The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation

Abstract

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Keywords: kidney disease; proteomics.

Fig. 1

Three different types of glomerular filtration defects are based on the pore model. The discovery of selective glomerular hypofiltration syndromes with selectively reduced filtration of 5–30 kDa molecules, for example shrunken or elongated pore syndrome, means that different classes of filtration defects can be defined as schematically illustrated in the figure. Part (a) represents normal filtration. Part (b) represents reduced filtration caused by the loss of unaltered pores. Part (c) represents selectively reduced filtration of 5–30 kDa molecules in, for example shrunken or elongated pore syndrome, but normal filtration of small molecules. Part (d) represents reduced filtration of all types of molecules, but a more severe reduction of the filtration of 5–30 kDa molecules. Parts (c,d) represent selective glomerular hypofiltration syndromes, which are associated with higher morbidity and mortality than the type of filtration defect described in (b) in which no selective reduction of filtration of 5–30 kDa molecules occurs. Variations in the endothelial fenestrae are used to illustrate the variation in the filtration process in the pore model, for example representing shrunken or elongated pores (selective glomerular hypofiltration syndromes). eGFR_creatinine, creatinine‐based estimation of GFR; eGFR_{cystatin C}, cystatin C‐based estimation of GFR; GFR, glomerular filtration rate; mGFR, measured GFR.

Fig. 2

Glomerular sieving coefficients (θ) versus Stokes–Einstein radii for a few proteins and other substances. (θ) for insulin and cystatin C have been estimated from theory [73] and [97]. The solid blue line represents a theoretically predicted sieving curve for proteins [73]. The red solid line and yellow dashed line are simulated scenarios with elongated or shrunken pores, respectively. A longer pore has little effect on proteins larger than 3 nm (>40 kDa). In contrast, a smaller (shrunken) pore would have a significant impact on proteins larger than 3 nm (but smaller than the pore size of 3.7 nm/70 kDa). For a more detailed analysis see [91]. FLC, human myeloma‐free light chain; HRP, horse radish peroxidase. Source: Data from [95, 96].

Fig. 3

Protein–protein associations between currently identified proteins known to be associated with selective glomerular hypofiltration syndromes. Nodes represent proteins. Lines represent protein–protein interactions. Known interactions: light blue: from curated databases, purple: experimentally determined. Predicted interactions: green: gene neighbourhood, red: gene fusion, dark blue: gene co‐occurrence. Others: yellow: text mining, black: co‐expression, blue: protein homology pathway analysis was conducted using STRING: functional protein association networks (string‐db.org). Accessed 2022‐08‐09.