Heart – Kidney Interactions and Their Temporal Relationships

This thesis describes heart–kidney inter¬actions in patients with acquired heart disease, and was guided by four main objectives. First, to per¬form a critical appraisal of dynamic prediction modeling and interac¬tion testing in clinical studies. Second, to investigate how temporal trajectories of various kidney markers (glomerular: plasma creatinine and cystatin C; and tubular markers: urinary NAG and KIM-1, and plasma and urinary NGAL) relate to clinical prognosis in patients with chronic heart failure (HF). Moreover, in this context we explored the predictive utility of 29 new emerging HF biomarkers measured repeatedly during long-term (years) progression of HF. Third, to examine the dynamics of renal functioning during and just after acute coronary syndrome (ACS), as well as their predictive value for clinical prognosis. Kidney markers, cystatin C and NGAL, were also related to the coronary atherosclerotic burden in ACS patients by performing intravas-cular ultrasound (IVUS) virtual histology imaging of the patients’ non-culprit coronary vessels, and were related to clinical prognosis as well. Fourth, to evaluate the relationships between guideline-recommended HF medication adjustments and specific biomarker profiles, NYHA functional status and adverse clinical outcomes of patients with chronic HF during their long-term outpatient follow-up. In patients undergoing heart transplantation, we examined the relationship between preoperative right heart hemodynamic parameters and postoperative acute kidney injury. Finally, we used our 23-year long registry data of patients admitted for acute HF to assess the temporal trends of short- and long-term patient survival in relation to the presence of renal dysfunction and anemia

Renal tubular damage and worsening renal function in chronic heart failure:Clinical determinants and relation to prognosis (Bio-SHiFT study)

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes. Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants. Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation. Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]). Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive

Understanding of interaction (subgroup) analysis in clinical trials

Background: When the treatment effect on the outcome of interest is influenced by a baseline/demographic factor, investigators say that an interaction is present. In randomized clinical trials (RCTs), this type of analysis is typically referred to as subgroup analysis. Although interaction (or subgroup) analyses are usually stated as a secondary study objective, it is not uncommon that these results lead to changes in treatment protocols or even modify public health policies. Nonetheless, recent reviews have indicated that their proper assessment, interpretation and reporting remain challenging. Results: Therefore, this article provides an overview of these challenges, to help investigators find the best strategy for application of interaction analyses on binary outcomes in RCTs. Specifically, we discuss the key points of formal interaction testing, including the estimation of both additive and multiplicative interaction effects. We also provide recommendations that, if adhered to, could increase the clarity and the completeness of reports of RCTs. Conclusion: Altogether, this article provides a brief non-statistical guide for clinical investigators on how to perform, interpret and report interaction (subgroup) analyses in RCTs

Renal function and anemia in relation to short- and long-term prognosis of patients with acute heart failure in the period 1985-2008: A clinical cohort study

Background Renal dysfunction and anaemia are common in patients with acute heart failure (HF). It is not known whether their combined presence has additive prognostic value. We investigated their prognostic value separately and in combination, on prognosis in acute HF patients. Furthermore, we examined whether the improvement in prognosis was comparable between patients with and without renal dysfunction. Methods and results This prospective registry includes 1783 patients admitted to the (Intensive) Coronary Care Unit for acute HF in the period of 1985–2008. The outcome measure was the composite of all-cause mortality, heart transplantation and left ventricular assist device implantation. In patients without renal dysfunction, anemia was associated with worse 30-day outcome (HR 2.91; [95% CI 1.69–5.00]), but not with 10-year outcome (HR 1.13 [95% CI 0.93–1.37]). On the contrary, anemia was found to influence prognosis in patients with renal dysfunction, both at 30 days (HR 1.93 [95% CI 1.33–2.80]) and at 10 years (HR 1.27 [95% CI 1.10–1.47]). Over time, the 10-year survival rate improved in patients with preserved renal function (HR 0.73 [95% CI 0.55–0.97]), but not in patients with renal dysfunction. Conclusion The long-term prognosis of acute HF patients with a preserved renal function was found to have improved significantly. However, the prognosis of patients with renal dysfunction did not change. Anemia was a strong prognosticator for short-term outcome in all patients. In patients with renal dysfunction, anemia was also associated with impaired long-term prognosis

Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome:BIOMArCS study

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). Results: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2–3. During hospitalization for index ACS (median [IQR] duration: 5 (3–7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03–2.74]). Conclusion: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score

Renal tubular damage and worsening renal function in chronic heart failure: Clinical determinants and relation to prognosis (Bio-SHiFT study)

Background: It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes. Hypothesis: Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants. Methods: During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-β-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation. Results: Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m2 eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m2 eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]). Conclusion: Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive

Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: F

Preoperative right heart hemodynamics predict postoperative acute kidney injury after heart transplantation

Purpose: Acute kidney injury (AKI) frequently occurs after heart transplantation (HTx), but its relation to preoperative right heart hemodynamic (RHH) parameters remains unknown. Therefore, we aimed to determine their predictive properties for postoperative AKI severity within 30 days after HTx. Methods: From 1984 to 2016, all consecutive HTx recipients (n = 595) in our tertiary referral center were included and analyzed for the occurrence of postoperative AKI staged by the kidney disease improving global outcome criteria. The effects of preoperative RHH parameters on postoperative AKI were calculated using logistic regression, and predictive accuracy was assessed using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under the receiver operating characteristic curves (AUC). Results: Postoperative AKI occurred in 430 (72%) patients including 278 (47%) stage 1, 66 (11%) stage 2, and 86 (14%) stage 3 cases. Renal replacement therapy (RRT) was administered in 41 (7%) patients. Patients with higher AKI stages had also higher baseline right atrial pressure (RAP; median 7, 7, 8, and in RRT 11 mmHg, p trend = 0.021), RAP-to-pulmonary capillary wedge pressure ratio (median 0.37, 0.36, 0.40, 0.47, p trend = 0.009), and lower pulmonary artery pulsatility index (PAPi) values (median 2.83, 3.17, 2.54, 2.31, p trend = 0.012). Higher RAP and lower PAPi values independently predicted AKI severity [adjusted odds ratio (OR) per doubling of RAP 1.16 (1.02–1.32), p = 0.029; of PAPi 0.85 (0.75–0.96), p = 0.008]. Based on IDI, NRI, and delta AUC, inclusion of these parameters improved the models’ predictive accuracy. Conclusions: Preoperative PAPi and RAP strongly predict the development of AKI early after HTx and can be used as early AKI predictors

Plasma cystatin C and neutrophil gelatinase-associated lipocalin in relation to coronary atherosclerosis on intravascular ultrasound and cardiovascular outcome

Background and aims We investigated whether plasma cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) are associated with intravascular ultrasound (IVUS)-derived characteristics of coronary atherosclerosis and 1-year adverse coronary events in patients with normal and mildly-to-moderately impaired kidney function. Methods Between 2008 and 2011, virtual histology (VH)-IVUS of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography. Creatinine, CysC and NGAL were measured in pre-procedural blood samples. Presence of VH-IVUS-derived thin-cap fibroatheroma (TCFA) lesions, lesions with plaque burden (PB)≥70% and lesions with minimal luminal area (MLA)≤4 mm2 was assessed. Major adverse coronary events (MACE) comprised the composite of all-cause mortality, acute coronary syndrome, or unplanned coronary revascularization. Analyses were stratified using eGFRCr of 90 ml/min/1.73 m2 as the cut-off. Results In patients with normal kidney function, those with higher CysC levels had fewer lesions with PB ≥ 70% and fewer VH-TCFA lesions (adjusted odds ratios (ORs) and 95% confidence intervals (CIs): 0.46 [0.30–0.69] and 0.59 [0.44–0.83], respectively, per standard deviation (SD) ln[ng/mL] CysC). Those with higher NGAL levels also had fewer lesions with PB ≥ 70% (adjusted OR [95% CI]:0.49 [0.29–0.82]) In patients with impaired kidneys, no differences in high-risk lesions were observed for CysC or NGAL. However, those with higher CysC had higher risk of MACE (hazard ratio (HR):1.4, 95% CI [1.03–1.92]). This was not the case in patients with normal kidney function. NGAL did not influence risk of MACE. Conclusions: Mild-to-moderate kidney dysfunction modifies the relationship between CysC and high-risk coronary lesions. This has not been established before, and offers an explanation for the difference in findings between experimental and epidemiologic studies