The cardiorenal syndrome: Structural and functional aspects including associations with the shrunken pore syndrome

Mild to moderate renal impairment affects 10% of the general population. Renal impairment is difficult to detect because of the lack of symptoms, but it can be estimated by calculating the estimated glomerular filtration rate (eGFR) on the basis of plasma creatinine and/or cystatin C concentrations. Chronic kidney disease (CKD) is associated with an increased risk of development of cardiovascular disease and an increase in the mortality rate. As kidney function decreases, structural and functional changes in the heart increase. Cardiovascular disease also affects renal function, leading to CKD. This pathophysiological association between the two organs is referred to as cardiorenal syndrome (CRS). Mortality and morbidity rates are increased in patients with CRS, and early detection of this syndrome can lead to a reduction in the disease burden. To more accurately stage CKD and calculate the mortality risk, the eGFR based on creatinine (eGFRCR) and cystatin C (eGFRCYS) is recommended for use in clinical practice. The eGFRCYS and eGFRCR usually correspond well with each other. In some individuals, the eGFRCYS/eGFRCR ratio is < 0.7, and it is associated with increased morbidity and mortality. A selective decrease in renal filtration of cystatin C is thought to cause the difference between eGFRCYS and eGFRCR, and this condition is called shrunken pore syndrome (SPS). This thesis presents studies on the early detection of CRS and the association of SPS with mortality and morbidity in patients with heart failure (HF) and in individuals who were randomly chosen from a population-based cohort. In Paper I, data from 1504 individuals without HF from the Malmö Prevention Project, which is a population-based cohort, showed significant associations between mild to moderate impairment of renal function and echocardiographic markers of cardiac structure and diastolic function. These findings support the hypothesis that there is an interaction between the kidney and heart, even at eGFR 45–60 mL/min/1.73 m2. In Papers II and III, data from approximately 300 hospitalized patients with HF from the HeARt and brain failure inVESTigation trial showed an association between SPS and a doubled risk of all-cause mortality, higher risk of 30-day rehospitalization, and impaired quality of life. Proteomic analyses showed that in patients with HF, SPS was associated with proteins related to atherosclerosis and cell proliferation. These findings may help identify pathophysiological pathways involved in the known adverse effects of SPS. In Paper IV, data from 5061 individuals from the Malmö Diet and Cancer cardiovascular cohort, which is a population-based cohort, showed that SPS affected as much as 8% of the general middle-aged population, and that individuals with SPS had a 38% higher risk of all-cause mortality. In conclusion, structural changes in the heart can develop already at mild to moderate impairment of renal function. SPS is an important predictor of mortality in patients with HF and in individuals in the general population. Further studies are required to investigate the pathophysiology of SPS and the mechanism behind the association between SPS and mortality

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.publishedVersio

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

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. This article is protected by copyright. All rights reserved

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 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 identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterised by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules < 1kDa dominating the glomerular filtrate e.g., water, urea, 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 characterised 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. This article is protected by copyright. All rights reserved