Kidney Disease
Corey Diamond, PharmD
The utility of cystatin C—a protein biomarker similar to creatinine—has often been overlooked in routine practice as an alternative measurement of estimated glomerular filtration rate (eGFR) in patients with kidney disease. Two new studies published in 2023 in the American Journal of Kidney Diseases concluded that patients with a large disconnect between eGFRs, measured using creatinine (eGFRscr) versus cystatin C (eGFRcys), may have a significantly increased risk of morbidity and mortality. However, the mechanism behind these findings is debated.
Observational findings
Carrero and colleagues conducted a retrospective observational study, published in June 2023 in the American Journal of Kidney Diseases, that included eGFR data from over 150,000 Swedish patients from the Stockholm Creatinine Measurements project. Specifically, the authors looked at the discordances between eGFRscr and eGFRcys to calculate the difference in magnitude between the two for each patient. Patients with similar eGFRscr and eGFRcys were compared directly to patients with large differences in eGFRscr compared to eGFRcys.
The authors found that about 65% of patients had lower eGFRscr compared to eGFRcys. These patients tended to be female, older, and have more comorbid conditions. When the authors looked at rates of acute kidney injury, kidney failure with renal replacement therapy, atherosclerotic disease, heart failure, and all-cause mortality, they found significantly higher hazard ratios in patients with eGFRcys much lower than their eGFRscr. Carrero and colleagues’ analysis boasts the largest population studied to date regarding this phenomenon.
Post-hoc findings
Pinsino and colleagues conducted a post-hoc analysis, published in November 2023 in the American Journal of Kidney Diseases, using eGFR data from the PARADIGM-HF project—a multicenter, randomized trial that compared sacubitril/valsartan to enalapril in ambulatory patients with heart failure with reduced ejection fraction. The analysis included baseline cystatin C and creatinine measurements from over 1,900 patients.
Like the Carrero study, Pinsino and colleagues calculated the intraindividual differences between eGFRscr and eGFRcys. Similarly, the authors found that patients with more negative eGFR differences—having eGFRcys lower than eGFRscr—were statistically linked to worse outcomes in the PARADIGM-HF trial’s endpoints, including CV mortality, heart failure hospitalization, worsening kidney function, and all-cause mortality. The well-characterized and controlled population of the Pinsino study strengthens its findings.
Controversial conclusions
In general, sCr is the gold standard filtration marker for measuring kidney function. However, it may be affected by factors such as age, sex, and muscle mass. The Kidney Disease: Improving Global Outcomes (KDIGO) workgroup guidelines recommend using cystatin C for confirmatory testing when creatinine is deemed unreliable. However, cystatin C is likewise variable and may be effected by chronic inflammation, obesity, smoking, and hyperthyroidism.
It is for these reasons that both the Carrero and Pinsino studies point to the effect of nonrenal factors and comorbidities as the most logical explanation for the differences seen between eGFRcys and eGFRscr. However, a prevailing hypothesis, known as shrunken pore syndrome (SPS), may alternatively explain the higher morbidity and mortality in patients with lower eGFRcys than eGFRscr.
SPS is hypothesized to be caused by shrunken or elongated pores within the glomerular basement membrane of the kidney’s nephrons. In the presence of this pathology, the shrunken pores of the glomerulus are unable to filter protein molecules that are 5 kDa to 30 kDa large, such as cystatin C and major inflammatory cytokines, but still able to filter smaller molecules such as creatinine (<1 kDA). In patients who are afflicted with SPS, the effect is demonstrated by an eGFRcys
that is much lower than eGFRscr. Since 2015, it has been known that an eGFRcys/eGFRscr ratio of less than 0.60 to 0.70 is diagnostic for SPS and that such findings may increase risk for all-cause mortality by threefold.
An editorial published in the American Journal of Kidney Diseases by Grub and colleagues in September 2023 speaks to the conclusions drawn by the Carrero and Pinsino studies. “From our perspective, more than 30 investigations published after the initial report of shrunken pore syndrome strongly support that further development of diagnosing kidney disorders is not to try to find nonrenal factors explaining the superiority of cystatin C over creatinine in predicting the mortality and morbidity associated with kidney disorders,” the authors wrote.
The authors of the editorial go on to assert that current recommendations for diagnosing and monitoring kidney disease by KDIGO are insufficient. “Simultaneous use of creatinine and cystatin C will allow identification of selective glomerular hypofiltration syndromes, which is not possible with the present KDIGO criteria. Selective glomerular hypofiltration syndromes may represent 0.3% to 36% of the individuals in the patient cohorts so far studied,” they wrote. ■