Interview with Dr. A. Grubb - Cystatin C, GFR and SPS

26. Sep 2019 | 9 min read

Interview with Dr. A. Grubb - Cystatin C, GFR and SPS

Meet Dr. Grubb, PhD, MD

Dr. Anders Grubb (PHD, MD) is a Professor in Clinical Chemistry at Lund University in Sweden. He discovered cystatin C as a marker for Glomerular Filtration Rate (GFR) in 1979 [1-4]. Dr. Grubb also had a central role in discovering the previously unidentified kidney disorder Shrunken Pore Syndrome (SPS). The syndrome has a very high mortality and morbidity, and might also explain the superiority of eGFRcystatin C over eGFRcreatinine in identifying high-risk kidney patients.

In the recently launched AACC webinar, supported by Gentian, The Use of Biomarkers in Chronic Kidney Disease and the Novel Disorder Shrunken Pore Syndrome, Dr Grubb discusses cystatin C, creatinine and SPS.Gentian sat down with Dr. Grubb after the webinar to get more insight to how his research interest for cystatin C started, the relation between cystatin C and creatinine and what he thinks are the important research areas for the near future.

 

Cystatin C and GFR

 

Glomerular Filtration Rate (GFR) indicates the level of kidney function by measuring the rate water and dissolved substances are filtered out of the blood per unit time.

Cystatin C is a well-known marker used for both acute and chronic kidney diseases [5,6] and it is recommended by KDIGO and NICE [7]. Cystatin C is produced at a constant rate in nearly every nucleated cell in the human body [8]. It is freely filtered through a normal Glomerular membrane, before it is reabsorbed and almost entirely catabolised in the proximal tubules. Hence, the cystatin C concentration in human blood is closely related to GFR [9].

 

Dr-grubb-interview-3-web-ready


How did your interest/research of kidney diseases/ disorders and cystatin C start?


“I was working in the clinical routine and to diagnose tubular damage we used gel electrophoresis of urine. I then noticed in the tubular proteinuria pattern a protein for which nothing was known about its structure, function or possible use in diagnostics. I was interested in basic protein science, so I applied it on this this protein, now known as cystatin C.

Our group isolated the protein, produced antiserum against it and a manual immunochemical procedure to measure it. We then determined the protein´s primary and secondary structure and later, by X-ray studies, its 3-dimensional structure.

The function of the protein as an efficient inhibitor of cysteine proteases was found by homology studies of the amino acid sequence of its single polypeptide chain. We noted that it was produced by all cell lines we studied and asked ourselves where it was catabolised or excreted. As it is a small protein of about 13 kDa, we assumed that it would be catabolised by the kidney by glomerular filtration and subsequent degradation in the tubular cells. We therefore determined the plasma concentration of cystatin C in patients with known reductions in glomerular filtration rate and we observed that the plasma concentration of it was raised more than 10 times in some of these patients. We concluded that the kidneys were the major catabolic site of the protein and decided to return to more basic science studies of the protein.

However, my neighbour, Hans Thysell, an excellent nephrologist, told me that it was not morally acceptable to just leave the study of cystatin C as a marker for glomerular filtration considering the many problems associated with the use of creatinine as such a marker. I followed his advice and have now published at least 200 articles on cystatin C and especially its use as a marker of glomerular filtration rate.”


CWhat is the relation between cystatin C and creatinine?


“Cystatin C is much bigger than creatinine with a molecular mass at least 100 times bigger than that of creatinine. When it is used as a marker for GFR it therefore really shows the filtration of molecules with sizes similar to its own, for example signal proteins, whereas creatinine shows the filtration of molecules similar to its own size, for example water. However, these different types of filtration agree for most persons. Still, they do not agree in Shrunken Pore Syndrome (SPS).

Another major difference is that the cystatin C level, in contrast to the creatinine level, is virtually uninfluenced by muscle mass and that therefore efficient GFR-estimating equations based upon cystatin C do not require terms defining sex, age or ethnicity to estimate the muscle mass of a person.”

 

Dr-Grubb-interview-2_-web-ready

 

What are the pitfalls when measuring cystatin C?


“The level of cystatin C is nowadays determined by rapid automated immunochemical procedures. The presence of certain rheumatoid factors or heterophilic antibodies in the blood of the patients might in a few cases interfere in the immunochemical procedures and produce too high values of cystatin C. We have found that this occurs more rarely when you use avian antibodies than when you use rabbit antibodies, but we have no good explanation for that. If you refer to clinical pitfalls, the most common one is that the patient is treated with high doses of glucocorticoids, which induces increased production of cystatin C.”

 

Where do you think research areas should focus in the future relating to cystatin C and kidney markers?

 

“Research should in my opinion focus on the newly discovered disorder, SPS, as it is associated with a very big increase in mortality and cannot be diagnosed using the internationally recommended procedure by KDIGO 2012, i.e. estimating GFR using creatinine and analysing the urine albumin-creatinine ratio.”

 

Tell us more about the finding of Shrunken Pore Syndrome (SPS)

 

What impact can this have on patients’ life?

If a patient is diagnosed with SPS, it means that his/her long-term mortality will increase very much. The increase in mortality has, in a recent big study, been shown to be bigger than when the patient is diagnosed with cancer, cardiovascular disease, diabetes or conventionally diagnosed chronic kidney disease.

What do we know about the disease progression of SPS?

SPS has only been known for about 4 years so we do not know much about its progression more than that the diagnose is associated with a very big increase in the long-term mortality of the patient. However, we have suggested a pathophysiologic process for the disease, which allows treatment using, for example, monoclonal antibodies to reduce the high levels of atherosclerosis-promoting signal proteins occurring in shrunken pore syndrome.

 

Shrunken Pore Syndrome – further reading:


Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: ‘Shrunken pore syndrome’

Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting

Cystatin C is indispensable for evaluation of kidney disease

 

grubb-interview_web-ready

 

References:


1 Löfberg H, Grubb A: Quantitation of g-trace (cystatin C) in human biological fluids: indications for production in the central nervous system. (1979) Scand J Clin Lab Invest 39: 619-626.

2 Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H: Serum concentration of cystatin C, factor D and b2-microglobulin as a measure of glomerular filtration rate. (1985) Acta Med Scand 218: 499-503.

3 Simonsen O, Grubb A, Thysell H: The blood serum concentration of cystatin C (g-trace) as a measure of the glomerular filtration rate. (1985) Scand J Clin Lab Invest 45: 97-101.

4 Kyhse-Andersen J, Schmidt C, Nordin G, Andersson B, Nilsson-Ehle P, Lindström V, Grubb A: Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. (1994) Clin Chem 40: 1921-1926.

5 O.Z. Ismail, et al., 2017, http://dx.doi.org/10.1016/j.clinbiochem.2017.01.005

6 Tangri N, et al Kidney Int 2011;79:471-7

7 NCIC Clinical guideline (CG182) updated jan 2014 section 2.1 https://www.nice.org.uk/guidance/cg182/chapter/2-Implementati­on-getting-started

8 Abrahamson M et al: Biochem J 1990;268:287-94.

9 Laterza OF et al: Clin Chem 2002;48:63-99.

You may also read


Collaboration Proposal - COVID-19

Apr 03, 2020

Collaboration Proposal - COVID-19

We at Gentian AS believe it is the duty of all companies in the health industry to help combat the ongoing..

Statement to Customers on COVID-19 Concerns

Mar 13, 2020

Statement to Customers on COVID-19 Concerns

At Gentian, the health and safety of our employees, as well as our customers and partners, is of primary..

New article about calprotectin in Scientific Reports

Mar 11, 2020

New article about calprotectin in Scientific Reports

Calprotectin, a new biomarker for diagnosis of acute respiratory infections*