UNASSIGNED: Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM) patients. Shrunken pore syndrome (SPS) is defined as eGFRcystatin C/eGFRcreatinine ratio <0.70 and predicts high CVD mortality. The Framingham Risk Score (FRS) is used to estimate an individual\'s 10-year CVD risk. This study investigated the association between FRS and eGFRcystatin C/eGFRcreatinine ratio in T2DM patients.
UNASSIGNED: Patients aged 18-80 years who were newly diagnosed with T2DM were included in this retrospective study. Ordinal logistic regression analysis was used to investigate the association between risk factors of T2DM and FRS. A Generalized Linear Model was used to calculate odds ratios (OR) and 95% confidence intervals (CI).
UNASSIGNED: There were 270 patients included in the study. Only 27 patients (10%) met the diagnostic criteria of SPS. Ordinal logistic regression analysis showed that SPS was not correlated with FRS risk (OR = 1.99, 95%CI = 0.94-4.23, p = 0.07), whereas eGFRcystatin C/eGFRcreatinine (OR = 0.86, 95%CI = 0.77-0.97, p = 0.01) showed a significant negative association with FRS risk. Compared with eGFRcystatin C/eGFRcreatinine>0.85, eGFRcystatin C/eGFRcreatinine≤0.85 increased FRS risk (OR = 1.95, 95%CI = 1.18-3.21, p < 0.01). After adjustment for confounding factors, increased eGFRcystatin C/eGFRcreatinine ratio was associated with decreased FRS risk when considered as a continuous variable (OR = 0.87, 95%CI = 0.77-0.99, p = 0.03). The FRS risk in patients with eGFRcystatin C/eGFRcreatinine≤0.85 is 1.86 times higher than that in patients with eGFRcystatin C/eGFRcreatinine>0.85 (OR = 1.86, 95%CI = 1.08-3.21, p = 0.03).
UNASSIGNED: In the current study, no significant association between SPS and FRS was identified. However, lower eGFRcystatin C/eGFRcreatinine and eGFRcystatin C/eGFRcreatinine≤0.85 were associated with a significantly increased CVD risk in T2DM.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, β2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

BACKGROUND: Shrunken pore syndrome (SPS) is defined as cystatin C-based-eGFR (eGFRcys)/creatinine-based-eGFR (eGFRcreat) <0.6 or 0.7 and is associated with an increased cardiovascular risk. SPS has been described in children, but no link to increased morbi-mortality was demonstrated.
OBJECTIVE: Study the prevalence of SPS in a pediatric population using several glomerular filtration rate (GFR) estimating formulas and measured GFR and evaluate the potential link with cardiovascular risk.
METHODS: In 307 renal risk pediatric patients, we studied prevalence of SPS either with CKiDU25creat and cyst or with FAScreat and cyst and EKFCcreat. The characteristics of patients with SPS (defined with Full-age spectrum equation (FAS) and/or European Kidney Function Consortium equation (EKFC)) were compared.
CONCLUSIONS: The prevalence of SPS varies widely depending on the threshold and the formulas used. Higher C-reactive protein (CRP) and phosphate levels and smaller size are observed in children with SPS defined with FAS and/or EKFC and might be associated with long-term increased cardiovascular risk. Further studies in wider general pediatric populations are warranted.

Shrunken Pore Syndrome (SPS), defined as a reduced ratio between two estimated filtration rates (based on cystatin C and creatinine) is an increasingly recognized risk factor for long-term mortality. Although some patients with other conditions might be erroneously identified as SPS. Our aim was to bring the focus on possible pathophysiologic mechanisms influencing the ratio in the setting of SARS-CoV-2 pneumonia and acute kidney injury.
A single-centered prospective cohort study was conducted to investigate biomarkers in symptomatic COVID-19 pneumonia patients admitted to a hospital in Latvia. Nineteen biomarkers were measured in blood and three in urine samples. Associations were sought between these biomarkers, chronic diseases and the estimated GFRcystatinC/eGFRcreatinine ratio < 0.6, mortality rates, and acute kidney injury development. Data analysis was performed using SPSS Statistics, with significance set at p < 0.05.
We included 59 patients (average age 65.5 years, 45.8% female) admitted with COVID-19. Acute kidney injury occurred in 27.1%, and 25.4% died. Ratio < 0.6 was seen in 38.6%, associated with female sex, diabetes, hypothyroidism, and higher age. Ratio < 0.6 group had mortality notably higher - 40.9% vs. 16.2% and more cases of acute kidney injury (40.9% vs. 18.9%). Cystatin C showed strong associations with the ratio < 0.6 compared to creatinine. Urea levels and urea/creatinine ratio were higher in the ratio < 0.6 group. After excluding acute kidney injury patients, ratio < 0.6 remained associated with higher cystatin C and urea levels. Other biomarkers linked to a kidney injury as NGAL, and proteinuria did not differ.
We prove that reduced ratio is common in hospitalized patients with SARS-CoV-2 pneumonia and is associated with increased mortality during hospitalization. Factors that influence this ratio are complex and, in addition to the possible shrinkage of pores, other conditions such as thickening of glomerular basal membrane, comorbidities, prerenal kidney failure and others may play an important role and should be addressed when diagnosing SPS. We highlight the need for additional diagnostic criteria for SPS and larger studies to better understand its implications in acute COVID-19 settings.

In this issue of Clinical Kidney Journal, Stehlé and colleagues demonstrate that estimation of glomerular filtration rate (GFR) by use of creatinine and a measure, total lumbar muscle cross-sectional area, reflecting the total muscle mass of an individual, is superior to GFR-estimating equations based upon creatinine and demographic variables. The report by Stehlé et al. demonstrates one solution to the interference of muscle mass in the use of creatinine to estimate GFR. This interference was identified already at the start, in 1959, of using creatinine for estimation of GFR. Different ways of taking the muscle mass into account when creatinine-based estimations of GFR have been used generally include use of controversial race and sex coefficients. A new marker of GFR, cystatin C, introduced in 1979, has been shown to be virtually uninfluenced by muscle mass. In this editorial, the simultaneous use of creatinine and cystatin C to estimate GFR, muscle mass and selective glomerular hypofiltration syndromes is described.

Background Shrunken pore syndrome (SPS) as a novel phenotype of renal dysfunction is characterized by a difference in renal filtration between cystatin C and creatinine. The manifestation of SPS was defined as a cystatin C-based estimated glomerular filtration rate (eGFR) <60% of the creatinine-based eGFR. SPS has been shown to be associated with the progression and adverse prognosis of various cardiovascular and renal diseases. However, the predictive value of SPS for contrast-associated acute kidney injury (CA-AKI) and long-term outcomes in patients undergoing percutaneous coronary intervention remains unclear. Methods and Results We retrospectively observed 5050 consenting patients from January 2012 to December 2018. Serum cystatin C and creatinine were measured and applied to corresponding 2012 and 2021 Chronic Kidney Disease Epidemiology Collaboration equations, respectively, to calculate the eGFR. Chronic kidney disease (CKD) was defined as a creatinine-based eGFR <60 mL/min per 1.73 m2 without dialysis. CA-AKI was defined as an increase in serum creatinine ≥50% or 0.3 mg/dL within 48 hours after contrast medium exposure. Overall, 649 (12.85%) patients had SPS, and 324 (6.42%) patients developed CA-AKI. Multivariate logistic regression analysis indicated that SPS was significantly associated with CA-AKI after adjusting for potential confounding factors (odds ratio [OR], 4.17 [95% CI, 3.17-5.46]; P<0.001). Receiver operating characteristic analysis indicated that the cystatin C-based eGFR:creatinine-based eGFR ratio had a better performance and stronger predictive power for CA-AKI than creatinine-based eGFR (area under the curve: 0.707 versus 0.562; P<0.001). Multivariate logistic analysis revealed that compared with those without CKD and SPS simultaneously, patients with CKD and non-SPS (OR, 1.70 [95% CI, 1.11-2.55]; P=0.012), non-CKD and SPS (OR, 4.02 [95% CI, 2.98-5.39]; P<0.001), and CKD and SPS (OR, 8.62 [95% CI, 4.67-15.7]; P<0.001) had an increased risk of CA-AKI. Patients with both SPS and CKD presented the highest risk of long-term mortality compared with those without both (hazard ratio, 2.30 [95% CI, 1.38-3.86]; P=0.002). Conclusions SPS is a new and more powerful phenotype of renal dysfunction for predicting CA-AKI than CKD and will bring new insights for an accurate clinical assessment of the risk of CA-AKI.

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of patients with COVID-19 treated in an intensive care unit. SPS was defined as a ratio < 0.7 when the estimated glomerular filtration rate (eGFR), determined by cystatin C, calculated by the Cystatin C Caucasian-Asian-Pediatric-Adult equation (CAPA), was divided by the eGFR determined by creatinine, calculated by the revised Lund−Malmö creatinine equation (LMR). Clinical data were prospectively collected. In total, SPS was present in 86 (24%) of 352 patients with COVID-19 on ICU admission. Patients with SPS had a higher BMI, Simplified Physiology Score (SAPS3), and had diabetes and/or hypertension more frequently than patients without SPS. Ninety-nine patients in the total cohort were women, 50 of whom had SPS. In dexamethasone-naïve patients, C-reactive protein (CRP ), TNF-alpha, and interleukin-6 did not differ between SPS and non-SPS patients. Demographic factors (gender, BMI) and illness severity (SAPS3) were independent predictors of SPS. Age and dexamethasone treatment did not affect the frequency of SPS after adjustments for age, sex, BMI, and acute severity. SPS is frequent in severely ill COVID-19 patients. Female gender was associated with a higher proportion of SPS. Demographic factors and illness severity were independent predictors of SPS.

Childhood cancer survivors (CCS) are at risk of kidney dysfunction. Recently, the shrunken pore syndrome (SPS) has been described, which is characterized by selectively impaired filtration of larger molecules like cystatin C, while filtration of smaller molecules like creatinine is unaltered. It has been associated with increased mortality, even in the presence of a normal estimated glomerular filtration rate (eGFR). The aim of this study was to evaluate the prevalence of SPS in CCS exposed to potentially nephrotoxic therapy. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 Renal study, a nationwide cross-sectional cohort study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated, and 500 age- and sex-matched controls form Lifelines. SPS was defined as an eGFRcys/eGFRcr ratio <0.6 in the absence of non-GFR determinants of cystatin C and creatinine metabolism (i.e. hyperthyroidism, corticosteroids, underweight). Three pairs of eGFR-equations were used; CKD-EPIcys/CKD-EPIcr, CAPA/LMR, and FAScys/FASage. Median age was 32 years. Although an eGFRcys/eGFRcr ratio <0.6 was more common in CCS (1.0%) than controls (0%) based on the CKD-EPI equations, most cases were explained by non-GFR determinants. The prevalence of SPS in CCS was 0.3% (CKD-EPI equations), 0.2% (CAPA/LMR) and 0.1% (FAS equations), and not increased compared to controls. CCS treated with nephrotoxic therapy are not at increased risk for SPS compared to controls. Yet, non-GFR determinants are more common and should be taken into account when estimating GFR.

To assess the association between cystatin C-derived estimates of kidney function and mortality and acute kidney injury (AKI) in sepsis.
Post-hoc analysis of sepsis patients in the FINNAKI-cohort (n = 802). Primary outcome was 90-day mortality. We measured plasma cystatin C and creatinine at intensive care unit (ICU) admission and estimated glomerular filtration rates (eGFRcys, eGFRcrea) and shrunken pore syndrome (SPS; defined as eGFRcys/eGFRcrea ratio < 0.7). Associations were assessed using Cox- or logistic regression.
Increased cystatin C and decreased eGFRcys were associated with mortality in unadjusted analyses and in analyses adjusted for illness severity and creatinine. Hazard ratios (HRs) in unadjusted analyses were 3.30 (95% CI; 2.12-5.13, p < 0.001) and 3.26 (95% CI; 2.12-5.02, p < 0.001) respectively. SPS was associated with mortality in an unadjusted- (HR 1.78, 95% CI; 1.33-2.37, p < 0.001) and in an adjusted analysis (HR 1.54, 95% CI; 1.07-2.22, p = 0.021). All cystatin C-derived measures were associated with mortality also after adjustment for AKI development. Cystatin C was associated with AKI in unadjusted analyses but not in analyses adjusted for creatinine.
Cystatin C and derived measures of kidney function at ICU admission are associated with an increased 90-day mortality. Increased AKI incidence does not fully explain this association.

Impaired renal function is associated both with the development of cardiovascular disease and its prognosis. A new syndrome called \'Shrunken Pore Syndrome\' has been suggested, as the estimated glomerular filtration rate for cystatin C (eGFRcystatin C) is affected earlier due to differences in molecular size compared to eGFRcreatinine. The aim was to investigate if a lower eGFRcystatin C/eGFRcreatinine ratio in a prospective setting increases the risk of later developing a first-ever myocardial infarction (MI) independently of other cardiovascular risk factors. We used a nested case-referent study design within the Northern Sweden Health and Disease Study, and 545 subjects (29.0% women) were identified who prospectively developed a first-ever MI, and their 1054 matched referents. For women, but not for men, one standard deviation (SD) increase of ln z-scores of eGFRcystatin C/eGFRcreatinine ratio was associated with a lower risk of a future MI: odds ratio [95% confidence interval] 0.58 [0.34-0.99], adjusted for apolipoprotein B/A1 ratio, CRP, homocysteine, systolic blood pressure, body mass index, and diabetes. Furthermore, a high eGFRcreatinine associated independently with an increased risk of future MI in men only: OR 1.25 [1.05-1.48]. Thus, for women, a lower eGFRcystatin C/eGFRcreatinine ratio is associated with a higher risk of having a future first-ever MI, and it may be a valuable, easily implemented biomarker for risk of cardiovascular disease.