivariable Cox regression analyses, a high CaScore was associated with overall graft failure ( = 0.004) and death with a functioning graft ( = 0.002), but not with death-censored graft failure and graft function decline. This study demonstrated that pre-transplant aorto-iliac calcification is associated with one-year eGFR in univariate, but not in multivariable linear regression analyses. Moreover, this study underlines that transplantation in patients with a high CaScore does not result in earlier transplant function decline or worse death censored graft survival, although ongoing efforts for the prevention of death with a functioning graft remain essential.
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http://dx.doi.org/10.3390/jcm10020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829792PMC
January 2021

[F]-sodium fluoride autoradiography imaging of nephrocalcinosis in donor kidneys and explanted kidney allografts.

Sci Rep 2021 Jan 19;11(1):1841. Epub 2021 Jan 19.

Department of Surgery, Division of Transplant Surgery, University Medical Center Groningen, University of Groningen, P.O. Box 30 001, 9700 RB, Groningen, The Netherlands.

Nephrocalcinosis is present in up to 43% of kidney allograft biopsies at one-year after transplantation and is associated with inferior graft function and poor graft survival. We studied [F]-sodium fluoride ([F]-NaF) imaging of microcalcifications in donor kidneys (n = 7) and explanted kidney allografts (n = 13). Three µm paraffin-embedded serial sections were used for histological evaluation of calcification (Alizarin Red; Von Kossa staining) and ex-vivo [F]-NaF autoradiography. The images were fused to evaluate if microcalcification areas corresponded with [F]-NaF uptake areas. Based on histological analyses, tubulointerstitial and glomerular microcalcifications were present in 19/20 and 7/20 samples, respectively. Using autoradiography, [F]-NaF uptake was found in 19/20 samples, with significantly more tracer activity in kidney allograft compared to deceased donor kidney samples (p = 0.019). Alizarin Red staining of active microcalcifications demonstrated good correlation (Spearman's rho of 0.81, p < 0.001) and Von Kossa staining of consolidated calcifications demonstrated significant but weak correlation (0.62, p = 0.003) with [F]-NaF activity. This correlation between ex-vivo [F]-NaF uptake and histology-proven microcalcifications, is the first step towards an imaging method to identify microcalcifications in active nephrocalcinosis. This may lead to better understanding of the etiology of microcalcifications and its impact on kidney transplant function.
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http://dx.doi.org/10.1038/s41598-021-81144-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815841PMC
January 2021

Association of time-updated plasma calcium and phosphate with graft and patient outcomes after kidney transplantation.

Am J Transplant 2021 Jul 12;21(7):2437-2447. Epub 2021 Jan 12.

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

Disturbances in calcium-phosphate homeostasis are common after kidney transplantation. We aimed to assess the relationship between deregulations in plasma calcium and phosphate over time and mortality and death-censored graft failure (DCGF). In this prospective cohort study, we included kidney transplant recipients with ≥2 plasma calcium and phosphate measurements. Data were analyzed using time-updated Cox regression analyses adjusted for potential confounders including time-updated kidney function. We included 2769 patients (mean age 47 ± 14 years, 42.3% female) with 138 496 plasma calcium and phosphate levels (median [IQR] 43 [31-61] measurements per patient). During follow-up of 16.3 [8.7-25.2] years, 17.2% developed DCGF and 7.9% died. Posttransplant hypercalcemia was associated with an increased risk of mortality (1.63 [1.31-2.00], p < 0.0001), but not with DCGF. Hyperphosphatemia was associated with both DCGF (2.59 [2.05-3.27], p < .0001) and mortality (3.14 [2.58-3.82], p <  .0001). Only the association between hypercalcemia and mortality remained significant in sensitivity analyses censored by a simultaneous eGFR <45 mL/min/1.73 m . Hypocalcemia and hypophosphatemia were not consistently associated with either outcome. Posttransplant hypercalcemia, even in the presence of preserved kidney function, was associated with an increased mortality risk. Associations of hyperphosphatemia with DCGF and mortality may be driven by eGFR.
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http://dx.doi.org/10.1111/ajt.16457DOI Listing
July 2021

Serum uric acid is associated with increased risk of posttransplantation diabetes in kidney transplant recipients: a prospective cohort study.

Metabolism 2021 03 13;116:154465. Epub 2020 Dec 13.

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

Background: Serum uric acid (SUA) is associated with fasting glucose in healthy subjects, and prospective epidemological studies have shown that elevated SUA is associated with increased risk of type 2 diabetes. Whether SUA is independently associated with higher risk of posttransplantation diabetes mellitus (PTDM) in kidney transplant recipients (KTR) remains unknown.

Methods: We performed a longitudinal cohort study of 524 adult KTR with a functioning graft ≥1-year, recruited at a university setting (2008-2011). Multivariable-adjusted Cox proportional-hazards regression analyses were performed to assess the association between time-updated SUA and risk of PTDM (defined according the American Diabetes Association's diagnostic criteria).

Results: Mean (SD) SUA was 0.43 (0.11) mmol/L at baseline. During 5.3 (IQR, 4.1-6.0) years of follow-up, 52 (10%) KTR developed PTDM. In univariate prospective analyses, SUA was associated with increased risk of PTDM (HR 1.75, 95% CI 1.36-2.26 per 1-SD increment; P < 0.001). This finding remained materially unchanged after adjustment for components of the metabolic syndrome, lifestyle, estimated glomerular filtration rate, immunosuppressive therapy, cytomegalovirus and hepatitis C virus infection (HR 1.89, 95% CI 1.32-2.70; P = 0.001). These findings were consistent in categorical analyses, and robust in sensitivity analyses without outliers.

Conclusions: In KTR, higher SUA levels are strongly and independently associated with increased risk of PTDM. Our findings are in agreement with accumulating evidence supporting SUA as novel independent risk marker for type 2 diabetes, and extend the evidence, for the first time, to the clinical setting of outpatient KTR.
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http://dx.doi.org/10.1016/j.metabol.2020.154465DOI Listing
March 2021

Soluble CD59 in peritoneal dialysis: a potential biomarker for peritoneal membrane function.

J Nephrol 2021 06 11;34(3):801-810. Epub 2020 Dec 11.

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

Introduction: Various studies have reported the importance of complement regulators in preventing mesothelial damage during peritoneal dialysis (PD). Its assessment, however, is limited in clinical practice due to the lack of easy access to the peritoneal membrane. Recently, a soluble form of the complement regulatory protein CD59 (sCD59) has been described. We therefore aimed to investigate the role of sCD59 in PD.

Methods: Plasma sCD59 was measured in 48 PD patients, 41 hemodialysis patients, 15 non-dialysis patients with chronic kidney disease and 14 healthy controls by ELISA (Hycult; HK374-02). Additionally, sCD59 and sC5b-9 were assessed in the peritoneal dialysate.

Results: sCD59 and sC5b-9 were detectable in the peritoneal dialysate of all patients, and marginally correlated (r = 0.27, P = 0.06). Plasma sCD59 levels were significantly higher in PD patients than in patients with chronic kidney disease and healthy controls, but did not differ from hemodialysis patients. During follow-up, 19% of PD patients developed peritoneal membrane failure and 27% of PD patients developed loss of residual renal function. In adjusted models, increased sCD59 levels in the dialysate (HR 3.44, 95% CI 1.04-11.40, P = 0.04) and in plasma (HR 1.08, 95% CI 1.01-1.17, P = 0.04) were independently associated with the occurrence of peritoneal membrane failure. Higher plasma levels of sCD59 were also associated with loss of residual renal function (HR 1.10, 95% CI 1.04-1.17, P < 0.001).

Conclusions: Our study suggests that sCD59 has potential as a biomarker to predict peritoneal membrane function and loss of residual renal function in PD, thereby offering a tool to improve patient management.
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http://dx.doi.org/10.1007/s40620-020-00934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192357PMC
June 2021

Corrigendum to 'Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial' (Br J Anaesth 2017; 118: 720-32).

Br J Anaesth 2021 01 20;126(1):340-341. Epub 2020 Nov 20.

Department of Anaesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

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http://dx.doi.org/10.1016/j.bja.2020.10.024DOI Listing
January 2021

Pre-Transplant Plasma Potassium as a Potential Risk Factor for the Need of Early Hyperkalaemia Treatment after Kidney Transplantation: A Cohort Study.

Nephron 2021 19;145(1):63-70. Epub 2020 Nov 19.

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

Introduction: Plasma potassium (K+) abnormalities are common among patients with chronic kidney disease and are associated with higher rates of death, major adverse cardiac events, and hospitalization in this population. Currently, no guidelines exist on how to handle pre-transplant plasma K+ in renal transplant recipients (RTR).

Objective: The aim of this study is to examine the relation between pre-transplant plasma K+ and interventions to resolve hyperkalaemia within 48 h after kidney transplantation.

Methods: In a single-centre cohort study, we addressed the association between the last available plasma K+ level before transplantation and the post-transplant need for dialysis or use of K+-lowering medication to resolve hyperkalaemia within 48 h after renal transplantation using multivariate logistic regression analysis.

Results: 151 RTR were included, of whom 51 (33.8%) patients received one or more K+ interventions within 48 h after transplantation. Multivariate regression analysis revealed that a higher pre-transplant plasma K+ was associated with an increased risk of post-transplant intervention (odds ratio 2.2 [95% CI: 1.1-4.4]), independent of donor type (deceased or living) and use of K+-lowering medication within 24 h prior to transplantation).

Conclusions: This study indicates that a higher pre-transplant plasma K+ is associated with a higher risk of interventions necessary to resolve hyperkalaemia within 48 h after renal transplantation. Further research is recommended to determine a cutoff level for pre-transplant plasma K+ that can be used in practice.
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http://dx.doi.org/10.1159/000511404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845431PMC
November 2020

A Method to Improve Continuous Renal Replacement Therapy Circuit Survival Time in Critically Ill Coronavirus Disease 2019 Patients With Acute Kidney Injury.

Crit Care Explor 2020 Oct 15;2(10):e0258. Epub 2020 Oct 15.

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

Objectives: Optimizing continuous renal replacement therapy circuit survival in coronavirus disease 2019 patients admitted to the ICU.

Design: Single-center prospective observational cohort study.

Setting: Tertiary academic teaching ICU.

Patients: Between March 19, 2020, and May 18, 2020, 11 out of 101 coronavirus disease 2019 patients were treated with continuous renal replacement therapy comprising 127 continuous renal replacement therapy days.

Interventions: A nonrandomized observational comparison of circuit anticoagulation modalities using standard regional citrate anticoagulation, continuous IV heparin anticoagulation, or the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin.

Measurements And Main Results: Circuit patency was shorter than 24 hours using standard regional citrate anticoagulation or continuous IV heparin anticoagulation. Median circuit survival increased with at least 165% when the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin was applied.

Conclusions: Continuous renal replacement therapy circuit patency is diminished in coronavirus disease 2019 ICU patients. Combining regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin increases filter survival as compared with regional citrate anticoagulation alone in this nonrandomized observational study.
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http://dx.doi.org/10.1097/CCE.0000000000000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566862PMC
October 2020

Postoperative Ultrasound in Kidney Transplant Recipients: Association Between Intrarenal Resistance Index and Cardiovascular Events.

Transplant Direct 2020 Aug 15;6(8):e581. Epub 2020 Jul 15.

Division of Transplant Surgery, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Doppler ultrasound, including intrarenal resistance index (RI) measurement, is a widely used modality to assess kidney transplantation (KTx) vascularization. The aim of this study is to gain insight in the associations between early postoperative RI measurements and cardiovascular events (CVEs), all-cause mortality, and death-censored graft survival.

Methods: From 2015 to 2017, a prospective cohort study was conducted in patients in which RI measurement was performed immediately after KTx. The RI was calculated as (peak systolic velocity-end-diastolic velocity)/peak systolic velocity. End points were CVEs, all-cause mortality, and graft failure. Kaplan-Meier analyses (logrank test) were used for differences in end points. Univariate and multivariate associations were investigated by means of Cox regression analyses.

Results: RI cutoff of 0.70 was used. We included 339 recipients, of which 271 (80%) had an RI ≤ 0.70 and 68 (20%) had an RI > 0.70. CVEs were observed in 27 (8%) patients, 27 (8%) patients died, and 17 (5%) patients had graft failure during a median follow-up of 37 months (interquartile range, 33-43). Kaplan-Meier analyses and univariate Cox regression indicated a significant association with overall CVE-free survival (hazard ratios [HR], 2.79; = 0.011; logrank test, = 0.008) and all-cause mortality (HR, 2.59; = 0.017; logrank test, = 0.013) for patients with an RI above and below 0.70. An independent association was shown between an RI > 0.70 and CVE-free survival (HR, 2.48; = 0.042) when deceased donation was not included in the model.

Conclusions: In the early postoperative period, a high RI showed to be associated with CVEs after adjustment for cardiovascular risk factors, whereas no independent association was found with overall survival and graft failure. For the interpretation of RI measurements after KTx surgery, patients' cardiovascular state should be taken into consideration.
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http://dx.doi.org/10.1097/TXD.0000000000001034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581034PMC
August 2020

Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial.

J Clin Med 2020 Oct 7;9(10). Epub 2020 Oct 7.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, The Netherlands.

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) ( < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.
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http://dx.doi.org/10.3390/jcm9103216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600059PMC
October 2020

Vibration threshold in non-diabetic subjects.

PLoS One 2020 7;15(10):e0237733. Epub 2020 Oct 7.

Department of Neurosurgery, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands.

Measuring vibration perception threshold (VPT) accurately classifies and quantifies the severity of loss of vibration perception. A biothesiometer (Bio-thesiometer®; Bio Medical Instrument Co, Ohio, USA) appears to be the most suitable tool to determine VPT due to its low inter-rater variability and low occurence of adaption to the sensation. Different VPT values for a biothesiometer have been described, however, specification on age, height and different measurement locations is currently lacking. The objective of our study was to identify determinants of vibration perception in non-diabetic subjects, in order to provide individualized normal values of VPTs for clinical practice. Measurements of the vibration perception were performed on the big toes, insteps, lateral malleoli, and wrists. A total of 205 healthy subjects were included (108 (52.7%) males) with a median [interquartile range] age of 59 [51;64] (range 21-80) years. Mean height was 174.45 ± 9.20 cm and mean weight was 82.94 ± 14.84 kg, resulting in a mean BMI of 27.19 ± 4.00 kg/m2. In stepwise forward linear regression analyses, age (st. β = 0.51, p < 0.001) and height (st. β = 0.43, p < 0.001) were found to be the independent unmodifiable determinants of the VPT at the big toe. Regression coefficients for quantiles of the determinants age and height were incorporated in the corresponding regression equations. This study provides equations to calculate age- and height-specific normal values for VPT that can be used in clinical practice and in large research studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237733PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540842PMC
November 2020

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

Aorto-Iliac Artery Calcification Prior to Kidney Transplantation.

J Clin Med 2020 Sep 7;9(9). Epub 2020 Sep 7.

Department of Surgery, Division of Transplant Surgery, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.

As vascular calcification is common in kidney transplant candidates, aorto-iliac vessel imaging is performed for surgical planning. The aim of the present study was to investigate whether a novel non-contrast enhanced computed tomography-based quantification technique for aorto-iliac calcification can be used for cardiovascular risk stratification prior to kidney transplantation. In this dual-center cohort study, we measured the aorto-iliac calcium score (CaScore) of 547 patients within three years prior to transplantation (2005-2018). During a median (interquartile range) follow-up of 3.1 (1.4, 5.2) years after transplantation, 80 (14.7%) patients died, of which 32 (40.0%) died due to cardiovascular causes, and 84 (15.5%) patients had a cardiovascular event. Kaplan-Meier survival curves showed significant differences between the CaScore tertiles for cumulative overall-survival (Log-rank test < 0.0001), cardiovascular survival ( < 0.0001), and cardiovascular event-free survival ( < 0.001). In multivariable Cox regression, the aorto-iliac CaScore was associated with all-cause mortality (hazard ratio 1.53, 95%CI 1.14-2.06, = 0.005), cardiovascular mortality (2.04, 1.20-3.45, = 0.008), and cardiovascular events (1.35, 1.01-1.80, = 0.042). These independent associations of the aorto-iliac CaScore with the outcome measures can improve the identification of patients at risk for (cardiovascular) death and those who could potentially benefit from stringent cardiovascular monitoring to improve their prognosis after transplantation.
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http://dx.doi.org/10.3390/jcm9092893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563260PMC
September 2020

Properdin Pattern Recognition on Proximal Tubular Cells Is Heparan Sulfate/Syndecan-1 but Not C3b Dependent and Can Be Blocked by Tick Protein Salp20.

Front Immunol 2020 7;11:1643. Epub 2020 Aug 7.

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

Proteinuria contributes to progression of renal damage, partly by complement activation on proximal tubular epithelial cells. By pattern recognition, properdin has shown to bind to heparan sulfate proteoglycans on tubular epithelium and can initiate the alternative complement pathway (AP). Properdin however, also binds to C3b(Bb) and properdin binding to tubular cells might be influenced by the presence of C3b(Bb) on tubular cells and/or by variability in properdin proteins . In this study we carefully evaluated the specificity of the properdin - heparan sulfate interaction and whether this interaction could be exploited in order to block alternative complement activation. Binding of various properdin preparations to proximal tubular epithelial cells (PTEC) and subsequent AP activation was determined in the presence or absence of C3 inhibitor Compstatin and properdin inhibitor Salp20. Heparan sulfate proteoglycan dependency of the pattern recognition of properdin was evaluated on PTEC knocked down for syndecan-1 by shRNA technology. Solid phase binding assays were used to evaluate the effectivity of heparin(oids) and recombinant Salp20 to block the pattern recognition of properdin. Binding of serum-derived and recombinant properdin preparations to PTECs could be dose-dependently inhibited ( < 0.01) and competed off ( < 0.01) by recombinant Salp20 (IC50: ~125 ng/ml) but not by Compstatin. Subsequent properdin-mediated AP activation on PTECs could be inhibited by Compstatin ( < 0.01) and blocked by recombinant Salp20 ( < 0.05). Syndecan-1 deficiency in PTECs resulted in a ~75% reduction of properdin binding ( = 0.057). In solid-phase binding assays, properdin binding to C3b could be dose-dependently inhibited by recombinant Salp20> heparin(oid) > C3b. In this study we showed that all properdin preparations recognize heparan sulfate/syndecan-1 on PTECs with and without Compstatin C3 blocking conditions. In contrast to Compstatin, recombinant Salp20 prevents heparan sulfate pattern recognition by properdin on PTECs. Both complement inhibitors prevented properdin-mediated C3 activation. Binding of properdin to C3b could also be blocked by heparin(oids) and recombinant Salp20. This work indicates that properdin serves as a docking station for AP activation on PTECs and a Salp20 analog or heparinoids may be viable inhibitors in properdin mediated AP activation.
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http://dx.doi.org/10.3389/fimmu.2020.01643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426487PMC
April 2021

Protein Intake, Fatigue and Quality of Life in Stable Outpatient Kidney Transplant Recipients.

Nutrients 2020 Aug 14;12(8). Epub 2020 Aug 14.

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

Fatigue is a frequent complaint in kidney transplant recipients (KTR), often accompanied by poor quality of life (QoL). The role of nutrition as determinant of fatigue in KTR is largely unexplored. The aims of this study are to examine the association of protein intake with fatigue and QoL in KTR and to identify other determinants of fatigue. This cross-sectional study is part of the TransplantLines Cohort and Biobank Study (NCT03272841). Protein intake was calculated from urinary urea nitrogen (UUN) in 24-h urine samples. Fatigue was assessed by the Checklist Individual Strength (CIS) questionnaire; moderate and severe fatigue were defined as a CIS score of 20-34 and ≥ 35, respectively. QoL was assessed with the RAND-36-Item Health Survey (RAND-36). Associations of protein intake with fatigue and QoL were analyzed using multinomial logistic and linear regression analyses. We included 730 stable outpatient KTR (median age 58 year [IQR 48-65], 57% male) with a mean protein intake of 82.2 ± 21.3 g/d. Moderate and severe fatigue were present in 254 (35%) and 245 (34%) of KTR. Higher protein intake was significantly associated with lower risk of moderate fatigue (OR 0.89 per 10 g/d; 95%CI 0.83-0.98, = 0.01), severe fatigue (OR 0.85; 95%CI 0.78-0.92, 0.001) and was associated with higher physical component summary score of QoL (β 0.74 per 10 g/d; 95%CI 0.39-1.09, < 0.001). Higher BMI, a history of dialysis, glomerulonephritis as primary kidney disease and a history of combined organ transplantation were also associated with severe fatigue. In conclusion, amongst the potential modifiable factors of fatigue, higher protein intake is independently associated with lower risk of moderate and severe fatigue and with better QoL in KTR. These findings underline the need to incorporate nutritional assessment in the diagnostic work-up of fatigue. Intervention studies are needed to assess the benefits and safety of higher protein intake in KTR.
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http://dx.doi.org/10.3390/nu12082451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469059PMC
August 2020

Improving outcomes for donation after circulatory death kidney transplantation: Science of the times.

PLoS One 2020 29;15(7):e0236662. Epub 2020 Jul 29.

Department of Surgery and Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236662PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390443PMC
September 2020

Transitions in frailty state after kidney transplantation.

Langenbecks Arch Surg 2020 Sep 20;405(6):843-850. Epub 2020 Jul 20.

Department of Surgery, Division of Vascular and Transplantation Surgery, University Medical Centre Groningen, P.O. Box 30 001, 9700 RB, Groningen, The Netherlands.

Purpose: Frailty is the body's failure to return to homeostasis after every day or acute stressful events, causing adverse outcomes. To study its dynamics in kidney transplant recipients (KTR), we determined whether the degree of frailty and its domains are affected by kidney transplantation (KT).

Methods: Between 2015 and 2017, 176 KTR were included. Frailty scores were measured using the Groningen Frailty Indicator (GFI), assessed preoperatively and during follow-up. Transitions in frailty state and changes in the individual domains were determined.

Results: Mean age (±SD) was 51.8 (± 14.1) years, and 63.1% of KTR were male. Thirty patients were considered frail (GFI ≥ 4) at baseline. After a mean follow-up of 22.8 ± 8.3 months, 34 non-frail patients (19.3%) became frail, 125 patients (71.0%) remained the same, and 17 frail patients (9.7%) became non-frail (GFI < 4). In the domain psychosocial functioning, 28.4% of the patients had an increase in GFI score after follow-up. Patients who scored a point in the domain cognition at baseline had a greater chance of becoming frail (OR 4.38, 95% CI 0.59-32.24).

Conclusion: In conclusion, almost one-fifth of non-frail KTR transitioned to a frail state after their transplantation. These results could be used to predict the impact of KT on frailty course and help with implementing prehabilitation for patients at risk.
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http://dx.doi.org/10.1007/s00423-020-01936-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471154PMC
September 2020

Galectin-3 and Risk of Late Graft Failure in Kidney Transplant Recipients: A 10-year Prospective Cohort Study.

Transplantation 2021 05;105(5):1106-1115

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

Background: Galectin-3 may play a causal role in kidney inflammation and fibrosis, which may also be involved in the development of kidney graft failure. With novel galectin-3-targeted pharmacological therapies increasingly coming available, we aimed to investigate whether galectin-3 is associated with risk of late graft failure in kidney transplant recipients (KTR).

Methods: We studied adult KTR who participated in TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study, recruited in a university setting (2001-2003). Follow-up was performed for a median of 9.5 (interquartile range, 6.2-10.2) years. Overall and stratified (Pinteraction < 0.05) multivariable-adjusted Cox proportional-hazards regression analyses were performed to study the association of galectin-3 with risk of graft failure (restart of dialysis or retransplantation).

Results: Among 561 KTR (age 52 ± 12 y; 54% males), baseline median galectin-3 was 21.1 (interquartile range, 17.0-27.2) ng/mL. During follow-up, 72 KTR developed graft failure (13, 18, and 44 events over increasing tertiles of galectin-3). Independent of adjustment for donor, recipient, and transplant characteristics, galectin-3-associated with increased risk of graft failure (hazard ratios [HR] per 1 SD change, 2.12; 95% confidence interval [CI], 1.63-2.75; P < 0.001), particularly among KTR with systolic blood pressure ≥140 mmHg (HR, 2.29; 95% CI, 1.80-2.92; P < 0.001; Pinteraction = 0.01) or smoking history (HR, 2.56; 95% CI, 1.95-3.37; P < 0.001; Pinteraction = 0.03). Similarly, patients in the highest tertile of galectin-3 were consistently at increased risk of graft failure.

Conclusions: Serum galectin-3 levels are elevated in KTR, and independently associated with increased risk of late graft failure. Whether galectin-3-targeted therapies may represent novel opportunities to decrease the long-standing high burden of late graft failure in stable KTR warrants further studies.
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http://dx.doi.org/10.1097/TP.0000000000003359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078111PMC
May 2021

Bone Mineral Density and Aortic Calcification: Evidence for a Bone-vascular Axis After Kidney Transplantation.

Transplantation 2021 01;105(1):231-239

Medical Imaging Center, Department of Nuclear and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Chronic kidney disease mineral and bone disorders (CKD-MBD) and vascular calcification are often seen in kidney transplantation recipients (KTR). This study focused on the bone-vascular axis hypothesis, the pathophysiological mechanisms driving both bone loss and vascular calcification, supported by an association between lower bone mineral density (BMD) and higher risk of vascular calcification.

Methods: KTR referred for a dual-energy X-ray absorptiometry procedure within 6 mo after transplantation were included in a cross-sectional study (2004-2014). Areal BMD was measured at the proximal femur, and abdominal aortic calcification (AAC) was quantified (8-points score) from lateral single-energy images of the lumbar spine. Patients were divided into 3 AAC categories (negative-AAC: AAC 0; low-AAC: AAC 1-3; and high-AAC: AAC 4-8). Multivariable-adjusted multinomial logistic regression models were performed to study the association between BMD and AAC.

Results: We included 678 KTR (51 ± 13 y old, 58% males), 366 (54%) had BMD disorders, and 266 (39%) had detectable calcification. High-AAC was observed in 9%, 11%, and 25% of KTR with normal BMD, osteopenia, and osteoporosis, respectively (P < 0.001). Higher BMD (T-score, continuous) was associated with a lower risk of high-AAC (odds ratio 0.61, 95% confidence interval 0.42-0.88; P = 0.008), independent of age, sex, body mass index, estimated glomerular filtration rate, and immunosuppressive therapy. KTR with normal BMD were less likely to have high-AAC (odds ratio 0.24, 95% confidence interval 0.08-0.72; P = 0.01).

Conclusions: BMD disorders are highly prevalent in KTR. The independent inverse association between BMD and AAC may provide evidence to point toward the existence, while highlighting the clinical and epidemiological relevance, of a bone-vascular axis after kidney transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003226DOI Listing
January 2021

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

Kidney Infarction in Patients With COVID-19.

Am J Kidney Dis 2020 09 29;76(3):431-435. Epub 2020 May 29.

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

Coronavirus disease 2019 (COVID-19) is a contagious life-threatening infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings indicate an increased risk for acute kidney injury during COVID-19 infection. The pathophysiologic mechanisms leading to acute kidney injury in COVID-19 infection are unclear but may include direct cytopathic effects of the virus on kidney tubular and endothelial cells, indirect damage caused by virus-induced cytokine release, and kidney hypoperfusion due to a restrictive fluid strategy. In this report of 2 cases, we propose an additional pathophysiologic mechanism. We describe 2 cases in which patients with COVID-19 infection developed a decrease in kidney function due to kidney infarction. These patients did not have atrial fibrillation. One of these patients was treated with therapeutic doses of low-molecular-weight heparin, after which no further deterioration in kidney function was observed. Our findings implicate that the differential diagnosis of acute kidney injury in COVID-19-infected patients should include kidney infarction, which may have important preventive and therapeutic implications.
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http://dx.doi.org/10.1053/j.ajkd.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258815PMC
September 2020
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