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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 and identification of shrunken pore syndrome (SPS)

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Kidney function

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Glomerulus and Bowman's capsule. The blood filtered through the glomerular filtration barrier corresponds to the primary urine collected in the Bowman's capsule.

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.[1][2][3] It should be noted that proteins < 30 kDa comprise about 36% of the total human proteome.[2][4]

Identification of the syndrome

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Pores in one of the structures of the glomerular filtration barrier

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.[5] 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.[6] 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.[7][8][9][10] 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,[11] 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)”.[1][2]

Invasive studies of pore size

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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.[12][13][14]

Clinical consequences of SPS

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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.[15] 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.[16][17][18][19] 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.[20] The increased total mortality in SPS concerned many specific death causes with cardiovascular disorders and cancer as the dominating ones.[20] In addition to premature death, patients with SPS often display heart conditions.[21] It should be emphasized that SPS has been identified in children, but so far the clinical consequences of it in children are unknown.[22]

Pathophysiology of SPS. Treatment options.

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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.[18] These changes included raised levels of at least 18 proteins described as promoting, or being associated with, the development of atherosclerosis.[18] Also previous and ongoing studies of SPS indicate that many changes in protein concentrations are specific for SPS.[16][17] [23] 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.[1][2][16][17] [18][20] 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.[24][25][26][27] 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.[28] 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.[29]

Diagnosing SPS

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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.[1][2] 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.[20] 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.[30] Since several studies of SPS have demonstrated that SPS may occur in the absence of reduced GFR[1][2][20] and without albuminuria,[20] the KDIGO recommendations for classification of chronic kidney disease will miss a significant number of patients with SPS[2][20] 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.[2][20]

References

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  1. ^ a b c d e Grubb A, Lindström V, Jonsson M, Bäck SE, Åhlund T, Rippe B, Christensson A (July 2015). "Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome'". Scandinavian Journal of Clinical and Laboratory Investigation. 75 (4): 333–40. doi:10.3109/00365513.2015.1025427. PMC 4487590. PMID 25919022.
  2. ^ a b c d e f g h Grubb A (June 2020). "Shrunken pore syndrome - a common kidney disorder with high mortality. Diagnosis, prevalence, pathophysiology and treatment options". Clinical Biochemistry. Online ahead of print. doi:10.1016/j.clinbiochem.2020.06.002. PMID 32544475.
  3. ^ Zhou H, Yang M, He X, Xu N (Nov 2019). "eGFR, cystatin C and creatinine in shrunken pore syndrome". Clinica Chimica Acta. 498: 1–5. doi:10.1016/j.cca.2019.08.001. PMID 31398310.
  4. ^ Compton PD, Zamdborg L, Thomas PM, Kelleher NL (Sep 2011). "On the scalability and requirements of whole protein mass spectrometry". Analytical Chemistry. 83 (17): 6868–6874. doi:10.1021/ac2010795. PMC 3165072. PMID 21744800.
  5. ^ McIntosh JF, Möller E, Van Slyke DD (Dec 1928). "Studies of urea excretion. III: The influence of body size on urea output". Journal of Clinical Investigation. 6 (3): 467–483. doi:10.1172/JCI100207. PMID 16693840.
  6. ^ Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, Sterner G, Bäck SE (Sep 2014). "Measuring GFR: a systematic review". American Journal of Kidney Disease. 64 (3): 411–424. doi:10.1053/j.ajkd.2014.04.010. PMID 24840668.
  7. ^ Nyman U, Grubb A, Sterner G, Björk J (Sep 2009). "Different equations to combine creatinine and cystatin C to predict GFR. Arithmetic mean of existing equations performs as well as complex combinations". Scandinavian Journal of Clinical and Laboratory Investigation. 69 (5): 619–627. doi:10.1080/00365510902946992. PMID 19731180.
  8. ^ Grubb A (Apr 2010). "Non-invasive estimation of glomerular filtration rate (GFR). The Lund model: Simultaneous use of cystatin C- and creatinine-based GFR-prediction equations, clinical data and an internal quality check". Scandinavian Journal of Clinical and Laboratory Investigation. 70 (2): 65–70. doi:10.3109/00365511003642535. PMC 4673578. PMID 20170415.
  9. ^ Grubb A, Nyman U, Björk J (Feb 2012). "Improved estimation of glomerular filtration rate (GFR) by comparison of eGFRcystatin C and eGFRcreatinine". Scandinavian Journal of Clinical and Laboratory Investigation. 72 (1): 73–77. doi:10.3109/00365513.2011.634023. PMC 3279136. PMID 22121923.
  10. ^ Grubb A (Dec 2017). "Cystatin C is Indispensable for Evaluation of Kidney Disease". EJIFCC. 28 (4): 268–276. PMC 5746836. PMID 29333146.
  11. ^ Rippe B, Haraldsson B (Jan 1994). "Transport of macromolecules across microvascular walls: the two-pore theory". Physiological Reviews. 74 (1): 163–219. doi:10.1152/physrev.1994.74.1.163. PMID 8295933.
  12. ^ Beattie J, Corcoran AC (May 1952). "Renal clearances of grass polysaccharide: Observations on glomerular porosity and on the relation of this function to proteinuria in renal disease". Journal of Clinical Investigation. 31 (5): 445–450. doi:10.1172/JCI102628. PMID 8295933.
  13. ^ Roberts M, Lindheimer MD, Davison JM (Feb 1996). "Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy". American Journal of Physiology. 270 (2 Pt 2): F338–343. doi:10.1152/ajprenal.1996.270.2.F338. PMID 8779896.
  14. ^ Oberbauer R, Nenov V, Weidekamm C, Haas M, Szekeres T, Mayer G (2001). "Reduction in mean glomerular pore size coincides with the development of large shunt pores in patients with diabetic nephropathy". Experimental Nephrology. 9 (1): 49–53. doi:10.1159/000020698. PMID 11053980.
  15. ^ Dardashti A, Nozohoor S, Grubb A, Bjursten H (2016). "Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting". Scandinavian Journal of Clinical and Laboratory Investigation. 76 (1): 74–81. doi:10.3109/00365513.2015.1099724. PMC 4720044. PMID 26647957.
  16. ^ a b c Purde MT, Nock S, Risch L, Medina Escobar P, Grebhardt C, Nydegger UE, Stanga Z, Risch M (Mar 2016). "The cystatin C/creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors". Translational Research. 169 (e1-2): 80–90. doi:10.1016/j.trsl.2015.11.001. PMID 26637934.
  17. ^ a b c Purde MT, Nock S, Risch L, Medina Escobar P, Grebhardt C, Nydegger UE, Stanga Z, Risch M (Jul 2016). "Ratio of cystatin C and creatinine-based estimates of the glomerular filtration rate predicts mortality in healthy seniors independent of kidney function". Scandinavian Journal of Clinical and Laboratory Investigation. 76 (4): 341–343. doi:10.3109/00365513.2016.1149882. PMID 26981764.
  18. ^ a b c d Sällman Almén M, Björk J, Nyman U, Lindström V, Jonsson M, Abrahamson M, Schiller Vestergren AL, Lindhe Ö, Franklin G, Christensson A, Grubb A (Sep 2018). "Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins". Kidney International Reports. 4 (1): 67–79. doi:10.1016/j.ekir.2018.09.002. PMC 6308389. PMID 30596170.
  19. ^ Herou E, Dardashti A, Nozohoor S, Zindovic I, Ederoth P, Grubb A, Bjursten H (May 2019). "The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-ratio". Scandinavian Journal of Clinical and Laboratory Investigation. 79 (3): 167–173. doi:10.1080/00365513.2019.1576101. PMID 30767571.
  20. ^ a b c d e f g h Åkesson A, Lindström V, Nyman U, Jonsson M, Abrahamson M, Christensson A, Björk J, Grubb A (May 2020). "Shrunken pore syndrome and mortality: a cohort study of patients with measured GFR and known comorbidities". Scandinavian Journal of Clinical and Laboratory Investigation. Online ahead of print: 1–12. doi:10.1080/00365513.2020.1759139. PMID 32459111.
  21. ^ Christensson A, Grubb A, Molvin J, Holm H, Gransbo K, Tasevska-Dinevska G, Bachus E, Jujic A, Magnusson M (Nov 2016). "The shrunken pore syndrome is associated with declined right ventricular systolic function in a heart failure population – the HARVEST study". Scandinavian Journal of Clinical and Laboratory Investigation. 76 (7): 568–574. doi:10.1080/00365513.2016.1223338. PMID 27622713.
  22. ^ den Bakker E, Gemke R, van Wijk J, Hubeek I, Stoffel-Wagner B, Bökenkamp A (Feb 2020). "Evidence for shrunken pore syndrome in children". Scandinavian Journal of Clinical and Laboratory Investigation. 80 (1): 32–38. doi:10.1080/00365513.2019.1692231. PMID 31755786.
  23. ^ Christensson A, Ash JA, DeLisle RK, Gaspar FW, Ostroff R, Grubb A, Lindström V, Bruun L, Williams SA (May 2018). "The impact of the glomerular filtration rate on the human plasma proteome". Proteomics Clinical Applications. 12 (3): e1700067. doi:10.1002/prca.201700067. PMID 29281176.
  24. ^ Kurlak OL, Mistry HD, Pecks U, Pariza P, Lindström V, Grubb A, Strevens H (July 2016). "Changed renal function after pregnancy both with and without a hypertensive disorder: Medical complications of pregnancy related to hypertensive syndromes". Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 6 (3): 166. doi:10.1016/j.preghy.2016.08.061.
  25. ^ Damm D, Pariza P, Grubb A, Strevens H (Oct 2018). "Predicting maternal morbidity in hypertension in pregnancy with the 'shrunken pore syndrome' ratio for optimal timing of delivery". Pregnancy Hypertension Supplement 1. 13: S108–S109. doi:10.1016/j.preghy.2018.08.321.
  26. ^ Kristensen K, Wide-Swensson D, Schmidt C, Blirup-Jensen S, Lindström V, Strevens H, Grubb A (2007). "Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia". Acta Obstetrica Gynecologica Scandinavia. 86 (8): 921–926. doi:10.1080/00016340701318133. PMID 17653875.
  27. ^ Kristensen K, Lindström V, Schmidt C, Blirup-Jensen S, Grubb A, Wide-Swensson D, Strevens H (2007). "Temporal changes of the plasma levels of cystatin C, beta-trace protein, beta-2-microglobulin, urate and creatinine during pregnancy indicate continuous alterations in the renal filtration process". Scandinavian Journal of Clinical and Laboratory Investigation. 67 (6): 612–618. doi:10.1080/00365510701203488. PMID 17852800.
  28. ^ Kotsovilis S, Andreakos E (2014). "Therapeutic human monoclonal antibodies in inflammatory diseases". Methods in molecular biology. 1060: 37–59. doi:10.1007/978-1-62703-586-6_3. PMID 24037835.
  29. ^ Girndt M, Fiedler R, Martus P, Pawlak M, Storr M, Bohler T, Glomb MA, Liehr K, Henning C, Templin M, Trojanowicz B, Ulrich C, Werner K, Zickler D, Schindler R (Dec 2015). "High cut-off dialysis in chronic haemodialysis patients". European Journal of Clinical Investigation. 45 (12): 1333–1340. doi:10.1111/eci.12559. PMID 26519693.
  30. ^ "Summary of Recommendation Statements". Kidney International Supplement (2011). 3 (1): 5–14. Jan 2013. doi:10.1038/kisup.2012.77. PMC 4284512. PMID 25598998.
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