Trajectories of Uremic Symptom Severity and Kidney Function in Patients with Chronic Kidney Disease

Kendra E Wulczyn, Sophia H Zhao, Eugene P Rhee, Sahir Kalim, Tariq Shafi, Kendra E Wulczyn, Sophia H Zhao, Eugene P Rhee, Sahir Kalim, Tariq Shafi

Abstract

Background and objectives: Uremic symptoms, including fatigue, anorexia, pruritus, nausea, paresthesia, and pain, are attributed to the accumulation of organic waste products normally cleared by the kidneys, but whether kidney function is the primary driver of changes in symptom severity over time is not known. The goal of our study was to evaluate the association between eGFR and uremic symptom severity score in patients with CKD.

Design, setting, participants, and measurements: We identified 3685 participants with CKD not on dialysis in the prospective, observational Chronic Renal Insufficiency Cohort (CRIC) Study with baseline assessment of eGFR and uremic symptom severity. Symptoms were assessed by separate questions on the Kidney Disease Quality of Life-36 instrument (zero- to 100-point scale). The longitudinal association between eGFR and uremic symptom severity score was examined with multivariable adjusted linear mixed-effects models with random intercepts and random slopes.

Results: The mean±SD eGFR at baseline was 44±15 ml/min per 1.73 m2, and participants had a median of six (interquartile range 3-11) simultaneous assessments of eGFR and uremic symptoms over the duration of follow-up. The most prevalent symptoms at baseline were pain (57%), fatigue (52%), paresthesia (45%), and pruritus (42%). In adjusted models, a decrease in eGFR of 5 ml/min per 1.73 m2 was associated with a worsening of the symptom severity score by two points or less for each uremic symptom (P<0.01; zero- to 100-point scale). The association between eGFR and uremic symptom severity score was nonlinear. When starting from a lower initial eGFR, a 5 ml/min per 1.73 m2 decrease in eGFR was associated with a greater magnitude of uremic symptom worsening.

Conclusions: The prevalence of uremic symptoms in CKD is high, with significant variability in patient symptom change over time. Declines in eGFR were associated with worsening of uremic symptom severity, but the magnitude of these changes is small and of uncertain clinical significance.

Keywords: chronic kidney disease; clinical epidemiology; depression; quality of life; uremia.

Copyright © 2022 by the American Society of Nephrology.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Severity of uremic symptoms at the baseline evaluation, stratified by baseline CKD stage. The severity of symptoms experienced by patients with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study was assessed in the preceeding 4 weeks by the Kidney Disease Quality of Life-36 instrument.
Figure 2.
Figure 2.
Longitudinal relationship of eGFR and uremic symptom severity score over a median of 7 years of follow-up in 3685 CRIC Study participants. (A) Fatigue. (B) Anorexia. (C) Pruritus. (D) Nausea. (E) Paresthesia. (F) Pain. (G) KDQOL symptom domain. Each point and associated confidence interval represent the average adjusted uremic symptom severity at a given eGFR. The line represents the slope of symptom change as eGFR decreases over time. Higher symptom scores represent greater symptom severity.

References

    1. Porter AC, Lash JP, Xie D, Pan Q, DeLuca J, Kanthety R, Kusek JW, Lora CM, Nessel L, Ricardo AC, Wright Nunes J, Fischer MJ; CRIC Study Investigators : Predictors and outcomes of health-related quality of life in adults with CKD. Clin J Am Soc Nephrol 11: 1154–1162, 2016
    1. Amro A, Waldum B, Dammen T, Miaskowski C, Os I: Symptom clusters in patients on dialysis and their association with quality-of-life outcomes. J Ren Care 40: 23–33, 2014
    1. Voskamp PWM, van Diepen M, Evans M, Caskey FJ, Torino C, Postorino M, Szymczak M, Klinger M, Wallquist C, van de Luijtgaarden MWM, Chesnaye NC, Wanner C, Jager KJ, Dekker FW: The impact of symptoms on health-related quality of life in elderly pre-dialysis patients: Effect and importance in the EQUAL study. Nephrol Dial Transplant 34: 1707–1715, 2019
    1. Davison SN, Levin A, Moss AH, Jha V, Brown EA, Brennan F, Murtagh FEM, Naicker S, Germain MJ, O’Donoghue DJ, Morton RL, Obrador GT; Kidney Disease: Improving Global Outcomes : Executive summary of the KDIGO Controversies Conference on Supportive Care in Chronic Kidney Disease: Developing a roadmap to improving quality care. Kidney Int 88: 447–459, 2015
    1. González AM, Gutman T, Lopez-Vargas P, Anumudu S, Arce CM, Craig JC, Dunn L, Eckardt KU, Harris T, Levey AS, Lightstone L, Scholes-Robertson N, Shen JI, Teixeira-Pinto A, Wheeler DC, White D, Wilkie M, Jadoul M, Winkelmayer WC, Tong A: Patient and caregiver priorities for outcomes in CKD: A multinational nominal group technique study. Am J Kidney Dis 76: 679–689, 2020
    1. Murphy EL, Murtagh FEM, Carey I, Sheerin NS: Understanding symptoms in patients with advanced chronic kidney disease managed without dialysis: Use of a short patient-completed assessment tool. Nephron Clin Pract 111: c74–c80, 2009
    1. Rocco MV, Gassman JJ, Wang S-R, Kaplan RM: Cross-sectional study of quality of life and symptoms in chronic renal disease patients: The modification of diet in renal disease study. Am J Kidney Dis 29: 888–896, 1997
    1. Hailpern SM, Melamed ML, Cohen HW, Hostetter TH: Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol 18: 2205–2213, 2007
    1. Shlipak MG, Lash JP, Yang W, Teal V, Keane M, Cappola T, Keller C, Jamerson K, Kusek J, Delafontaine P, He J, Miller ER 3rd, Schreiber M, Go AS; CRIC Investigators : Symptoms characteristic of heart failure among CKD patients without diagnosed heart failure. J Card Fail 17: 17–23, 2011
    1. Zhang X, Bansal N, Go AS, Hsu C-Y: Gastrointestinal symptoms, inflammation and hypoalbuminemia in chronic kidney disease patients: A cross-sectional study. BMC Nephrol 16: 211, 2015
    1. de Goeij MCM, Ocak G, Rotmans JI, Eijgenraam J-W, Dekker FW, Halbesma N: Course of symptoms and health-related quality of life during specialized pre-dialysis care. PLoS One 9: e93069, 2014
    1. Brown SA, Tyrer FC, Clarke AL, Lloyd-Davies LH, Stein AG, Tarrant C, Burton JO, Smith AC: Symptom burden in patients with chronic kidney disease not requiring renal replacement therapy. Clin Kidney J 10: 788–796, 2017
    1. Feldman HI, Appel LJ, Chertow GM, Cifelli D, Cizman B, Daugirdas J, Fink JC, Franklin-Becker ED, Go AS, Hamm LL, He J, Hostetter T, Hsu CY, Jamerson K, Joffe M, Kusek JW, Landis JR, Lash JP, Miller ER, Mohler ER 3rd, Muntner P, Ojo AO, Rahman M, Townsend RR, Wright JT; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators : The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and methods. J Am Soc Nephrol 14: S148–S153, 2003
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) : A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
    1. Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB: Development of the kidney disease quality of life (KDQOL) instrument. Qual Life Res 3: 329–338, 1994
    1. Peipert JD, Bentler PM, Klicko K, Hays RD: Psychometric properties of the Kidney Disease Quality of Life 36-Item Short-Form Survey (KDQOL-36) in the United States. Am J Kidney Dis 71: 461–468, 2018
    1. Taylor K, Chu NM, Chen X, Shi Z, Rosello E, Kunwar S, Butz P, Norman SP, Crews DC, Greenberg KI, Mathur A, Segev DL, Shafi T, McAdams-DeMarco MA: Kidney disease symptoms before and after kidney transplantation. Clin J Am Soc Nephrol 16: 1083–1093, 2021
    1. Littell RC, Pendergast J, Natarajan R: Modelling covariance structure in the analysis of repeated measures data. Stat Med 19: 1793–1819, 2000
    1. Laird NM, Ware JH: Random-effects models for longitudinal data. Biometrics 38: 963–974, 1982
    1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3 1–150, 2013
    1. Akaike H: Proceeding of the Second International Symposium on Information Theory, Budapest, Akademiai Kiado, 1973, pp 267–281
    1. Edwards LJ, Muller KE, Wolfinger RD, Qaqish BF, Schabenberger O: An R2 statistic for fixed effects in the linear mixed model. Stat Med 27: 6137–6157, 2008
    1. Crowther MJ, Abrams KR, Lambert PC: Joint modeling of longitudinal and survival data. Stata J 13: 165–184, 2013
    1. Liu Q, Smith AR, Mariani LH, Nair V, Zee J: Methods for assessing longitudinal biomarkers of time-to-event outcomes in CKD: A simulation study. Clin J Am Soc Nephrol 14: 1315–1323, 2019
    1. Janmaat CJ, van Diepen M, Meuleman Y, Chesnaye NC, Drechsler C, Torino C, Wanner C, Postorino M, Szymczak M, Evans M, Caskey FJ, Jager KJ, Dekker FW; EQUAL Study Investigators : Kidney function and symptom development over time in elderly patients with advanced chronic kidney disease: Results of the EQUAL cohort study. Nephrol Dial Transplant 36: 862–870, 2021
    1. van de Luijtgaarden MWM, Caskey FJ, Wanner C, Chesnaye NC, Postorino M, Janmaat CJ, Rao A, Torino C, Klinger M, Drechsler C, Heimburger O, Szymczak M, Evans M, Dekker FW, Jager KJ; EQUAL study investigators : Uraemic symptom burden and clinical condition in women and men of ≥65 years of age with advanced chronic kidney disease: Results from the EQUAL study. Nephrol Dial Transplant 34: 1189–1196, 2019
    1. Sukul N, Speyer E, Tu C, Bieber BA, Li Y, Lopes AA, Asahi K, Mariani L, Laville M, Rayner HC, Stengel B, Robinson BM, Pisoni RL; CKDopps and CKD-REIN investigators : Pruritus and patient reported outcomes in non-dialysis CKD. Clin J Am Soc Nephrol 14: 673–681, 2019
    1. Rhee EP, Guallar E, Hwang S, Kim N, Tonelli M, Moe SM, Himmelfarb J, Thadhani RI, Powe NR, Shafi T: Prevalence and persistence of uremic symptoms in incident dialysis patients. Kidney360 1: 86–92, 2020
    1. Murtagh FEM, Addington-Hall J, Higginson IJ: The prevalence of symptoms in end-stage renal disease: A systematic review. Adv Chronic Kidney Dis 14: 82–99, 2007
    1. Meuleman Y, Chilcot J, Dekker FW, Halbesma N, van Dijk S: Health-related quality of life trajectories during predialysis care and associated illness perceptions. Health Psychol 36: 1083–1091, 2017
    1. Da Silva-Gane M, Wellsted D, Greenshields H, Norton S, Chandna SM, Farrington K: Quality of life and survival in patients with advanced kidney failure managed conservatively or by dialysis. Clin J Am Soc Nephrol 7: 2002–2009, 2012
    1. Grams ME, Surapaneni A, Appel LJ, Lash JP, Hsu J, Diamantidis CJ, Rosas SE, Fink JC, Scialla JJ, Sondheimer J, Hsu C, Cheung AK, Jaar BG, Navaneethan S, Cohen DL, Schrauben S, Xie D, Rao P, Feldman HI; CRIC Study Investigators : Clinical events and patient-reported outcome measures during CKD progression: Findings from the Chronic Renal Insufficiency Cohort Study. Nephrol Dial Transplant 36: 1685–1693, 2021
    1. Lockwood MB, Lash JP, Pauls H, Chung SY, Samra M, Ryan C, Park C, DeVon H, Bronas UG: Physical symptom cluster subgroups in chronic kidney disease. Nurs Res 69: 100–108, 2020
    1. Laville SM, Gras-Champel V, Moragny J, Metzger M, Jacquelinet C, Combe C, Fouque D, Laville M, Frimat L, Robinson BM, Stengel B, Massy ZA, Liabeuf S; Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) Study Group : Adverse drug reactions in patients with CKD. Clin J Am Soc Nephrol 15: 1090–1102, 2020
    1. McKillop G, Joy J: Patients’ experience and perceptions of polypharmacy in chronic kidney disease and its impact on adherent behaviour. J Ren Care 39: 200–207, 2013
    1. Meyer TW, Hostetter TH: Uremia. N Engl J Med 357: 1316–1325, 2007

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться