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Shrunken pore syndrome is a common kidney disorder in which the pores in the glomerular filtration barrier have shrunken so that the filtration of 5-30 kDa proteins, for example cystatin C, is reduced, which strongly increases the risk for serious disease and premature death.

Kidney function
It is generally agreed that kidneys are essential for maintaining a constant internal environment of the body and to do so they have to regulate pH, osmolarity, ion concentrations and volume of the extracellular fluid and excrete wastes and toxins. They are also known to produce the hormones renin and erythropoietin, which are involved in producing red blood cells and in regulating blood pressure. But it was not generally recognised that the kidneys also serve an important role in maintaining the equilibrium between production and catabolism of most proteins between about 5 and 30 kDa in molecular mass and that failure to do so results in serious disease and strongly increased mortality until 2014, when the kidney disorder shrunken pore syndrome was identified. It should be noted that proteins < 30 kDa comprise about 36% of the total human proteome.

Identification of the syndrome
The identification of the syndrome was based upon the parallel use of two different ways of estimating the glomerular filtration rate (GFR) of the kidneys. The GFR is the blood filtered through the glomerular filtration barrier per unit of time and corresponds to the amount of primary urine collected in the Bowman's capsule per unit of time. GFR is usually expressed as milliliter per minute (ml/min). GFR varies, not only with the state of the kidney, but also with kidney size, which varies with age and sex. To get reference values for GFR, useful for both adult men and women and children, GFR is often expressed normalized to the mean body surface area of an adult person using the figure 1.73m2. GFR can be invasively measured by following the disappearance rate from the blood of patients injected with substances, which are cleared from the body solely by glomerular filtration. But invasive diagnostic procedures are expensive, time-consuming and not without risks for the patients. GFR is therefore generally estimated by analysis of the plasma (or serum) levels of two substances, creatinine or cystatin C, which mainly are cleared by glomerular filtration. The estimations of GFR are done by using cystatin C- or creatinine-based GFR-estimating equations with anthropometric terms, for example age, in addition to the levels of cystatin C or creatinine. The estimates, eGFRcystatin C or eGFRcreatinine, normally agree within 20% and the mean of the estimates, eGFRmean, is generally the best estimate of GFR. However, in some patients eGFRcystatin C and eGFRcreatinine, do not agree. If known non-renal influences on creatinine (and thus on eGFRcreatinine) or on cystatin C (and thus on eGFRcystatin C) can be excluded, and the eGFRcystatin C/eGFRcreatinine-ratio is <0.60, or <0.70, a straightforward pathophysiological interpretation is, according to the pore model for the glomerular filtration barrier, a decrease in the diameter of a fraction of the pores of the glomerular membrane impairing the filtration of 5-30 kDa molecules, like cystatin C, more than that of small molecules like creatinine and water. This pathophysiological state was therefore designated as “Shrunken pore syndrome (SPS)”.

Invasive studies of pore size
Previous to the identification of SPS by use of the eGFRcystatin C/eGFRcreatinine-ratio, invasive studies of a limited numbers of patients by injections of glomerular filtration markers of different molecular mass demonstrated the phenomenon of shrunken pores in the glomerular barrier. In these studies, the glomerular filtration of the relatively high molecular mass substances neutral dextran, cystatin C and levan polysaccharide was compared to that of the low molecular mass substances iothalamate, inulin and mannitol.

Clinical consequences of SPS
The first study of the clinical consequences of SPS comprised a cohort of 1638 patients undergoing elective coronary artery bypass grafting. The long-term mortality of patients with SPS was markedly increased. In several subsequent studies of the mortality of SPS in different cohorts, the strong increase in long-term mortality of patients with SPS was corroborated. In an epidemiological study comprising about 3000 individuals, the mortality of SPS was higher than that of cancer, diabetes mellitus, cardiovascular disease or chronic kidney disease. The increased total mortality in SPS concerned many specific death causes with cardiovascular disorders and cancer as the dominating ones. In addition to premature death, patients with SPS often display heart conditions. It should be emphasized that SPS has been identified in children, but so far the clinical consequences of it in children are unknown.

Pathophysiology of SPS. Treatment options.
Proteomic studies of four groups of patients, with or without SPS and with normal or reduced GFR, showed that at least 30 changes in protein concentrations were specific for SPS. These changes included raised levels of at least 18 proteins described as promoting, or being associated with, the development of atherosclerosis. Also previous and ongoing studies of SPS indicate that many changes in protein concentrations are specific for SPS. So a reasonable hypothesis concerning the pathophysiology of SPS is that several 5-30 kDa proteins with signalling functions, e.g. cytokines, are increased in concentration and promote development of serious disorders like cancer and cardiovascular disorders. SPS is reversible as it is known that it is present in the three last months of all normal pregnancies, and in a more extreme form in preeclampsia, and yet disappears a few weeks after delivery. The suggested pathophysiological model for SPS means that different treatment options are available. One would be to reduce the high levels of the most detrimental disease-producing signal proteins by use of, for example, monoclonal antibodies analogously to the use of monoclonal antibodies in inflammatory disorders. Another one would be to develop haemodialysis procedures with sieving coefficients for 5–30 kDa proteins similar to those of healthy kidneys and a third one would be to perform a kidney transplantation with a kidney free of SPS.

Diagnosing SPS
An eGFRcystatin C/eGFRcreatinine-ratio <0.60, or <0.70, in the absence of non-renal influences on eGFRcystatin C or eGFRcreatinine, identifies a condition as SPS. Three different pairs of eGFRcystatin C- and eGFRcreatinine-estimation equations have been used to diagnose SPS, namely CAPA–LMR, CKD-EPIcystatin C–CKD-EPIcreatinine or FAScystatin C–FAScreatinine. The international organisation "Kidney Disease Improving Global Outcomes" (KDIGO) recommendations for classification of chronic kidney disease comprise determination, or estimation, of GFR and analysis of albuminuria. Since several studies of SPS have demonstrated that SPS may occur in the absence of reduced GFR  and without albuminuria, the KDIGO recommendations for classification of chronic kidney disease will miss a significant number of patients with SPS  and thus a significant part of all individuals with serious kidney disorders. This suggests that optimal classification and stratification of chronic kidney disease requires not only analysis of GFR (estimated or measured) and albuminuria, but also determination of the eGFRcystatin C/eGFRcreatinine-ratio to assess the presence of SPS.