Kidney function

Introduction

Kidney function in oncologic patients is an important parameter for several reasons. In some specific cases, like urologic cancers, the tumor itself can cause acute or chronic kidney dysfunction. However, the renal function parameter is more frequently followed in oncologic patients because, on one hand, they are likely to get nephrotoxic drugs, and on the other hand, some oncologic patients have chronic kidney disease (CKD) that would necessitate a dosage adaptation for potentially toxic chemotherapies. ^, Indeed, excretory renal function plays a fundamental role both in the pharmacokinetics and pharmacodynamics of several drugs. This is particularly the case for water soluble compounds and/or their active metabolites. Even for non-renally-excreted drugs, severe CKD can modify the pharmacokinetics by several mechanisms. For this reason, it is now recommended that both pharmacokinetics and pharmacodynamics of every new drug be studied in the context of CKD. Dosage-adjustment according to excretory renal function is required for many medications. However, there is a debate in the literature regarding the best way to estimate excretory function or glomerular filtration rate (GFR) for the purpose of pharmacotherapy.

Serum creatinine

The word “creatinine” was probably used for the first time by Justus von Liebig in 1847. This German chemist was thus describing the product obtained from heating creatine with mineral salts. Nowadays, serum creatinine is one of the most frequently prescribed analysis in Clinical Chemistry. Serum creatinine is the only renal plasma biomarker used in daily clinical practice to estimate GFR. ^, However, a good interpretation of the creatinine result remains sometimes problematic, or at least not so simple. To explain these difficulties, there are both physiologic (serum creatinine is not an “ideal” renal marker) and analytical reasons. First, serum creatinine can be measured by two main methods: methods derived from the classical Jaffe reaction on one part, and enzymatic methods on the other part. The Jaffe method is based on a reaction between picrate and creatinine in alkaline milieu that gives a red-orange product. Some components (so-called pseudochromogens) can however also interact with picrate: acetoacetate, pyruvate, ketonic acids, proteins, glucose, and ascorbic acid. These pseudochromogens take part in 15% to 20% of the Jaffe reaction if the serum creatinine is in the normal range. This limitation of Jaffe methods remains even after different technological innovations. The second method is known as the enzymatic and is based on successive enzymatic steps. Different types of reactions have been described, but they all share a higher specificity to measure serum creatinine, compared to Jaffe assays. Enzymatic methods are thus considered as more accurate and precise than Jaffe methods. These methods are recommended even if they are more expensive and not fully free from some interferences. There are two methods to measure creatinine but for each method, there are also several different assays (according to the manufacturers). Until recently, a great heterogeneity was observed between the assays, because of differences in calibration. ^, Nowadays, several improvements have been done in a quest to standardization, and it is recommended to measure serum creatinine with a standardized, calibrated, and so-called isotope dilution mass spectrometry ( IDMS )-traceable method. This traceability is of the highest importance in the context of creatinine-based equations. ^,

Beyond analytical issues, there are also physiologic limitations to serum creatinine. The molecular weight of creatinine is 113 Daltons. Creatinine is the anhydric catabolite of creatine and phosphocreatine. Creatinine is a catabolite final product and has no physiologic role. The vast majority of creatine (98%) will be found in muscles where creatine is phosphorylated in phosphocreatine by creatine kinase. Each day, 1% to 2% of the muscle creatine is converted into creatinine. ^, It is thus obvious that serum creatinine concentration is highly dependent on muscle mass. If the global creatine concentration is constant in healthy subjects, this concentration will strongly vary notably in muscular pathologies or, from a larger point of view, in all diseases with anorexia and muscle mass decreasing, as it is frequently observed in oncologic diseases. In these situations, serum creatinine will decrease, or will not increase when GFR is decreasing. ^{, ,} The second important limitation is the tubular secretion of creatinine, which explains that creatinine clearance overestimated measured GFR (mGFR). Moreover, even if creatinine clearance, calculated on a 24-hour urine collection, is a relatively simple way to assess GFR, such a clearance also lacks precision, especially because of large errors in urine collection. Therefore creatinine clearance is not recommended for GFR estimation. A last point needs to be underlined: the relationship between serum creatinine and GFR is not linear but hyperbolic ( Fig. 1.1 ). ^, To keep this point in mind is fundamental for a good interpretation of a creatinine result. Actually, this hyperbolic relation implies that a little creatinine change will have great consequences in terms of GFR in low creatinine levels, although the same creatinine variation in higher ranges will be negligible in terms of GFR. ^{, ,}