Cystatin C and Health

Cystatin C-Based GFR-Estimating Equations and Selective Glomerular Hypofiltration Syndromes, e.g. Shrunken Pore Syndrome.
Development of New Drugs against Amyloidosis, Viruses and Multiresistant Gram-Positive Bacteria Based upon the Structure of Cystatin C.

Principal investigator; Grubb, Anders, Professor, MD/PhD

Clinical speciality: Clinical chemistry

Phone: +4646-702393773

Co-workers, Lund University: Abrahamson Magnus, Bjursten Henrik, Björk Jonas, Christensson Anders, Lindström Veronica, Magnusson Martin, Malmgren Linnea, Nyman Ul

Research area/areas: Biomedical Laboratory Science/Technology, Clinical Laboratory Medicine, General Medicine, Medicinal Chemistry, Microbiology in the medical area, Other Clinical Medicine

We sequenced in 1981 a protein with unknown function, now called cystatin C, which defined a new superfamily of cysteine protease inhibitors ("cystatins"). We have described several new cystatins and shown that cystatin C is produced by a house-keeping gene and that a mutation in it causes the dominantly inherited disease "Hereditary Cystatin C Amyloid Angiopathy" in which L68Q-cystatin C is precipitated as amyloid in affected individuals, who die from brain hemorrhage before 40 years of age. We have demonstrated that cystatin C amyloid deposits may form by "propagated domain-swapping" and shown that inhibition of domain swapping prevents the in vitro formation of cystatin C amyloid. We have also demonstrated that cystatin C modulates the amyloid deposits in Alzheimer disease. We have demonstrated that certain peptidyl derivatives based upon the structure of cystatin C will kill grampositive bacteria resistant to all known presently available antibiotic compounds and some viruses.

We have shown that the plasma level of cystatin C is a better marker for glomerular filtration rate than creatinine, and especially in predicting the morbidity and mortality associated with renal disease. We demonstrated in 2015 that this superiority probably is connected to the capacity of cystatin C to identify a new common group of kidney disorders designated “selective glomerular hypofiltration disorders", e.g., “shrunken or elongated pore syndromes”. We produced an international calibrator for cystatin C in 2010.

We will further study the clinical consequences of “selective glomerular hypofiltration disorders”, and the pathophysiology of the syndromes to identify ways to reduce or eliminate the clinical consequences of these syndromes.

We will also produce new low molecular mass compounds preventing domain swapping of cystatin C and try to elucidate the antibacterial and antiviral mechanisms of cystatin-based antibacterial and antiviral compounds to create a new class of clinically useful antibacterial substances.

Five key publications

Grubb A. Shrunken pore syndrome – a common kidney disorder with high mortality. Diagnosis, prevalence, pathophysiology, and treatment options. (2020). Clin Biochem 83: 12-20. https://doi.org/10.1016/j.clinbiochem.2020.06.002

Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, Crews DC, Doria A, Estrella MM, Froissart M, Grams ME, Greene T, Grubb A, Gudnason V, Gutiérrez OM, Kalil R, Karger AB, Mauer M, Navis G, Nelson RG, Poggio ED, Rodby R, Rossing P, Rule AD, Selvin E, Seegmiller JC, Shlipak MG, Torres VE, Yang W, Ballew SH, Couture SJ, Powe NR, Levey AS; Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. (2021) N Engl J Med. 385:1737-1749. https://doi.org/10.1056/NEJMoa2102953

Ottosson Frost C, Gille-Johnson P, Blomstrand E, St-Aubin V, Leion F, Grubb A. Cystatin C-based equations for estimating glomerular filtration rate do not require race or sex coefficients. (2022) Scand J Clin Lab Invest 82:162-166. https://doi.org/10.1080/00365513.2022.2031279

Malmgren L, Öberg C, den Bakker E, Leion F, Siódmiak J, Åkesson A, Lindström V, Herou E, Dardashti A, Xhakollari L, Grubb G, Strevens H, Abrahamson M, Helmersson-Karlqvist J, Magnusson M, Björk J, Nyman U, Ärnlöv J, Ridefelt P, Åkerfeldt T, Hansson M, Sjöström A, Mårtensson J, Itoh Y, Grubb D, Tenstad O, Hansson LO, Olafsson I, Campos AJ, Risch M, Risch L, Larsson A, Nordin G, Pottel H, Christensson A, Bjursten H, Bökenkamp A, Grubb A. The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation. (2023). J Intern Med 293:293-308. https://doi.org/10.1111/joim.13589

Pottel H, Björk J, Rule AD, Ebert E, Eriksen BO, Dubourg L, Vidal‐Petiot E, Grubb A, Hansson M, Lamb EJ, Littmann K, Mariat C, Melsom T, E. Schaeffner E, P.‐O. Sundin PO, A. Åkesson A, A. Larsson A, Cavalier E, Bukabau JB, Sumaili EK, Yayo E, Monnet D, Flamant M, Nyman U, Delanaye. Cystatin C–Based Equation to Estimate GFR without the Inclusion of Race and Sex. (2023) N Engl J Med 388:333-43. https://doi.org/10.1056/NEJMoa2203769