The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

The Shrunken pore syndrome is associated with poor prognosis and lower quality of life in heart failure patients: the HARVEST-Malmö study.

AIMS: This study aimed to investigate the association between the 'Shrunken pore syndrome' (SPS) and risk of death, 30 day rehospitalization, and health-related quality of life (QoL) in heart failure (HF) patients. SPS is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C /eGFRcreatinine ratio. METHODS AND RESULTS: A total of 373 patients hospitalized for HF [mean age 74.8 (±12.1) years; 118 (31.6%) women] were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmö). Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used for estimation of glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatin C  ≤ 60% of eGFRcreatinine . In Cox regression multivariate models, associations between SPS, risk of death (median follow-up time 1.8 years), and risk of 30 day rehospitalization were studied. Associations between SPS and impaired QoL were studied using multivariate logistic regressions. In multivariate models, SPS was associated with all-cause mortality [124 events; hazard ratio (HR) 1.99; 95% confidence interval (95% CI) 1.23-3.21; P = 0.005] and with 30 day rehospitalization (70 events; HR 1.82; CI 95% 1.04-3.18; P = 0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score < 50, revealed that SPS was associated with higher risk of low health-related QoL (odds ratios 2.15; CI 95% 1.03-4.49; P = 0.042). CONCLUSIONS: The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms.

Proteins linked to atherosclerosis and cell proliferation are associated with the shrunken pore syndrome in heart failure patients: Shrunken pore syndrome and proteomic associations.

PURPOSE: The "Shrunken pore syndrome" (SPS) is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatinC /eGFRcreatinine -ratio. Studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with SPS. In this discovery study, we explored associations between SPS and proteins implicated in cardiovascular disease and inflammation in patients with heart failure. EXPERIMENTAL DESIGN: Plasma samples from 300 individuals in HARVEST-Malmö trial hospitalized for the diagnosis of heart failure (mean age 74.9 ± 11.5 years; 30.0% female), were analyzed with a proximity extension assay consisting of 92 proteins. A Bonferroni-corrected p-value of 0.05/92 = 5.4 × 10-4 was considered significant in the initial age and sex-adjusted analyses. Presence of SPS was defined as eGFRcystatinC ≤ 60% of eGFRcreatinine . RESULTS: SPS presented with significant associations (p < 5.4 × 10-4 ) in age and sex-adjusted logistic regressions with elevated levels of six proteins; scavenger receptor cysteine rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosine-protein kinase receptor UFO. All proteins remained associated (p < 0.05) with SPS after multivariate adjustments. CONCLUSIONS AND CLINICAL RELEVANCE: In heart failure patients, SPS was associated with proteins linked to atherosclerosis and cell proliferation.

Echocardiographic Findings in Patients with Mild to Moderate Chronic Kidney Disease without Symptomatic Heart Failure: A Population-Based Study.

BACKGROUND: Renal dysfunction is an established risk factor for cardiovascular disease, but early disease states in both organs are poorly studied. OBJECTIVE: This cross-sectional population-based study aims to investigate if there is an early association between kidney function and echocardiographic markers of cardiac structure and diastolic function. METHODS: The study population consisted of 1,504 individuals with no prior history of congestive heart failure or asymptomatic left ventricular ejection fraction ≤40% and an estimated glomerular filtration rate (eGFR) based on cystatin C >15 mL/min/1.73 m2. The participants were categorized according to eGFR ≥90, 75-89, 60-74, 45-59, 30-44, and 15-29 mL/min/1.73 m2. We evaluated associations between eGFR categories and echocardiographic findings specific to cardiac structure and diastolic function. RESULTS: Associations between eGFR categories and echocardiographic findings were found for left atrium area/body surface area (p = 0.013) indicating structural changes, and peak early mitral valve velocity (A; p = 0.003), peak late atrial mitral valve velocity/peak systolic myocardial velocity at mitral annulus in the lateral wall (E/Élat; p = 0.002), É mean of lateral and septal wall/Á mean of lateral and septal wall (mean É/Á; p = 0.027) indicating diastolic dysfunction. Associations between E/Élat and mean É/Á and eGFR categories were already present in individuals with eGFR 45-60 mL/min/1.73 m2. In sex-specific analysis these associations were only significant among men. CONCLUSION: A significant association between mild to moderate impairment of renal function and echocardiographic markers of cardiac structure and diastolic function was observed, supporting the hypothesis that interaction between the kidney and heart exists even in the early stages of renal impairment.