Publications by authors named "Marco van Londen"

34 Publications

Early increase in single-kidney glomerular filtration rate after living kidney donation predicts long-term kidney function.

Kidney Int 2022 Jun 26;101(6):1251-1259. Epub 2022 Feb 26.

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

Single-kidney glomerular filtration rate (GFR) increases after living kidney donation due to compensatory hyperfiltration and structural changes. The implications of inter-individual variability in this increase in single-kidney GFR are unknown. Here, we aimed to identify determinants of the increase in single-kidney GFR at three-month postdonation, and to investigate its relationship with long-term kidney function. In a cohort study in 1024 donors, we found considerable inter-individual variability of the early increase in remaining single-kidney estimated GFR (eGFR) (median [25th-75th percentile]) 12 [8-18] mL/min/1.73m. Predonation eGFR, age, and cortical kidney volume measured by CT were the main determinants of the early postdonation increase in single-kidney eGFR. Individuals with a stronger early increase in single-kidney eGFR had a significantly higher five-year postdonation eGFR, independent of predonation eGFR and age. Addition of the postdonation increase in single-kidney eGFR to a model including predonation eGFR and age significantly improved prediction of a five-year postdonation eGFR under 50 mL/min/1.73m. Results at ten-year follow-up were comparable, while accounting for left-right differences in kidney volume did not materially change the results. Internal validation using I-iothalamate-based measured GFR in 529 donors and external validation using eGFR data in 647 donors yielded highly similar results. Thus, individuals with a more pronounced increase in single-kidney GFR had better long-term kidney function, independent of predonation GFR and age. Hence, the early postdonation increase in single-kidney GFR, considered indicative for kidney reserve capacity, may have additional value to eGFR and age to personalize follow-up intensity after living kidney donation.
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http://dx.doi.org/10.1016/j.kint.2022.01.034DOI Listing
June 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

Age-adapted percentiles of measured glomerular filtration in healthy individuals: extrapolation to living kidney donors over 65 years.

Clin Chem Lab Med 2022 02 21;60(3):401-407. Epub 2021 Oct 21.

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

Objectives: Most data on glomerular filtration rate (GFR) originate from subjects <65 years old, complicating decision-making in elderly living kidney donors. In this retrospective multi-center study, we calculated percentiles of measured GFR (mGFR) in donors <65 years old and extrapolated these to donors ≥65 years old.

Methods: mGFR percentiles were calculated from a development cohort of French/Belgian living kidney donors <65 years (n=1,983), using quantiles modeled as cubic splines (two linear parts joining at 40 years). Percentiles were extrapolated and validated in an internal cohort of donors ≥65 years (n=147, France) and external cohort of donors and healthy subjects ≥65 years (n=329, Germany, Sweden, Norway, France, The Netherlands) by calculating percentages within the extrapolated 5th-95th percentile (P5-P95).

Results: Individuals in the development cohort had a higher mGFR (99.9 ± 16.4 vs. 86.4 ± 14 and 82.7 ± 15.5 mL/min/1.73 m) compared to the individuals in the validation cohorts. In the internal validation cohort, none (0%) had mGFR below the extrapolated P5, 12 (8.2%) above P95 and 135 (91.8%) between P5-P95. In the external validation cohort, five subjects had mGFR below the extrapolated P5 (1.5%), 25 above P95 (7.6%) and 299 (90.9%) between P5-P95.

Conclusions: We demonstrate that extrapolation of mGFR from younger donors is possible and might aid with decision-making in elderly donors.
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http://dx.doi.org/10.1515/cclm-2021-1011DOI Listing
February 2022

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

Assessment of kidney function: clinical indications for measured GFR.

Clin Kidney J 2021 Aug 22;14(8):1861-1870. Epub 2021 Feb 22.

Institute of Public Health, Charité Universitätsmedizin Berlin, Berlin, Germany.

In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C-based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.
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http://dx.doi.org/10.1093/ckj/sfab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323140PMC
August 2021

Meat intake and risk of mortality and graft failure in kidney transplant recipients.

Am J Clin Nutr 2021 10;114(4):1505-1517

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

Background: It is unknown whether meat intake is beneficial for long-term patient and graft survival in kidney transplant recipients (KTR).

Objectives: We first investigated the association of the previously described meat intake biomarkers 1-methylhistidine and 3-methylhistidine with intake of white and red meat as estimated from a validated food frequency questionnaire (FFQ). Second, we investigated the association of the meat intake biomarkers with long-term outcomes in KTR.

Methods: We measured 24-h urinary excretion of 1-methylhistidine and 3-methylhistidine by validated assays in a cohort of 678 clinically stable KTR. Cross-sectional associations were assessed by linear regression. We used Cox regression analyses to prospectively study associations of log2-transformed biomarkers with mortality and graft failure.

Results: Urinary 1-methylhistidine and 3-methylhistidine excretion values were median: 282; interquartile range (IQR): 132-598 µmol/24 h and median: 231; IQR: 175-306 µmol/24 h, respectively. Urinary 1-methylhistidine was associated with white meat intake [standardized β (st β): 0.20; 95% CI: 0.12, 0.28; P < 0.001], whereas urinary 3-methylhistidine was associated with red meat intake (st β: 0.30; 95% CI: 0.23, 0.38; P < 0.001). During median follow-up for 5.4 (IQR: 4.9-6.1) y, 145 (21%) died and 83 (12%) developed graft failure. Urinary 3-methylhistidine was inversely associated with mortality independently of potential confounders (HR per doubling: 0.55; 95% CI: 0.42, 0.72; P < 0.001). Both urinary 1-methylhistidine and urinary 3-methylhistidine were inversely associated with graft failure independent of potential confounders (HR per doubling: 0.84; 95% CI: 0.73, 0.96; P = 0.01; and 0.59; 95% CI: 0.41, 0.85; P = 0.004, respectively).

Conclusions: High urinary 3-methylhistidine, reflecting higher red meat intake, is independently associated with lower risk of mortality. High urinary concentrations of both 1- and 3-methylhistidine, of which the former reflects higher white meat intake, are independently associated with lower risk of graft failure in KTR. Future intervention studies are warranted to study the effect of high meat intake on mortality and graft failure in KTR, using these biomarkers.
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http://dx.doi.org/10.1093/ajcn/nqab185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488867PMC
October 2021

The Association between Body Composition Measurements and Surgical Complications after Living Kidney Donation.

J Clin Med 2021 Jan 5;10(1). Epub 2021 Jan 5.

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

Obesity is considered a risk factor for peri- and postoperative complications. Little is known about this risk in overweight living kidney donors. The aim of this study was to assess if anthropometric body measures and/or surgical determinants are associated with an increased incidence of peri- and postoperative complications after nephrectomy. We included 776 living kidney donors who donated between 2008 and 2018 at the University Medical Center Groningen. Prenephrectomy measures of body composition were body mass index (BMI), body surface area (BSA), waist circumference, weight, and waist-hip ratio. Incidence and severity of peri- and postoperative complications were assessed using the Comprehensive Complication Index. Mean donor age was 53 ± 11 years; 382 (49%) were male, and mean BMI at donor screening was 26.2 ± 3.41 kg/m. In total, 77 donors (10%) experienced peri- and postoperative complications following donor nephrectomy. Male sex was significantly associated with fewer surgical complications (OR 0.59, 0.37-0.96 95%CI, = 0.03) in binomial logistic regression analyses. Older age (OR: 1.03, 1.01-1.05 95%CI, = 0.02) and a longer duration of surgery (OR: 1.01, 1.00-1.01 95%CI, = 0.02) were significantly associated with more surgical complications in binomial logistic regression analyses. Multinomial logistic regression analyses did not identify any prenephrectomy measure of body composition associated with a higher risk of surgical complications. This study shows that higher prenephrectomy BMI and other anthropometric measures of body composition are not significantly associated with peri- and postoperative complications following living donor nephrectomy.
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http://dx.doi.org/10.3390/jcm10010155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794883PMC
January 2021

Identifying donors with no recovery of kidney function.

Kidney Int 2020 11;98(5):1349-1350

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

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http://dx.doi.org/10.1016/j.kint.2020.07.028DOI Listing
November 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

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

Urinary sulfate excretion and risk of late graft failure in renal transplant recipients - a prospective cohort study.

Transpl Int 2020 07 23;33(7):752-761. Epub 2020 Mar 23.

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

Hydrogen sulfide (H S), produced from metabolism of dietary sulfur-containing amino acids, is allegedly a renoprotective compound. Twenty-four-hour urinary sulfate excretion (USE) may reflect H S bioavailability. We aimed to investigate the association of USE with graft failure in a large prospective cohort of renal transplant recipients (RTR). We included 704 stable RTR, recruited at least 1 year after transplantation. We applied log-rank testing and Cox regression analyses to study association of USE, measured from baseline 24 h urine samples, with graft failure. Median age was 55 [45-63] years (57% male, eGFR was 45 ± 19 ml/min/1.73 m ). Median USE was 17.1 [13.1-21.1] mmol/24 h. Over median follow-up of 5.3 [4.5-6.0] years, 84 RTR experienced graft failure. RTR in the lowest sex-specific tertile of USE experienced a higher rate of graft failure during follow-up than RTR in the middle and highest sex-specific tertiles (18%, 13%, and 5%, respectively, log-rank P < 0.001). In Cox regression analyses, USE was inversely associated with graft failure [HR per 10 mmol/24 h: 0.37 (0.24-0.55), P < 0.001]. The association remained independent of adjustment for potential confounders, including age, sex, eGFR, proteinuria, time between transplantation and baseline, BMI, smoking, and high sensitivity C-reactive protein [HR per 10 mmol/24 h: 0.51 (0.31-0.82), P = 0.01]. In conclusion, this study demonstrates a significant inverse association of USE with graft failure in RTR, suggesting high H S bioavailability as a novel, potentially modifiable factor for prevention of graft failure in RTR.
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http://dx.doi.org/10.1111/tri.13600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383851PMC
July 2020

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

Circulating Advanced Glycation Endproducts and Long-Term Risk of Cardiovascular Mortality in Kidney Transplant Recipients.

Clin J Am Soc Nephrol 2019 10 17;14(10):1512-1520. Epub 2019 Sep 17.

Division of Nephrology.

Background And Objectives: In kidney transplant recipients, elevated circulating advanced glycation endproducts (AGEs) are the result of increased formation and decreased kidney clearance. AGEs trigger several intracellular mechanisms that ultimately yield excess cardiovascular disease. We hypothesized that, in stable kidney transplant recipients, circulating AGEs are associated with longterm risk of cardiovascular mortality, and that such a relationship is mediated by inflammatory, oxidative stress, and endothelial dysfunction biomarkers.

Design, Setting, Participants, & Measurements: Prospective cohort study of stable kidney transplant recipients recruited between 2001 and 2003 in a university setting. We performed multivariableadjusted Cox regression analyses to assess the association of AGEs (, N [Carboxymethyl]lysine (CML) and N [Carboxyethyl]lysine (CEL), measured by tandem mass spectrometry) with cardiovascular mortality. Mediation analyses were performed according to Preacher and Hayes's procedure.

Results: We included 555 kidney transplant recipients (age 51±12 years, 56% men). During a median followup of 6.9 years, 122 kidney transplant recipients died (52% deaths were due to cardiovascular causes). CML and CEL concentrations were directly associated with cardiovascular mortality (respectively, hazard ratio, 1.55; 95% confidence interval, 1.24 to 1.95; <0.001; and hazard ratio, 1.53; 95% confidence interval 1.18 to 1.98; =0.002), independent of age, diabetes, smoking status, body mass index, eGFR and proteinuria. Further adjustments, including cardiovascular history, did not materially change these findings. In mediation analyses, free thiol groups and soluble vascular cell adhesion molecule1 consistently explained approximately 35% of the association of CML and CEL with cardiovascular mortality.

Conclusions: In stable kidney transplant recipients, circulating levels of AGEs are independently associated with longterm risk of cardiovascular mortality.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_17_CJN00540119.mp3.
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http://dx.doi.org/10.2215/CJN.00540119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777589PMC
October 2019

CKD: A Call for an Age-Adapted Definition.

J Am Soc Nephrol 2019 10 10;30(10):1785-1805. Epub 2019 Sep 10.

Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.
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http://dx.doi.org/10.1681/ASN.2019030238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779354PMC
October 2019

Clinical and neurohumoral associates of variations in plasma Na in the PREVEND cohort.

Am J Physiol Renal Physiol 2019 10 24;317(4):F978-F985. Epub 2019 Jul 24.

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

Plasma Na concentration is regulated within narrow limits. Yet, substantial interindividual differences exist even in the normal range. The determinants of these differences are not well understood. We therefore investigated the clinical and neurohumoral associates of plasma Na. We studied 2,364 men (age: 48 ± 12 yr) and 2,710 women (age: 47 ± 12 yr) from the prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort study. In the present study, we investigated the neurohumoral factors NH-terminal prohormone of brain natriuretic peptide (NT-proBNP) and aldosterone as volume markers and copeptin as a marker for osmoregulation. Clinical associating variables of plasma Na were age, sex, and plasma glucose. Furthermore, plasma Na levels were associated with log copeptin (men: standardized β = 0.18, < 0.001; women: standardized β = 0.17, < 0.001), log NT-proBNP (men: standardized β = 0.07, = 0.008; women: standardized β = 0.12, < 0.001), and log aldosterone (men: standardized β = -0.06, = 0.005; women: standardized β = -0.09, < 0.001). Copeptin and NT-proBNP showed an interaction in their association with plasma Na. Thus, our data ) support that osmoregulation, as estimated from copeptin levels, is a main associate of plasma Na; 2) show a consistent association with volume markers, with higher NT-proBNP and lower aldosterone in individuals with higher plasma Na; and ) show that the interaction between copeptin and NT-proBNP illustrates that osmoregulation and volume regulation act in concert in the regulation of plasma Na.
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http://dx.doi.org/10.1152/ajprenal.00465.2018DOI Listing
October 2019

Effect of high compared with low dairy intake on blood pressure in overweight middle-aged adults: results of a randomized crossover intervention study.

Am J Clin Nutr 2019 08;110(2):340-348

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

Background: Observational studies suggest that high dairy intake is associated with a lower blood pressure (BP).

Objective: We aimed to investigate the effect of a high-dairy diet (HDD) as compared with a low-dairy diet (LDD) on BP in overweight middle-aged adults.

Methods: Fifty-two overweight men and women were included in a randomized crossover intervention study. Each subject consumed 2 isocaloric diets for 6 wk, an LDD (≤1 dairy portion per day) and an HDD (6 or 5 reduced-fat dairy portions for men and women, respectively), with a 4-wk washout period in between the diets during which the subjects consumed their habitual diet. BP was measured at the start and at the end of the intervention diets. The effect of the intervention study was evaluated by 2-sample t tests. Mixed-model analyses were used for adjustment for the potential influence of changes in dietary protein and mineral intake and risk factors for hypertension including body weight and plasma cholesterol.

Results: Consumption of an HDD as compared with an LDD resulted in a reduction of both systolic BP (mean ± SD: 4.6 ± 11.2 mm Hg, P < 0.01) and diastolic BP (3.0 ± 6.7 mm Hg, P < 0.01). In further analyses, these reductions appeared dependent on the concomitant increase in calcium intake.

Conclusions: This intervention study shows that an HDD results in a reduction of both systolic and diastolic BP in overweight middle-aged men and women. If the results of our study are reproduced by other studies, advice for high dairy intake may be added to treatment and prevention of high BP. This trial was registered at trialregister.nl as NTR4899.
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http://dx.doi.org/10.1093/ajcn/nqz116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669052PMC
August 2019

Crohn's Disease in Clinical Remission Is Marked by Systemic Oxidative Stress.

Front Physiol 2019 26;10:499. Epub 2019 Apr 26.

Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Crohn's disease (CD) is characterized by chronic and relapsing inflammation of the gastro-intestinal tract. It is assumed that oxidative stress contributes to CD pathogenesis, but systemic biomarkers for oxidative stress in CD are not yet identified. A reduction in free thiol groups in plasma proteins ("plasma free thiols") reflects systemic oxidative stress since they are prime substrates for reactive oxygen species. Here, we determined the concentrations of plasma free thiols in CD patients and healthy controls and studied the putative correlation with disease parameters. Free thiols were quantified in plasma of patients with CD in clinical remission [according to the Harvey Bradshaw Index (HBI)] and healthy controls and adjusted for plasma albumin. Albumin-adjusted free thiol concentrations were analyzed for associations with clinical and biochemical disease markers. Mean plasma free thiol concentrations were significantly lower in patients with CD ( = 51) compared to healthy controls ( = 27) (14.7 ± 2.4 vs. 17.9 ± 1.8 μmol/g albumin; < 0.001). Patients with CD with above-average free thiols had significantly lower CRP levels (median 1.4 [interquartile range] [0.4; 2.6] vs. 3.6 [0.6; 7.0] mg/L; < 0.05) and BMI (23.6 ± 4.8 vs. 27.1 ± 5.2 kg/m; < 0.05). Patients with CD having solely colonic disease demonstrated markedly reduced plasma free thiol concentrations compared to patients with ileocolonic involvement (13.2 ± 1.8 vs. 15.2 ± 2.2 μmol/g; < 0.05). Finally, plasma free thiol concentrations negatively correlated with biomarkers of inflammation, including hsCRP, SAA, IL-17A (all < 0.05), and VEGF. Plasma free thiols are reduced in patients with CD in clinical remission compared to healthy controls. Thus, subclinical CD disease activity is reflected by systemic oxidative stress and plasma free thiols may be a relevant therapeutic target and biomarker to monitor disease activity in CD.
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http://dx.doi.org/10.3389/fphys.2019.00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497730PMC
April 2019

Plasma ADMA, urinary ADMA excretion, and late mortality in renal transplant recipients.

Amino Acids 2019 Jun 26;51(6):913-927. Epub 2019 Mar 26.

Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Sector A, University of Groningen, PO Box 30.001, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Cardiovascular disease (CVD) is the leading cause of death in renal transplant recipients (RTR). Elevated plasma asymmetric dimethylarginine (pADMA), an endogenous nitric oxide synthase inhibitor produced from the turnover of methylated arginine moieties in proteins, is a risk factor for CVD and mortality. It is unknown how urinary ADMA excretion (uADMA), one of the main ADMA elimination routes, is associated with long-term survival. Furthermore, the association of pADMA and uADMA with markers for turnover of arginine-methylated proteins is unknown. We analyzed ADMA using a validated GC-MS/MS method in plasma and 24-h urine samples of 685 RTR, included ≥ 1 year after transplantation. We also analyzed urine symmetric dimethylarginine (uSDMA) using the same method. Urinary creatinine and urea excretions were used as markers for turnover of muscle protein and amino acids, respectively. We applied Cox regression analyses to study associations of pADMA, uADMA, and uSDMA with all-cause and CVD mortality. Mean pADMA was 0.61 ± 0.12 µM, uADMA was 31 ± 13 µmol/24 h, and uSDMA was 52 ± 19 µmol/24 h. Over median follow-up of 5.4 [4.9-6.1] years, 147 RTR died, of which 58 (39%) from CVD. High pADMA was associated with high all-cause mortality (HR per SD [95% CI]: 1.45 [1.26-1.67], P < 0.001), while high uADMA was associated with low all-cause and CVD mortality (HR per SD [95% CI]: 0.57 [0.47-0.69], P < 0.001, and 0.55 [0.40-0.74], P < 0.001, respectively). The associations were independent of adjustment for potential confounders. Creatinine excretion was associated with both pADMA (st. β:- 0.21, P = 0.003) and uADMA (st. β: 0.49, P < 0.001), and urea excretion was associated with uADMA (st. β: 0.56, P < 0.001). Associations of uSDMA with outcomes and with creatinine excretion and urea excretion were comparable to those of uADMA. The associations of pADMA, uADMA and uSDMA with mortality were strongly affected by adjustment for creatinine excretion and urea excretion. We found for the first time that high uADMA and high uSDMA are associated with less risk of all-cause and CVD mortality. The links of uADMA and uSDMA with markers of muscle protein and amino acid turnover may serve to further understand ADMA and SDMA homeostasis and their clinical implications.
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http://dx.doi.org/10.1007/s00726-019-02725-2DOI Listing
June 2019

Muscle mass determined from urinary creatinine excretion rate, and muscle performance in renal transplant recipients.

J Cachexia Sarcopenia Muscle 2019 06 25;10(3):621-629. Epub 2019 Mar 25.

Department of Internal Medicine, University of Groningen, Groningen, The Netherlands.

Background: Muscle mass, as determined from 24-h urinary creatinine excretion rate (CER), is an independent predictor for mortality and graft failure in renal transplant recipients (RTR). It is currently unknown whether CER is comparable with healthy controls after transplantation and whether it reflects muscle performance besides muscle mass. We aimed to compare urinary CER and muscle performance between RTR and healthy controls and to investigate whether urinary CER is associated with muscle performance in RTR.

Methods: We included RTR, transplanted between 1975 and 2016 in the University Medical Center Groningen. Healthy controls were subjects screened for kidney donation. CER was calculated from a 24-h urine collection. Muscle performance was assessed by handgrip strength, sit-to-stand test, and 2-min walk test. Statistical analyses were performed using linear regression analyses.

Results: We included 184 RTR (mean age 56.9 ± 11.9 years, 54% male recipient) and 78 healthy controls (age 57.9 ± 9.9, 47% male recipient). RTR were at a median time of 4.0 (1.1-8.8) years after transplantation. Mean CER was lower in RTR compared to healthy controls (11.7 ± 4.0 vs. 13.1 ± 5.2 mmol/24 h; P = 0.04). Significantly poorer results in muscle performance were found in RTR compared to controls for the handgrip strength (30.5 [23.7-41.1] N vs. 38.3 [29.3-46.0] N, P < 0.001) and the 2-min walk test (151.5 ± 49.2 m vs. 172.3 ± 12.2 m, P < 0.001) but not for the sit-to-stand (12.2 ± 3.3 m vs. 11.9 ± 2.8 m, P = 0.46). In RTR, CER was significantly associated with handgrip strength (std. β 0.33; P < 0.001), independent of adjustment for potential confounders. In RTR, CER was neither associated with the time used for the sit-to-stand test (std. β -0.09; P = 0.27) nor with the distance covered during the 2-min walk test (std. β 0.07; P = 0.40).

Conclusions: Muscle mass as measured by CER in RTR is lower compared to controls. CER is positively associated with muscle performance in RTR. The results demonstrate that CER does not only reflect muscle mass but also muscle performance in this patient setting. Determination of CER could be an interesting addition to the imaging technique armamentarium available and applied for evaluation of muscle mass in clinical intervention studies and observational studies.
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http://dx.doi.org/10.1002/jcsm.12399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596455PMC
June 2019

Dermal tissue remodeling and non-osmotic sodium storage in kidney patients.

J Transl Med 2019 03 18;17(1):88. Epub 2019 Mar 18.

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

Background: Excess dietary sodium is not only excreted by the kidneys, but can also be stored by non-osmotic binding with glycosaminoglycans in dermal connective tissue. Such storage has been associated with dermal inflammation and lymphangiogenesis. We aim to investigate if skin storage of sodium is increased in kidney patients and if this storage is associated with clinical parameters of sodium homeostasis and dermal tissue remodeling.

Methods: Abdominal skin tissue of 12 kidney patients (5 on hemodialysis) and 12 healthy kidney donors was obtained during surgery. Skin biopsies were processed for dermal sodium measurement by atomic absorption spectroscopy, and evaluated for CD macrophages, CD T-cells, collagen I, podoplanin + lymph vessels, and glycosaminoglycans by qRT-PCR and immunohistochemistry.

Results: Dermal sodium content of kidney patients did not differ from healthy individuals, but was inversely associated with plasma sodium values (p < 0.05). Compared to controls, kidney patients showed dermal tissue remodeling by increased CD macrophages, CD T-cells and Collagen I expression (all p < 0.05). Also, both N- and O-sulfation of heparan sulfate glycosaminoglycans were increased (all p < 0.05), most outspoken in hemodialysis patients. Plasma and urinary sodium associates with dermal lymph vessel number (both p < 0.05), whereas loss of eGFR, proteinuria and high systolic blood pressure associated with dermal macrophage density (all p < 0.05).

Conclusion: Kidney patients did not show increased skin sodium storage compared to healthy individuals. Results do indicate that kidney failure associates with dermal inflammation, whereas increased sodium excretion and plasma sodium associate with dermal lymph vessel formation and loss of dermal sodium storage capacity. Trial registration The cohort is registered at clinicaltrials.gov as NCT (September 6, 2017). NCT, NCT03272841. Registered 6 September 2017-Retrospectively registered, https://clinicaltrials.gov.
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http://dx.doi.org/10.1186/s12967-019-1815-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421653PMC
March 2019

Effect of renal function on homeostasis of asymmetric dimethylarginine (ADMA): studies in donors and recipients of renal transplants.

Amino Acids 2019 Mar 4;51(3):565-575. Epub 2019 Jan 4.

Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Sector A, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Asymmetric dimethylarginine (ADMA) is a methylated form of arginine and an endogenous nitric oxide synthase inhibitor. Renal function decline is associated with increase of plasma ADMA in chronic kidney disease populations. It is yet unknown how isolated renal function impairment affects ADMA homeostasis in healthy humans. Here, we measured plasma concentrations and urinary excretion of ADMA using GC-MS/MS in 130 living kidney donors before and at 1.6 (1.6-1.9) months after donation. We additionally analyzed 201 stable renal transplant recipients (RTR) that were included > 1 year after transplantation, as a model for kidney disease in the context of single kidney state. We measured true glomerular filtration rate (mGFR) using I-iothalamate. To study enzymatic metabolism of ADMA, we also measured L-citrulline as primary metabolite. Mean age was 52 ± 10 years in donors and 54 ± 12 years in RTR. Renal function was significantly reduced from pre- to post-donation (mGFR: 104 ± 17 vs. 66 ± 10 ml/min per 1.73 m BSA, - 36 ± 7%, P < 0.001). Urinary ADMA excretion strongly and significantly decreased from pre- to post-donation (60.6 ± 16.0 vs. 40.5 ± 11.5 µmol/24 h, - 31.5 ± 21.5%, P < 0.001), while plasma ADMA increased only slightly (0.53 ± 0.08 vs. 0.58 ± 0.09 µM, 11.1 ± 20.1%, P < 0.001). Compared to donors post-donation, RTR had significantly worse renal function (mGFR: 49 ± 18 ml/min/1.73 m, - 25 ± 2%, P < 0.001) and lower urinary ADMA excretion (30.9 ± 12.4 µmol/24 h, - 23.9 ± 3.4%, P < 0.001). Plasma ADMA in RTR (0.60 ± 0.11 µM) did not significantly differ from donors post-donation (2.9 ± 1.9%, P = 0.13). Plasma citrulline was inversely associated with mGFR (st. β: - 0.23, P < 0.001), consistent with increased ADMA metabolism to citrulline with lower GFR. In both groups, the response of urinary ADMA excretion to renal function loss was much larger than that of plasma ADMA. As citrulline was associated with GFR, our data indicate that with renal function impairment, a decrease in urinary ADMA excretion does not lead to a corresponding increase in plasma ADMA, likely due to enhanced metabolism, thus allowing for lower renal excretion of ADMA.
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http://dx.doi.org/10.1007/s00726-018-02693-zDOI Listing
March 2019

Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients.

BMJ Open 2018 12 31;8(12):e024502. Epub 2018 Dec 31.

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

Introduction: In the past decades, short-term results after solid organ transplantation have markedly improved. Disappointingly, this has not been accompanied by parallel improvements in long-term outcomes after transplantation. To improve graft and recipient outcomes, identification of potentially modifiable risk factors and development of biomarkers are required. We provide the rationale and design of a large prospective cohort study of solid organ transplant recipients (TransplantLines).

Methods And Analysis: TransplantLines is designed as a single-centre, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. Data will be collected from transplant candidates before transplantation, during transplantation, at 3 months, 6 months, 1 year, 2 years and 5 years, and subsequently every 5 years after transplantation. Data from living organ donors will be collected before donation, during donation, at 3 months, 1 year and 5 years after donation, and subsequently every 5 years. The primary outcomes are mortality and graft failure. The secondary outcomes will be cause-specific mortality, cause-specific graft failure and rejection. The tertiary outcomes will be other health problems, including diabetes, obesity, hypertension, hypercholesterolaemia and cardiovascular disease, and disturbances that relate to quality of life, that is, physical and psychological functioning, including quality of sleep, and neurological problems such as tremor and polyneuropathy.

Ethics And Dissemination: Ethical approval has been obtained from the relevant local ethics committee. The TransplantLines cohort study is designed to deliver pioneering insights into transplantation and donation outcomes. The study design allows comprehensive data collection on perioperative care, nutrition, social and psychological functioning, and biochemical parameters. This may provide a rationale for future intervention strategies to more individualised, patient-centred transplant care and individualisation of treatment.

Trial Registration Number: NCT03272841.
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http://dx.doi.org/10.1136/bmjopen-2018-024502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318532PMC
December 2018

Kidney Function Reserve Capacity in Early and Later Stage Autosomal Dominant Polycystic Kidney Disease.

Clin J Am Soc Nephrol 2018 11 25;13(11):1680-1692. Epub 2018 Sep 25.

Departments of Nephrology and

Background And Objectives: It is assumed that in autosomal dominant polycystic kidney disease (ADPKD), kidney function remains in the normal range for several decades because of hyperfiltration of remnant nephrons. In this study, we investigate the extent to which patients with ADPKD hyperfilter.

Design, Setting, Participants, & Measurements: In this cross-sectional study, we measured GFR as urinary clearance using continuous infusion of I-iothalamate. Kidney function reserve capacity was determined as increase in measured GFR after adding a dopamine infusion of 4.4-6 mg/h. Potential kidney donors were used as healthy controls and matched by age and sex to patients with ADPKD for comparisons across age groups and CKD stages. Hyperfiltration was defined by a loss of kidney function reserve capacity compared with healthy controls.

Results: A total of 300 participants were studied. In the youngest age group (18-29 years), measured GFR was not different between patients with ADPKD and healthy controls (103±21 versus 111±9 ml/min per 1.73 m; =0.14). In this age group kidney function reserve capacity was higher compared with healthy controls (11.1%±8.3% versus 5.3%±6.5%; =0.04). Moreover, kidney function reserve capacity was similar to healthy controls in patients with ADPKD with early-stage disease (eGFR≥60 ml/min per 1.73 m), either overall or when divided into fast or slow progressors according to their Mayo height-adjusted total kidney volume class. However, in patients with ADPKD, lower measured GFR was associated with lower kidney function reserve capacity (=1.0 [95% confidence interval, 0.5 to 1.5] % per 10 ml/min per 1.73 m; <0.001). Kidney function reserve capacity was therefore lower compared with healthy controls at older age and later CKD stages.

Conclusions: Patients with early-stage ADPKD, either classified as having rapidly or slowly progressive disease, are able to increase their GFR in response to dopamine. Hyperfiltration, defined by a loss of kidney function reserve capacity, may therefore not be an early phenomenon in ADPKD.
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http://dx.doi.org/10.2215/CJN.03650318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237049PMC
November 2018

Renal functional reserve capacity before and after living kidney donation.

Am J Physiol Renal Physiol 2018 12 8;315(6):F1550-F1554. Epub 2018 Aug 8.

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

Compensatory gomerular filtration rate (GFR) increase after kidney donation results in a GFR above 50% of the predonation value. The renal functional reserve (RFR) assessed by the renal response to dopamine infusion (RFR) is considered to reflect functional reserve capacity and is thought to be a tool for living donor screening. However, it is unknown if the RFR predicts long-term kidney function. Between 1984 and 2017, we prospectively measured GFR (I-iothalamate) and RFR by dopamine infusion in 937 living kidney donors. We performed linear regression analysis of predonation RFR and postdonation GFR. In donors with 5-yr follow-up after donation we assessed the association with long-term GFR. Mean donor age was 52  yr (SD 11); 52% were female. Mean predonation GFR was 114  ml/min (SD 22), GFR was 124 ml/min (SD 24), resulting in an RFR of 9 ml/min (SD 10). Three months postdonation, GFR was 72 ml/min (SD 15) and GFR was 75 ml/min (SD 15), indicating that donors still had RFR [3 ml/min (SD 6), P < 0.001]. Predonation RFR was not associated with predonation GFR [standardized (st.) β -0.009, P = 0.77] but was positively associated with GFR 3 mo after donation (st. β 0.12, P < 0.001). In the subgroup of donors with 5-yr follow-up data ( n = 383), RFR was not associated with GFR at 5 yr postdonation (st. β 0.05, P = 0.35). In conclusion, RFR is a predictor of short-term GFR after living kidney donation but not of long-term kidney function. Therefore, measurement of the RFR is not a useful tool for donor screening. Studies investigating long-term renal adaptation are warranted to study the effects of living kidney donation and improve donor screening.
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http://dx.doi.org/10.1152/ajprenal.00064.2018DOI Listing
December 2018

Estimated glomerular filtration rate for longitudinal follow-up of living kidney donors.

Nephrol Dial Transplant 2018 06;33(6):1054-1064

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

Background: Living kidney donor safety requires reliable long-term follow-up of renal function after donation. The current study aimed to define the precision and accuracy of post-donation estimated glomerular filtration rate (eGFR) slopes compared with measured GFR (mGFR) slopes.

Methods: In 349 donors (age 51 ± 10, 54% female), we analysed eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault/body surface area (CG/BSA), creatinine clearance (CrCl) and mGFR (125I-iothalamate) changes from 3 months until 5 years post-donation.

Results: Donors had a pre-donation mGFR of 116 ± 23 mL/min, at 3 months post-donation mGFR was 73  ± 14 mL/min and at 5 years it was 79 ± 16 mL/min. Between 3 months and 5 years post-donation, 28% of donors had a declining mGFR (-0.82 ± 0.79 mL/min/year), 47% were stable and 25% had an increasing mGFR. Overall, eGFR equations showed good slope estimates (bias eGFRCKD-EPI 0.13 ± 2.16 mL/min/year, eGFRMDRD 0.19 ± 2.10 mL/min/year, eGFRCG/BSA -0.08 ± 2.06 mL/min/year, CrCl -0.12 ± 4.75 mL/min/year), but in donors with a decreasing mGFR the slope was underestimated (bias eGFRCKD-EPI 1.41 ± 2.03 mL/min/year, eGFRMDRD 1.51 ± 1.96 mL/min/year, eGFRCG/BSA 1.20 ± 1.87 mL/min/year). The CrCl had a high imprecision [bias interquartile range -1.51-3.41 mL/min/year].

Conclusions: All eGFR equations underestimated GFR slopes in donors with a declining GFR between 3 months and 5 years post-donation. This study underlines the value of mGFR in the follow-up of donors with risk of progressive GFR loss.
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http://dx.doi.org/10.1093/ndt/gfx370DOI Listing
June 2018

Overweight young female kidney donors have low renal functional reserve postdonation.

Am J Physiol Renal Physiol 2018 09 3;315(3):F454-F459. Epub 2018 Jan 3.

Department of Obstetrics and Gynecology, Division of Women and Baby, University Medical Center Utrecht , Utrecht , The Netherlands.

Maintenance of adequate renal function after living kidney donation is important for donor outcome. Overweight donors, in particular, may have an increased risk for end-stage kidney disease (ESKD), and young female donors have an increased preeclampsia risk. Both of these risks may be associated with low postdonation renal functional reserve (RFR). Because we previously found that higher body mass index (BMI) was associated with lower postdonation RFR, we now studied the relationship between BMI and RFR in young female donors. RFR, the rise in glomerular filtration rate (GFR) (I-iothalamate clearance) during dopamine, was measured in female donors (<45 yr) before and after kidney donation. Donors who are overweight (BMI >25) and nonoverweight donors were compared by Student's t-test; the association was subsequently explored with regression analysis. We included 105 female donors [age 41 (36-44) median(IQR)] with a BMI of 25 (22-27) kg/m. Predonation GFR was 118 (17) ml/min [mean(SD)] rising to 128 (19) ml/min during dopamine; mean RFR was 10 (10) ml/min. Postdonation GFR was 76 (13) ml/min, rising to 80 (12); RFR was 4 (6) ml/min ( P < 0.001 vs. predonation). In overweight donors, RFR was fully lost after donation (1 ml/min vs. 10 ml/min predonation, P < 0.001), and BMI was inversely associated with RFR after donation, independent of confounders (standardized β 0.37, P = 0.02). Reduced RFR might associate with the risk of preeclampsia and ESKD in kidney donors. Prospective studies should explore whether RFR is related to preeclampsia and whether BMI reduction before conception is of benefit to overweight female kidney donors during and after pregnancy.
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http://dx.doi.org/10.1152/ajprenal.00492.2017DOI Listing
September 2018

BMI and short-term outcomes in living kidney donors: Where surgery and nephrology meet: High BMI and male sex as risk factor for increased short-term renal impairment in living kidney donors - Retrospective analysis of 289 consecutive cases.

Int J Surg 2017 12 7;48:313-314. Epub 2017 Oct 7.

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

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http://dx.doi.org/10.1016/j.ijsu.2017.10.005DOI Listing
December 2017
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