Cystatin C, GFR and Shrunken Pore Syndrome: Insights from Dr. A. Grubb

Expanding the understanding of kidney disease 

Shrunken Pore Syndrome (SPS) and Selective Glomerular Hypofiltration Syndromes (SGHS)

Research has shown that creatinine-based estimated GFR alone does not identify all forms of kidney dysfunction. The discovery of Shrunken Pore Syndrome (SPS), part of a broader group of Selective Glomerular Hypofiltration Syndromes (SGHS), revealed impaired filtration of low-molecular-weight proteins such as cystatin C, despite preserved creatinine-based Glomerular Filtration Rate (GFR). These syndromes are consistently associated with substantially increased morbidity and mortality, highlighting a clinically significant blind spot in current kidney assessment practices.^1-3

Pioneer of cystatin C and Shrunken Pore Syndrome - Dr. A. Grubb

Dr. Anders Grubb (PhD, MD) discovered cystatin C (link) as a marker for glomerular filtration rate (GFR) in 1979.^4-7 The introduction of an international cystatin C calibrator in 2008, with Professor Grubb as chair of the working group, enabled global standardisation and reliable clinical implementation.⁸

Dr. Grubb also played a central role in discovering the previously unidentified kidney disorder Shrunken Pore Syndrome (SPS), later also referred to as Selective Glomerular Hypofiltration Syndrome (SGHS). The syndrome is associated with very high mortality and morbidity and may also explain the superiority of eGFR cystatin C over eGFR creatinine in identifying high-risk kidney patients.^1-3

Considerations for expanding KDIGO guidelines to recognise selective glomerular hypofiltration syndromes

A recent international review, which Dr. Grubb has been part of, concludes that current KDIGO guidelines fail to identify many patients with SGHS and calls for expanded use of cystatin C alongside creatinine, particularly at initial assessment and follow-up, to improve diagnosis, GFR estimation, and risk stratification.⁹

The growing clinical importance of cystatin C and SGHS has prompted renewed international collaboration. In 2026, experts in nephrology, laboratory medicine, and public health will meet in Lund, Sweden, to review the evidence, address diagnostic strategies, and discuss potential guideline updates. This reflects a shift toward recognising cystatin C as an essential component of modern kidney disease assessment.

Insights from a pioneer in cystatin C: Dr. Anders Grubb

In this interview from 2020, Professor Anders Grubb reflects on the discovery of cystatin C, its overall clinical value, and SPS. As evidence has accumulated and discussions on expanding KDIGO guidelines to include cystatin C have recently intensified, his perspectives have gained renewed relevance, underscoring why broader adoption of cystatin C is central to improving kidney disease detection, risk stratification, and patient care.

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.”

What 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.”

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.

Gentian’s cystatin C assay on instruments already in your lab

Gentian is one of the largest suppliers of cystatin C assays and the open channel assay is available on most instruments: 

• Abbott Laboratories (CLIA for Alinity c)
• Beckman Coulter (CLIA for AU480, AU5800, AU680, DxC 700 AU and Immage 800)
• Mindray
• Roche
• Siemens Healthineers
  
  

The calibrator for the Gentian Cystatin C Immunoassay is available in two versions, one-level calibrator for auto-dilution or a 6-point pre-diluted calibrator kit. Both types of calibrators are standardised against the international calibrator standard ERM-DA471/IFCC.

• FDA 510(k) cleared since 2007
• CE-marked in compliance with IVDR 2017/746 (CE 0123)
• Less interference due to avian antibodies
  
  

Bring cystatin C into routine kidney assessment

Get in touch to learn how Gentian’s cystatin C assay delivers reliable performance, standardisation, and seamless integration into your laboratory workflow.

References:

1. Grubb A. et al. Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome'. Scand J Clin Lab Invest, 2015
2. Malmgren L. et al. The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation. J Intern Med, 2023
3. Dardashti A. et al. Shrunken Pore Syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting. Scand J Clin Lab Invest, 2016
4. Löfberg H. and AO. Grubb. Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system. Scand J Clin Lab Invest, 1979
5. Grubb A. et al. Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate. Acta Med Scand, 1985
6. Simonsen O. et al. The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate. Scand J Clin Lab Invest, 1985
7. Kyhse-Andersen J. et al. Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. Clin Chem, 1994
8. Blirup-Jensen S. et al. Standardization of Cystatin C: development of primary and secondary reference preparations. Scand J Clin Lab Invest Suppl, 2008
9. Åkesson A. et al. Identification of cystatin C as a new marker of glomerular filtration rate, and of shrunken pore syndrome - a new kidney disorder defining selective glomerular hypofiltration syndromes - calls for expansion of the international KDIGO guidelines. Scand J Clin Lab Invest, 2025