Junglee Phd Thesis 2015.Pdf

Bangor University DOCTOR OF PHILOSOPHY Physical activity, kidney function and kidney injury Junglee, Naushad Ali Award date: 2015 Awarding institution: Bangor University Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 PHYSICAL ACTIVITY, KIDNEY FUNCTION AND KIDNEY INJURY Dr Naushad Ali Junglee PhD supervisors Dr Jamie Macdonald, Dr Mahdi Jibani and Professor Andy Lemmey Submitted in fulfilment of the requirements for the degree of PhD School of Sport, Health and Exercise Sciences Bangor University November 2015 SUMMARY OF FINDINGS This PhD sought to exploit the acute effects of exercise upon the kidneys to make tenable links to pathological states such as acute kidney injury (AKI) and chronic kidney disease (CKD). It is surprising that such associations with their potential clinical implications have received limited attention so far despite the ever-increasing number of healthy individuals participating in vigorous and physiologically challenging activities. The work herein has shown how experimental in-vivo exercise models may be used to simulate a “stressed” kidney with features that resemble diseased states. Summarising the key findings briefly, the first study (chapter 2) demonstrated that maximal-intensity exercise in the form of an 800 metre sprint resulted in increased urinary concentrations of an AKI biomarker (neutrophil gelatinase-associated lipocalin / NGAL), suggesting mild kidney stress or a concentrating effect. However, plasma NGAL concentrations decreased and urinary rises were independent of post-exercise proteinuria. There was also an inverse relationship between urinary volume and urinary NGAL concentrations – an observation that is also seen in oliguric AKI. The systematic review in the second study (chapter 3) found promise in post-exercise proteinuria as a predictor for CKD progression. Five studies (N = 351) that met inclusion criteria, examined prospective cohorts of Type I diabetics who were at risk of CKD. Through combining the results of the primary outcome in four studies (N = 318), the presence of post- exercise proteinuria was highly associated with elevated resting proteinuria at follow-up (χ2 test, P < 0.0001) and significant odds ratios (developing CKD following a positive exercise test vs. not developing CKD) were noted in each of these four studies (OR 2.3-52.0). However, there was great variability and questionable validity in the interventions that did not permit meta-analysis. It was evident that exercise interventions need to be refined and standardised before applying to other at-risk CKD populations. In the third study (chapter 4), it was demonstrated that a prior bout of muscle-damaging exercise established a pro-inflammatory state with elevated plasma interleukin-6 (IL-6) concentrations, and that with subsequent endurance-based exercise in the heat there was increased kidney stress as measured by increased urinary NGAL and plasma creatinine concentrations. The latter elevations met clincial criteria for AKI. Also, plasma IL-6 and plasma NGAL concentrations were positively correlated. II Lastly, the final study (chapter 5) extended the findings of chapter 4 by isolating the role of pro-inflammatory IL-6 in AKI. Through infusion of recombinant IL-6 in healthy males to concentrations above 100 pg/ml, elevations in plasma NGAL concentrations were shown but not to AKI ranges. In addition, there were no changes to plasma concentrations of other AKI biomarkers such as creatinine or cystatin C. Overall, this suggests that IL-6 is able to modulate NGAL but is not responsible per se for AKI or kidney dysfunction. Thus, it is likely that additional physiological aberrations are needed. III This work has been published and presented in the following peer-reviewed journals and international conferences: Chapter 2 Junglee NA, Lemmey AB, Burton M, Searell C, Jones D, Lawley JS, Jibani MM, Macdonald JH (2012). Does proteinuria-inducing physical activity increase biomarkers of acute kidney injury? Kidney Blood Press Res 36, 278-289. Junglee NA, Lemmey AB, Burton M, Searell C, Jones D, Lawley JS, Jibani MM, Macdonald JH The response of neutrophil gelatinase-associated lipocalin to proteinuria-inducing physical activity: an observational prospective cohort study. Poster presentation at British Renal Society 2012 conference, Manchester, UK. Chapter 3 Junglee NA, Jibani MM, Lemmey AB, Macdonald JH. Can exercise-induced proteinuria predict the onset or progression of chronic kidney disease? A systematic review. Poster presentation at the American Society of Nephrology Kidney Week 2015, San Diego, USA. Chapter 4 Junglee NA, Di Felice U, Dolci A Fortes MB, Jibani MM, Lemmey AB, Walsh NP, Macdonald JH (2013). Exercising in a hot environment with muscle damage: effects on acute kidney injury biomarkers and kidney function. Am J Physiol Renal Physiol 305, F813-820. Fortes MB, Di Felice U, Dolci A, Junglee NA, Crockford MJ, West L, Hillier-Smith R, Macdonald JH, Walsh NP (2013). Muscle-damaging exercise increases heat strain during subsequent exercise heat stress. Med Sci Sports Exerc 45, 1915-1924. IV Fortes MB, Di Felice U, Dolci A, Junglee NA, Crockford MJ, West L, Hillier-Smith R, Macdonald JH, Walsh NP. Exercising in a hot environment with muscle damage: effects on acute kidney injury biomarkers and kidney function. Oral abstract presentation (AKI clinical studies I) at the American Society of Nephrology 2012 Kidney Week, San Diego, USA. Chapter 5 Junglee NA, Searell CR, Jibani MM, Macdonald JH (2014). Experimental acute kidney injury. Nephrol Dial Transplant 29, iii90-iii101 [abstract]. Junglee NA, Searell CR, Jibani MM, Macdonald JH. Infusion of recombinant IL-6 in healthy humans elevated plasma NGAL concentrations without a reduction in renal function. Poster presentation at the 51st European Renal Association congress 2014, Amsterdam, Netherlands. V LIST OF CONTENTS Index…………...…………………….…………………………..……...…...………...VII-X List of tables ……………..…………..……………………………..………….….…XI-XIII List of figures..…………………….………………..…………………….....……XIV-XXII Commonly used abbreviations…….…………………………………..………............XXIII Acknowledgements………….…….…………………………………..….…..…….....XXIV Authors declarations and consent ..……………….………………………….…XXV-XXIX Format of PhD thesis…………….……………………………………………………..XXX VI INDEX CHAPTER 1 GENERAL INTRODUCTION 1.1. Physiological changes to kidney function during exercise 1.1.1. Kidney blood flow 3-5 1.1.2. Glomerular filtration rate 6-9 1.1.3. Urine production 9-10 1.1.4. Post-exercise proteinuria 10-15 1.1.5. Post-exercise haematuria 15-18 1.1.6. Urinary sediments 18 1.1.7. Electrolyte metabolism 18-19 1.2. Examining the boundary between physiological stress and pathological states of organs during strenuous physical exertion 1.2.1. Endurance exercise and troponin elevation 20-21 1.2.2. Mechanisms of troponin release during endurance exercise 21-22 1.2.3. Endurance exercise and cardiac imaging 22-23 1.3. Acute kidney injury (AKI) 1.3.1. Development of AKI definition 24-25 1.3.2. Traditional biomarkers of AKI 25-26 1.3.3. Novel biomarkers of AKI 26-27 1.4. Does AKI occur during strenuous physical activity? 1.4.1. Exertional rhabdomyolysis. 1.4.1.1. Definition 29 1.4.1.2. Incidence 29-30 1.4.1.3. Pathophysiology 30 1.4.1.4. Diagnosis 30-33 1.4.1.5. Treatment and prognosis of AKI in exertional rhabomyolysis 33 1.4.2. Exertional Heat Stroke 1.4.2.1. Definition 33-34 1.4.2.2. Incidence 34 1.4.2.3. Pathophysiology 34-36 1.4.2.4. Diagnosis 36-37 VII 1.4.2.5. Treatment and prognosis 37-38 1.4.3. Acute Renal Failure with Severe Loin Pain and Patchy Renal Ischaemia after Anaerobic Exercise 1.4.3.1. Definition 38 1.4.3.2. Incidence 38 1.4.3.3. Pathophysiology 38 1.4.3.4. Diagnosis 39 1.4.3.5. Treatment and prognosis 39 1.5. Aims of PhD study 40-41 CHAPTER 2 DOES PROTEINURIA-INDUCING PHYSICAL ACTIVITY INCREASE BIOMARKERS OF ACUTE KIDNEY INJURY? 2.1. Abstract 43 2.2. Introduction 44-45 2.3. Materials and methods 46-49 2.4. Results 50-56 2.5. Discussion 57-60 CHAPTER 3 CAN EXERCISE-INDUCED PROTEINURIA PREDICT THE ONSET OR PROGRESSION OF CHRONIC KIDNEY DISEASE? A SYSTEMATIC REVIEW. 3.1. Abstract 62 3.2. Introduction 63-64 3.3. Materials and methods 65-69 3.4. Results 70-78 3.5. Discussion 79-82 CHAPTER 4 EXERCISING IN A HOT ENVIRONMENT WITH MUSCLE DAMAGE: EFFECT ON ACUTE INJURY BIOMARKERS AND KIDNEY FUNCTION 4.1. Abstract 84 4.2. Introduction 85-86 4.3. Materials and methods 87-92 VIII 4.4. Results 93-99 4.5. Discussion 100-103 CHAPTER 5 INFUSION OF RECOMBINANT IL-6 IN HEALTHY HUMANS ELEVATES PLASMA NGAL CONCENTRATIONS WITHOUT A REDUCTION IN RENAL FUNCTION. 5.1. Abstract 105 5.2. Introduction 106-107 5.3. Materials and methods 108-110 5.4. Results 111-114 5.5. Discussion 115-118 CHAPTER 6 SUMMARY OF STUDIES, GENERAL DISCUSSION AND FUTURE DIRECTIONS 6.1. Summary of studies 120 6.2. Finding common ground – linking study finding together 6.2.1. Use of novel kidney injury biomarkers in other studies of physical activity 121 6.2.2. Measurement of AKI biomarkers in urine 122 6.2.3. Normalisation against urinary creatinine 122-123 6.2.4.

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