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  1. Article ; Online: Cancer and mTOR Inhibitors in Transplant Recipients.

    de Fijter, Johan W

    Transplantation

    2017  Volume 101, Issue 1, Page(s) 45–55

    Abstract: Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/ ... ...

    Abstract Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma, and posttransplant lymphoproliferative disease have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated posttransplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors, such as Kaposi sarcoma and mantle cell lymphoma. Because mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. Nonmelanoma skin cancers, in particular cutaneous squamous cell carcinoma, have the highest standardized incidence ratios in transplant recipients. Recent meta-analyses and randomized trials on secondary prevention of squamous cell carcinoma observed a reduction in cumulative tumor load, suggesting most benefit to be gained by early conversion to an mTOR inhibitor-based maintenance regime. There is ongoing debate on the mechanisms involved including withdrawal of the carcinogenic effects of calcineurin inhibitors and/or their impact on chronic (oncogenic) viral infections. At present, there is, however, insufficient evidence for the primary use of mTORis as protective agents against most other cancer types.
    MeSH term(s) Animals ; Anticarcinogenic Agents/adverse effects ; Anticarcinogenic Agents/therapeutic use ; Calcineurin Inhibitors/adverse effects ; Drug Therapy, Combination ; Graft Rejection/enzymology ; Graft Rejection/immunology ; Graft Rejection/mortality ; Graft Rejection/prevention & control ; Graft Survival/drug effects ; Humans ; Immunocompromised Host ; Immunosuppressive Agents/adverse effects ; Immunosuppressive Agents/therapeutic use ; Neoplasms/immunology ; Neoplasms/mortality ; Neoplasms/prevention & control ; Neoplasms/virology ; Opportunistic Infections/immunology ; Opportunistic Infections/virology ; Organ Transplantation/adverse effects ; Organ Transplantation/mortality ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/therapeutic use ; Risk Factors ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; Treatment Outcome ; Tumor Virus Infections/immunology ; Tumor Virus Infections/virology
    Chemical Substances Anticarcinogenic Agents ; Calcineurin Inhibitors ; Immunosuppressive Agents ; Protein Kinase Inhibitors ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2017-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/TP.0000000000001447
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Recurrence of glomerulonephritis: an underestimated and unmet medical need.

    de Fijter, Johan W

    Kidney international

    2017  Volume 92, Issue 2, Page(s) 294–296

    Abstract: Recurrent glomerulonephritis is increasingly recognized as an important contributor to premature renal allograft failure. The incidence of recurrent glomerulonephritis varies widely depending on original disease, renal biopsy policy, and time of ... ...

    Abstract Recurrent glomerulonephritis is increasingly recognized as an important contributor to premature renal allograft failure. The incidence of recurrent glomerulonephritis varies widely depending on original disease, renal biopsy policy, and time of observation. Biopsy-documented clinical recurrence rates underestimate the true prevalence. The impact of recurrent glomerulonephritis on graft survival parameters also widely varies and requires large collaborative efforts with more detailed and balanced evaluations, such as other major causes for chronic renal allograft dysfunction.
    MeSH term(s) Glomerulonephritis/surgery ; Graft Survival ; Humans ; Kidney Transplantation ; Nephrectomy ; Recurrence
    Language English
    Publishing date 2017
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1016/j.kint.2017.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Transplanting the Elderly: Mandatory Age- and Minimal Histocompatibility Matching.

    Dreyer, Geertje J / de Fijter, Johan W

    Frontiers in immunology

    2020  Volume 11, Page(s) 359

    Abstract: Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, ... ...

    Abstract Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria (i.e., HLA-DR matching) followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia.
    MeSH term(s) Age Factors ; Aged ; Aged, 80 and over ; Cold Ischemia ; Graft Rejection ; HLA Antigens/immunology ; Histocompatibility Testing ; Humans ; Immunosuppressive Agents/therapeutic use ; Isoantibodies/blood ; Kidney Transplantation/adverse effects ; Kidney Transplantation/mortality ; Tissue and Organ Procurement
    Chemical Substances HLA Antigens ; Immunosuppressive Agents ; Isoantibodies
    Language English
    Publishing date 2020-03-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.00359
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Peripheral Blood Immune Cell Composition After Autologous MSC Infusion in Kidney Transplantation Recipients.

    Hendriks, Sanne H / Heidt, Sebastiaan / Schulz, Axel R / de Fijter, Johan W / Reinders, Marlies E J / Koning, Frits / van Kooten, Cees

    Transplant international : official journal of the European Society for Organ Transplantation

    2023  Volume 36, Page(s) 11329

    Abstract: Tacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion of mesenchymal stromal cells (MSC) 6 and 7 weeks post- ... ...

    Abstract Tacrolimus is the backbone of immunosuppressive agents to prevent transplant rejection. Paradoxically, tacrolimus is nephrotoxic, causing irreversible tubulointerstitial damage. Therefore, infusion of mesenchymal stromal cells (MSC) 6 and 7 weeks post-transplantation was assessed to facilitate withdrawal of tacrolimus in the randomized phase II TRITON trial. Here, we performed detailed analysis of the peripheral blood immune composition using mass cytometry to assess potential effects of MSC therapy on the immune system. We developed two metal-conjugated antibody panels containing 40 antibodies each. PBMC samples from 21 MSC-treated patients and 13 controls, obtained pre-transplant and at 24 and 52 weeks post-transplantation, were analyzed. In the MSC group at 24 weeks, 17 CD4
    MeSH term(s) Humans ; Tacrolimus ; Kidney Transplantation/methods ; Leukocytes, Mononuclear ; Immunosuppressive Agents/therapeutic use ; Graft Rejection ; Mesenchymal Stem Cells
    Chemical Substances Tacrolimus (WM0HAQ4WNM) ; Immunosuppressive Agents
    Language English
    Publishing date 2023-06-23
    Publishing country Switzerland
    Document type Clinical Trial, Phase II ; Randomized Controlled Trial ; Journal Article
    ZDB-ID 639435-8
    ISSN 1432-2277 ; 0934-0874
    ISSN (online) 1432-2277
    ISSN 0934-0874
    DOI 10.3389/ti.2023.11329
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Serum bile acids associate with liver volume in polycystic liver disease and decrease upon treatment with lanreotide.

    Dekker, Shosha E I / Bierau, Jörgen / Giera, Martin / Blomberg, Niek / Drenth, Joost P H / Mayboroda, Oleg A / de Fijter, Johan W / Soonawala, Darius

    European journal of clinical investigation

    2023  Volume 54, Issue 4, Page(s) e14147

    Abstract: Background: Polycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD ... ...

    Abstract Background: Polycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease.
    Methods: With liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care.
    Results: Baseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression.
    Conclusion: In ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume.
    MeSH term(s) Humans ; Polycystic Kidney, Autosomal Dominant/drug therapy ; Polycystic Kidney, Autosomal Dominant/complications ; Polycystic Kidney, Autosomal Dominant/pathology ; Liver/pathology ; Liver Diseases/drug therapy ; Liver Diseases/complications ; Somatostatin/therapeutic use ; Somatostatin/pharmacology ; Somatostatin/analogs & derivatives ; Bile Acids and Salts ; Cysts ; Peptides, Cyclic
    Chemical Substances lanreotide (0G3DE8943Y) ; Somatostatin (51110-01-1) ; Bile Acids and Salts ; Peptides, Cyclic
    Language English
    Publishing date 2023-12-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 186196-7
    ISSN 1365-2362 ; 0014-2972 ; 0960-135X
    ISSN (online) 1365-2362
    ISSN 0014-2972 ; 0960-135X
    DOI 10.1111/eci.14147
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Cell-free DNA measurement of three genomes after allogeneic MSC therapy in kidney transplant recipients indicates early cell death of infused MSC.

    Dreyer, Geertje J / Drabbels, Jos Jm / de Fijter, Johan W / van Kooten, Cees / Reinders, Marlies Ej / Heidt, Sebastiaan

    Frontiers in immunology

    2023  Volume 14, Page(s) 1240347

    Abstract: Introduction: Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is ... ...

    Abstract Introduction: Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death.
    Methods: In this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined.
    Results: We observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range.
    Discussion: Our results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy.
    MeSH term(s) Kidney Transplantation/adverse effects ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells ; Cell Death ; Hematopoietic Stem Cell Transplantation ; Cell-Free Nucleic Acids/genetics
    Chemical Substances Cell-Free Nucleic Acids
    Language English
    Publishing date 2023-11-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1240347
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients.

    Zhai, Qinglian / Moes, Dirk Jan A R / van Gelder, Teun / van der Lee, Maaike / Sanders, Jan-Stephan / Bemelman, Frederike J / de Fijter, Johan W / Klein, Kathrin / Schwab, Matthias / Swen, Jesse J

    Clinical and translational science

    2024  Volume 17, Issue 2, Page(s) e13729

    Abstract: CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded- ... ...

    Abstract CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.
    MeSH term(s) Male ; Humans ; Cyclosporine/pharmacokinetics ; Cytochrome P-450 CYP3A/genetics ; Immunosuppressive Agents/pharmacokinetics ; Transcription Factors/genetics ; Kidney Transplantation/adverse effects ; Prospective Studies ; Genotype ; Polymorphism, Single Nucleotide
    Chemical Substances Cyclosporine (83HN0GTJ6D) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Immunosuppressive Agents ; Transcription Factors ; CYP3A4 protein, human (EC 1.14.14.55)
    Language English
    Publishing date 2024-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.13729
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  8. Article ; Online: Hypertension and diabetes, but not leptin and adiponectin, mediate the relationship between body fat and chronic kidney disease.

    Lengton, Robin / Dekker, Friedo W / van Rossum, Elisabeth F C / de Fijter, Johan W / Rosendaal, Frits R / van Dijk, Ko Willems / Rabelink, Ton J / Le Cessie, Saskia / de Mutsert, Renée / Hoogeveen, Ellen K

    Endocrine

    2024  

    Abstract: Purpose: Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and ... ...

    Abstract Purpose: Obesity may promote kidney damage through hemodynamic and hormonal effects. We investigated the association between body mass index (BMI), total body fat (TBF) and chronic kidney disease (CKD) and whether hypertension, diabetes, leptin and adiponectin mediated these associations.
    Methods: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, 6671 participants (45-65 y) were included. We defined CKD as eGFR <60 ml/min/1.73 m
    Results: At baseline mean (SD) age was 56 (6), BMI 26.3 (4.4), 44% men, and 4% had CKD. Higher BMI and TBF were associated with 1.08 (95%CI 1.05; 1.11) and 1.05-fold (95%CI 1.02; 1.08) increased odds of CKD, respectively. As adiponectin was not associated with any of the outcomes, it was not studied further as a mediating factor. The association between BMI and CKD was 8.5% (95%CI 0.5; 16.5) mediated by diabetes and 22.3% (95%CI 7.5; 37.2) by hypertension. In addition, the association between TBF and CKD was 9.6% (95%CI -0.4; 19.6) mediated by diabetes and 22.4% (95%CI 4.2; 40.6) by hypertension. We could not confirm mediation by leptin in the association between BMI and CKD (35.6% [95%CI -18.8; 90.3]), nor between TBF and CKD (59.7% [95%CI -7.1; 126.6]).
    Conclusion: Our results suggest that the relations between BMI, TBF and CKD are in part mediated by diabetes and hypertension.
    Language English
    Publishing date 2024-04-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1194484-5
    ISSN 1559-0100 ; 1355-008X ; 0969-711X
    ISSN (online) 1559-0100
    ISSN 1355-008X ; 0969-711X
    DOI 10.1007/s12020-024-03811-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Multiplex LC-MS/MS Testing for Early Detection of Kidney Injury: A Next-Generation Alternative to Conventional Immunoassays?

    van Duijl, Tirsa T / Ruhaak, L Renee / van Kooten, Cees / de Fijter, Johan W / Cobbaert, Christa M

    The journal of applied laboratory medicine

    2022  Volume 7, Issue 4, Page(s) 923–930

    Abstract: Background: LC-MS/MS has enabled the translation of many novel biomarkers to the clinical laboratory, but its potential for measurement of urinary proteins is still unexplored. In this study we examined the correlation and agreement between immunoassay ... ...

    Abstract Background: LC-MS/MS has enabled the translation of many novel biomarkers to the clinical laboratory, but its potential for measurement of urinary proteins is still unexplored. In this study we examined the correlation and agreement between immunoassay and LC-MS/MS in the quantitation of kidney injury biomarkers and evaluated the application of technical LC-MS/MS meta-data assessment to ensure test result validity.
    Methods: NGAL, IGFBP7, TIMP2, and KIM-1 were quantified in 345 urine samples with one multiplex lab-developed test that combines immunocapture with mass spectrometry read-out and 4 singleplex sandwich-type immunoassays. Assay performance and imprecision were monitored by 2 urine-based quality controls. Ion ratios, signal intensity, and retention time were monitored over all study samples.
    Results: The LC-MS/MS retention time drift was ≤1.2%, ion ratios were within 20% of the target values at concentrations of >100 pmol/L, and peptides originating from the same protein were in agreement (slopes between 1.03 and 1.41). The interassay CV was between 9.3% and 19.1% for LC-MS/MS analysis and between 4.2% and 10.9% for immunoassay. Direct LC-MS/MS analysis was correlated with immunoassay in the quantitation of NGAL (r = 0.93; range: 0.01-37 nmol/L), IGFBP7 (r = 0.80; range: 0.01-2.6 nmol/L), TIMP2 (r = 0.85; range: 0.01-6.3 nmol/L), and KIM-1 (r = 0.70; range 0.01-0.4 nmol/L), but the analytical methodologies differed in measurands and calibration strategies.
    Conclusions: LC-MS/MS is explored as a next-generation technology for multiplex urinary protein measurement. It has great potential to overcome nonselectivity and lack of standardization because of its capability of directly measuring well-defined molecular proteins.
    MeSH term(s) Chromatography, Liquid/methods ; Humans ; Immunoassay/methods ; Kidney ; Lipocalin-2 ; Tandem Mass Spectrometry/methods
    Chemical Substances Lipocalin-2
    Language English
    Publishing date 2022-06-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2576-9456
    ISSN 2576-9456
    DOI 10.1093/jalm/jfac024
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  10. Article ; Online: Change in Urinary Myoinositol/Citrate Ratio Associates with Progressive Loss of Renal Function in ADPKD Patients.

    Dekker, Shosha E I / Verhoeven, Aswin / Frey, Daria / Soonawala, Darius / Peters, Dorien J M / Mayboroda, Oleg A / de Fijter, Johan W

    American journal of nephrology

    2022  Volume 53, Issue 6, Page(s) 470–480

    Abstract: Introduction: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers ... ...

    Abstract Introduction: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers all have their limitations. Metabolic profiling is a promising strategy for risk stratification. We determined the prognostic performance to identify patients with a fast progressive disease course and evaluated time-dependent changes in urinary metabolites.
    Methods: Targeted, quantitative metabolomics analysis (1H NMR-spectroscopy) was performed on spot urinary samples at two time points, baseline (n = 324, 61% female; mean age 45 years, SD 11; median eGFR 61 mL/min/1.73 m2, IQR 42-88; mean years of creatinine follow-up 3.7, SD 1.3) and a sample obtained after 3 years of follow-up (n = 112). Patients were stratified by their eGFR slope into fast and slow progressors based on an annualized change of > -3.0 or ≤ -3.0 mL/min/1.73 m2/year, respectively. Fifty-five urinary metabolites and ratios were quantified, and the significant ones were selected. Logistic regression was used to determine prognostic performance in identifying those with a fast progressive course using baseline urine samples. Repeated-measures ANOVA was used to analyze whether changes in urinary metabolites over a 3-year follow-up period differed between fast and slow progressors.
    Results: In a single urinary sample, the prognostic performance of urinary metabolites was comparable to that of a model including height-adjusted total kidney volume (htTKV, AUC = 0.67). Combined with htTKV, the predictive value of the metabolite model increased (AUC = 0.75). Longitudinal analyses showed an increase in the myoinositol/citrate ratio (p < 0.001) in fast progressors, while no significant change was found in those with slow progression, which is in-line with an overall increase in the myoinositol/citrate ratio as GFR declines.
    Conclusion: A metabolic profile, measured at a single time point, showed at least equivalent prognostic performance to an imaging-based risk marker in ADPKD. Changes in urinary metabolites over a 3-year follow-up period were associated with a fast progressive disease course.
    MeSH term(s) Citric Acid/metabolism ; Disease Progression ; Female ; Glomerular Filtration Rate ; Humans ; Inositol/metabolism ; Kidney ; Male ; Middle Aged ; Polycystic Kidney, Autosomal Dominant
    Chemical Substances Citric Acid (2968PHW8QP) ; Inositol (4L6452S749)
    Language English
    Publishing date 2022-05-25
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604540-6
    ISSN 1421-9670 ; 0250-8095
    ISSN (online) 1421-9670
    ISSN 0250-8095
    DOI 10.1159/000524851
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