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The estimated glomerular filtration rate (eGFR) and albuminuria are the two key measures of kidney function used to classify chronic kidney disease (CKD) due to their ease of determination from blood and urine samples. Since Rehberg’s studies of ‘filtration and readsorption in the human kidney’ almost 100 years ago [1], sophisticated GFR estimation equations have been developed for routine medical care [2, 3]. These formulae rely heavily on serum creatinine. However, creatinine is an imperfect filtration biomarker since it is dependent on age, muscle mass and meat consumption, and is actively secreted by the kidney tubules, especially when kidney function declines. The creatinine-based formulae show significant imprecision in the normal range of GFR, frequently leading to misclassification. These drawbacks of creatinine have spurred the search for novel filtration biomarkers. Beta-trace protein (BTP), cystatin C and beta-2-microglobulin (B2M) have emerged as promising candidates to replace creatinine since they are independent of muscle mass, freely filtered by the glomerulus, then catabolized and/or excreted, but not secreted by the kidney tubules [3]. These novel filtration markers have significant limitations that need consideration in their process of validation: B2M is increased in malignancy and inflammation and excreted under conditions of tubular dysfunction, and cystatin C and BTP are affected by steroid therapy. Expression of BTP, also known as lipocalin-type PGD(2) synthase (L-PGDS), is increased in certain inflammatory states [4, 5], and L-PGDS/BTP expressed in the kidney may promote the development of CKD by production of prostaglandin D(2) and subsequent activation of Th2-lymphocytes [6]. Complicating matters, LPGDS/BTP is a potential marker of kidney injury in type-2 diabetes [7]. Finally, international standardization of the assays of these markers has only recently been established for cystatin C [8]. In this edition of NDT, Tin et al. [9] now present a further important non-renal determinant of BTP concentrations: genetic variation. In a genome-wide association study (GWAS) on 6720 European Americans (EAs) of the general population in the ARIC study, single nucleotide polymorphisms (SNPs) at the locus containing the gene coding for BTP, prostaglandin D2 synthase (PTGDS), were significantly associated with BTP levels. The index SNP at the locus explained 1.1% of the variance of log(BTP) levels, and the index SNP’s effect allele was responsible for 5% higher BTP levels in EAs compared with the reference allele. Unfortunately, though BTP-based GFR estimation equations have been developed for transplant, Fabry and paediatric patients [10–12], no such formula is available for general population cohorts to determine the absolute difference in the eGFR attributable to the SNP. However, though this SNP’s effect size is large for the GWAS, the absolute eGFR difference due to the SNP will likely be of low clinical relevance. The PTGDS locus was validated in genetic association analysis in 1734 African Americans of the ARIC study, with a similar effect of the index SNP on BTP levels as in EAs. Interestingly, over a third of the difference of log(BTP) levels observed between the two ethnicities could be ascribed to the index SNP at the locus. The absolute difference in median BTP levels between ethnicities was only 0.09 mg/L, but this 15% difference is larger than the 4–7% difference in serum creatinine between Africans and Caucasians in NHANES [13]. Since it is unlikely that other factors such as inflammation play a major role in determining between-ethnicity differences of BTP, this finding suggests that genetic testing may become an important alternative to potentially inaccurate self-reported ethnicity when using GFR-estimating formulae. The index SNP was not associated with eGFR or albuminuria in either ethnicity in ARIC, indicating that the SNP affects BTP levels by modifying production or metabolism but not

It's not only the kidneys--genetic determinants of glomerular filtration marker levels