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Title: Variability in creatinine and estimated glomerular filtration rate in diabetic nephropathy
Author: Nair, Sunil
ISNI:       0000 0004 6422 3377
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Introduction: Diabetic nephropathy is a leading cause of end stage renal disease (ESRD) in the world. Accurate screening and staging of chronic kidney disease (CKD) is essential for timely intervention as recommended by national and international guidelines (KDOQI, 2007, RCP, 2006) and to guide dose adjustment of several medicines. Glomerular filtration rate (GFR) is recognised as the best measure of kidney function in health and disease, but measuring it by gold standard techniques such as inulin clearance, and radio-isotopic methods is clinically impractical. Therefore estimation of GFR using serum creatinine and other variables like age, gender race and body size is recommended (Levey, 2003, Levey, 2006). The most widely used formula to estimate GFR is the 4-variable MDRD equation. Aims & Methods: My thesis contains studies of variation in serum creatinine, estimated glomerular filtration rate and urinary albumin creatinine ratio. There are two main experimental studies and three further studies based on data analyses and validation. 1. Effect of obesity on eGFR in type 2 diabetes: The aim was to estimate the bias between isotopic glomerular filtration rate (GFR) and eGFR in patients with Type 2 diabetes with chronic kidney disease and relate it to their body mass indices (BMI). GFR was measured using 51Cr EDTA method and was estimated by 4v-MDRD eGFR using IDMS calibrated creatinine in 111 participants. 2. The performance of CKD-EPI formula compared to the MDRD equation in estimating GFR in participants with type 2 diabetes associated CKD: The aim was to use our dataset to compare the effect of obesity on eGFR calculated by the CKD-EPI formula (Levey and Stevens) and by the 4-variable MDRD equation. 3. Derivation of obesity correction equation for 4-variable MDRD: To derive a 'correction factor' for the 4-variable MDRD equation to adjust for the equation's underestimation of true (isotopic) GFR in obese subjects with Type2 diabetes. Linear and non-linear regression analyses were performed to derive equations which reduced the bias between estimated and measured GFR. 4. Effect of cooked meat protein on eGFR estimation in type 2 Diabetes related chronic kidney disease: To estimate the biological variation in creatinine levels caused by a standardised cooked meat meal in subjects with diabetes mellitus and various stages of chronic kidney disease, compared to healthy volunteers. 64 participants in chronic kidney disease stages 1-4 and 16 healthy volunteers were fed cooked meat and non-meat protein meals to study the effect of cooked meat protein on creatinine and eGFR. 5. Effect of cooked meat protein on urinary albumin creatinine ratio in patients with type2 Diabetes related chronic kidney disease: To determine the effect of a cooked meat meal on UACR in diabetic patients with diabetes related chronic kidney disease. 80 participants had their urinary albumin creatinine ratio calculated before and 4 hours after a cooked meat meal. Results & Conclusions: 1. The 4-v MDRD formula underestimates GFR in overweight and obese patients with Type 2 diabetes. The bias between estimated and measured GFR in the obese type 2 diabetic subjects persists across the range of CKD stages. This may have Implications for management of obese patients with Type 2 diabetes, where treatment options for the management of hyperglycaemia, hypertension and other concomitant conditions are often determined by the eGFR. 2. The bias between estimated and measured GFR significantly worsens when eGFR was calculated using the CKD-Epi compared to the 4 variable MDRD formulas in patients with type2 diabetes and chronic kidney disease. There remains a need for better-validated equations to estimate GFR in the obese patients with diabetes. 3. The linear and non-linear equations derived from our study reduce the bias significantly in the external dataset; this improvement being more pronounced in the obese subjects and is best achieved by the ratio model equation which scores consistently well across all three ranges of GFR studied, including a very good positive predictive value in CKD stage 3 in the obese. This simple corrective factor if externally validated can be used when making management decisions in the obese with type2 diabetes based on eGFR. 4. Consumption of a standardised cooked meat meal significantly increased serum creatinine and resulted in significant fall in eGFR in all stages of CKD studied; 6 of 16 CKD 3a patients were misclassified as CKD 3b. This effect of cooked meat on serum creatinine disappears after 12 hours of fasting in all study participants. Creatine in meat is converted to creatinine on cooking. This is absorbed causing significant increase in serum creatinine levels and a consequent drop in eGFR. This could impact management as threshold for commencing and withdrawing certain medications and decisions regarding investigations is defined by eGFR. An eGFR calculated using fasting serum creatinine would be a better reflection of kidney function in these patients. 5. Urine albumin to creatinine ratio falls after a cooked meat meal in patients with diabetes associated chronic kidney disease. This fall in ACR increases with worsening stages of chronic kidney disease. Cooked meat consumption is a major factor leading to variation in ACR values, which should be considered when interpreting results.
Supervisor: Wilding, J. P. H. ; Hardy, K. J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral