Moderator's view: Estimating glomerular filtration rate—the past, present and future

Abstract

Modern renal physiology arose during the scientific revolution of the 1840s in Europe with mechanistic experiments playing a central role. Carl Ludwig, a German physiologist, was the first to describe the principle of glomerular ultrafiltration driven by physical forces alone [1]. However, an understanding of the fundamental mechanisms of kidney function awaited the advent of micropuncture techniques by Wearn and Richards in 1924 [2]. Since then, numerous research groups have provided us with knowledge on glomerular haemodynamics, filtration barrier function and the processes of tubular reabsorption and secretion. We also know that tubular and interstitial pathological processes can affect glomerular function. Therefore, the glomerular filtration rate (GFR) is now regarded as the best overall measure of kidney function, reflecting reduced clearance of waste products and also to some extent disturbed regulation of electrolytes, water balance and hormone production. Inulin clearance was established early as the gold standard method for measuring the GFR. This substance completely fulfils the requirements of no extra-renal clearance, free filtration and no tubular reabsorption or secretion [3]. However, the method is complicated from both an analytical and a practical point of view with the need for continuous intravenous infusion. It has, therefore, seldom been used in clinical practice and nor is it widely used in research institutions today. Plasma clearance of exogenous markers like iothalamate, iohexol and EDTA is available instead for measuring the GFR in most hospitals and are considered equally accurate. Although considered as reference methods, their accuracy is not very high with coefficients of variation reported in the range of 5–20% [4]. Although less complicated than the classical inulin clearance technique, these methods are also very expensive and take hours per patient. Serum creatinine and various formulas based on this cheap, fast and universally available analyte, therefore, remains the cornerstone of kidney function assessment. The relationship between serum creatinine and GFR is non-linear and influenced by several non-kidney variables, and numerous formulas for estimating the GFR have been published over the past 40 years. The Cockcroft Gault formula gained worldwide popularity despite being based on only 249 hospitalized males with kidney function measured as 48-h urine creatinine clearance, which includes tubular creatinine secretion [5]. Later studies have shown that the formula gives a suboptimal performance as a proxy for true GFR in several settings including in the elderly and in advanced kidney disease, where tubular creatinine secretion can lead to 35% overestimation of GFR [6–8]. In 1999, Levey et al. [9] published a new formula based on 1628 chronic kidney disease (CKD) patients from the Modification of Diet in Renal Disease (MDRD) study with the GFR measured as urinary iothalamate. These patients all had a GFR of 60 mL/min/ 1.73 m. Ten years later, Levey et al., therefore, published a new serum creatinine-based formula [the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula] using the highest available standards: serum creatinine traceable to isotope-dilution mass spectrometry standards from an impressive 8254 subjects, iothalamate clearance for measuring true GFR, separate study groups for developing and validating the formula, a sufficiently high number of black participants and participants with a wide range of kidney functions [10]. P O L A R V IE W S IN N E P H R O L O G Y