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      Metabolic Acidosis Is Associated With an Accelerated Decline of Allograft Function in Pediatric Kidney Transplantation

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          Abstract

          Introduction

          We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx).

          Methods

          This registry study collected data up to 10 years posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m 2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of serum bicarbonate concentration (HCO 3 ) < 22 mmol/l (metabolic acidosis) and HCO 3  < 18 mmol/l (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome.

          Results

          We report on 1911 patients, of whom 347 reached the composite end point. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.54–2.60) and severe metabolic acidosis (HR, 2.49; 95% CI, 1.56–3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR, 1.75; 95% CI, 1.32–2.31 and HR, 2.09; 95% CI, 1.23–3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio [OR] 0.93/yr older; 95% CI, 0.91–0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84–0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54–5.40)

          Conclusion

          The degree of metabolic acidosis is associated with allograft dysfunction.

          Graphical abstract

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          Most cited references29

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          Marginal Structural Models and Causal Inference in Epidemiology

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            New equations to estimate GFR in children with CKD.

            The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.
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              Constructing inverse probability weights for marginal structural models.

              The method of inverse probability weighting (henceforth, weighting) can be used to adjust for measured confounding and selection bias under the four assumptions of consistency, exchangeability, positivity, and no misspecification of the model used to estimate weights. In recent years, several published estimates of the effect of time-varying exposures have been based on weighted estimation of the parameters of marginal structural models because, unlike standard statistical methods, weighting can appropriately adjust for measured time-varying confounders affected by prior exposure. As an example, the authors describe the last three assumptions using the change in viral load due to initiation of antiretroviral therapy among 918 human immunodeficiency virus-infected US men and women followed for a median of 5.8 years between 1996 and 2005. The authors describe possible tradeoffs that an epidemiologist may encounter when attempting to make inferences. For instance, a tradeoff between bias and precision is illustrated as a function of the extent to which confounding is controlled. Weight truncation is presented as an informal and easily implemented method to deal with these tradeoffs. Inverse probability weighting provides a powerful methodological tool that may uncover causal effects of exposures that are otherwise obscured. However, as with all methods, diagnostics and sensitivity analyses are essential for proper use.
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                Author and article information

                Contributors
                Journal
                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                Elsevier
                2468-0249
                08 April 2024
                June 2024
                08 April 2024
                : 9
                : 6
                : 1684-1693
                Affiliations
                [1 ]Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Belgium
                [2 ]Renal Unit, UCL Great Ormond Street Hospital, London, UK
                [3 ]Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Belgium
                [4 ]Department of Pediatrics I, University Children’s Hospital Heidelberg, Germany
                [5 ]Department of Pediatric Nephrology and Rheumatology, CHU de Lyon, Bron, France
                [6 ]Pediatric Nephrology, Dialysis and Transplant Unit, Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women’s and Children’s Health, Padua University Hospital, Padua, Italy
                [7 ]Department of Nephrology, Kidney Transplantation and Arterial Hypertension, Children’s Memorial Health Institute, Warsaw, Poland
                [8 ]Division of Nephrology, Dialysis and Renal Transplant Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
                [9 ]Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
                [10 ]Department of Pedaitric Nephrology, Gazi University, Ankara, Turkey
                [11 ]Pediatric Nephrology, University Children‘s Hospital, Münster, Germany
                [12 ]Pediatric Nephrology Department, Ondokuz Mayis University, Samsun, Turkey
                [13 ]Department of Pediatric Nephrology and Transplantation, University Children’s Hospital, University Medical Center Hamburg/Eppendorf, Hamburg, Germany
                [14 ]Department of Pediatrics II, University Hospital of Essen, Essen, Germany
                [15 ]Royal Manchester Children’s Hospital, Manchester, UK
                Author notes
                [] Correspondence: Burkhard Tönshoff, Department of Pediatrics I, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Burkhard.Toenshoff@ 123456med.uni-heidelberg.de
                Article
                S2468-0249(24)01627-9
                10.1016/j.ekir.2024.04.007
                11184248
                38899185
                279557da-8aee-4a03-b1c2-b3c0d9180d37
                © 2024 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 5 February 2024
                : 26 March 2024
                : 1 April 2024
                Categories
                Clinical Research

                acidosis,pediatric,transplantation
                acidosis, pediatric, transplantation

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