Trajectories of Kidney Function in Heart Failure Over a 15-Year Follow-Up: Clinical Profiling and Mortality.

BACKGROUND: Limited data are available on the long-term trajectory of estimated glomerular filtration rate (eGFR) in patients with chronic heart failure. OBJECTIVES: The authors evaluated eGFR dynamics using the 2009 Chronic Kidney Disease Epidemiology Collaboration equation and its prognostic significance in a real-world cohort over a 15-year follow-up. METHODS: A prospective observational registry of ambulatory heart failure outpatients was conducted, with regular eGFR assessments at baseline and on a 3-month schedule for ≤15 years. Urgent kidney function assessments were excluded. Locally weighted error sum of squares curves were plotted for predefined subgroups. Multivariable longitudinal Cox regression analyses were conducted to assess associations with all-cause and cardiovascular death. RESULTS: A total of 2,672 patients were enrolled consecutively between August 2001 and December 2021. The average age was 66.8 ± 12.6 years, and 69.8% were men. Among 40,970 creatinine measurements, 28,634 were used for eGFR analysis, averaging 10.7 ± 8.5 per patient. Over the study period, a significant decline in eGFR was observed in the entire cohort, with a slope of -1.70 mL/min/1.73 m2 per year (95% CI: -1.75 to -1.66 mL/min/1.73 m2 per year). Older patients, those with diabetes, a preserved ejection fraction, a higher baseline eGFR, elevated hospitalization rates, and those who died during follow-up experienced more pronounced decreases in the eGFR. Moreover, the decrease in kidney function correlated independently with all-cause mortality and cardiovascular death. CONCLUSIONS: These findings highlight the sustained decline in eGFR over 15 years in patients with heart failure, with variations based on clinical characteristics, and emphasize the importance of regular eGFR monitoring in this population.

Albuminuria, Forgotten No More: Underlining the Emerging Role in CardioRenal Crosstalk.

Kidneys have an amazing ability to adapt to adverse situations, both acute and chronic. In the presence of injury, the kidney is able to activate mechanisms such as autoregulation or glomerular hyperfiltration to maintain the glomerular filtration rate (GFR). While these adaptive mechanisms can occur in physiological situations such as pregnancy or high protein intake, they can also occur as an early manifestation of diseases such as diabetes mellitus or as an adaptive response to nephron loss. Although over-activation of these mechanisms can lead to intraglomerular hypertension and albuminuria, other associated mechanisms related to the activation of inflammasome pathways, including endothelial and tubular damage, and the hemodynamic effects of increased activity of the renin-angiotensin-aldosterone system, among others, are recognized pathways for the development of albuminuria. While the role of albuminuria in the progression of chronic kidney disease (CKD) is well known, there is increasing evidence of its negative association with cardiovascular events. For example, the presence of albuminuria is associated with an increased likelihood of developing heart failure (HF), even in patients with normal GFR, and the role of albuminuria in atherosclerosis has recently been described. Albuminuria is associated with adverse outcomes such as mortality and HF hospitalization. On the other hand, it is increasingly known that the systemic effects of congestion are mainly preceded by increased central venous pressure and transmitted retrogradely to organs such as the liver or kidney. With regard to the latter, a new entity called congestive nephropathy is emerging, in which increased renal venous pressure can lead to albuminuria. Fortunately, the presence of albuminuria is modifiable and new treatments are now available to reverse this common risk factor in the cardiorenal interaction.

Global warming, renal function and heart failure over 20 years.

BACKGROUND: The impact of increasing temperatures on renal function in heart failure (HF) outpatients has never been specifically analyzed. METHODS: We retrieved creatinine and estimated glomerular filtration rate (eGFR) values of all HF outpatients followed at a HF clinic and temperature data from 2002 to 2021. For each patient and each year we averaged values of creatinine, eGFR and monthly temperatures during summer and the rest of the year. RESULTS: The study cohort included 2167 HF patients undergoing 25,865 elective visits, with a median of 14 visits for each patient (interquartile range 7-23). At the first visit, patients (70% men) had an age of 67 ± 13 years, and a left ventricular ejection fraction of 35 ± 14%. Creatinine was 1.25 ± 0.51 mg/dL, and eGFR was 65 ± 25 mL/min/1.73 m2. When pooling together all average values of creatinine and eGFR measured during summer or in the rest of the year, creatinine was significantly higher in summer (difference 0.04, 95% confidence interval [CI] 0.04 to 0.05, p < 0.001), and eGFR was slightly lower (difference - 2.0, 95% CI -2.3 to -1.8, p < 0.001). Temperature rise during summer increased from 2002 to 2021. The absolute (Δ) and percent (Δ%) elevation in temperature during summer displayed independent associations with Δ and Δ% creatinine and eGFR after adjusting for age, sex, plasma creatinine, and HF therapies. CONCLUSIONS: The magnitude of temperature elevation during summer has increased over 20 years. This elevation correlates with the decline in renal function during summer. This might be an example of how global warming is affecting human health.

The "FIFTY SHADOWS" of the RALES Trial: Lessons about the Potential Risk of Dietary Potassium Supplementation in Patients with Chronic Kidney Disease.

Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin-angiotensin-aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of "occult" CKD, HF, and in patients taking RAASis and/or MRAs.

Silver jubilee: 25 years of the first demonstration of the direct effect of phosphate on the parathyroid cell.

Although phosphorus is an essential element for life, it is not found in nature in its native state but rather combined in the form of inorganic phosphates (PO43-), with tightly regulated plasma levels that are associated with deleterious effects and mortality when these are out of bounds. The growing interest in the accumulation of PO43- in human pathophysiology originated in its attributed role in the pathogenesis of secondary hyperparathyroidism (SHPT) in chronic kidney disease. In this article, we review the mechanisms by which this effect was justified and we commemorate the important contribution of a Spanish group led by Dr. M. Rodríguez, just 25 years ago, when they first demonstrated the direct effect of PO43- on the regulation of the synthesis and secretion of parathyroid hormone by maintaining the structural integrity of the parathyroid glands in their original experimental model. In addition to demonstrating the importance of arachidonic acid (AA) and the phospholipase A2-AA pathway as a mediator of parathyroid gland response, these findings were predecessors of the recent description of the important role of PO43- on the activity of the calcium sensor-receptor, and also fueled various lines of research on the importance of PO43- overload not only for the pathophysiology of SHPT but also in its systemic pathogenic role.

No benefit from the obesity paradox for diabetic patients with heart failure.

AIMS: Paradoxically, obesity is associated with survival in heart failure (HF). Whether this is true for HF patients with comorbid type-2 diabetes (T2D) remains uncertain. Our aim was to address this issue in diabetic patients by collecting correlates for body mass index (BMI) and long-term mortality. METHOD AND RESULTS: Both BMI and survival after a mean follow-up of 4.3 ± 3.0 years (up to 10 years) were assessed for 2527 ambulatory patients (66.3% men; mean age 69 ± 12.3 years). A total of 1102 (43.6%) patients had T2D and ischaemic aetiology of HF was present in 47.8%; mean left ventricular ejection fraction was 38 ± 16%. Based on BMI scores, patients were categorized as either underweight, normal, overweight, or obese. A significant survival interaction was observed between BMI and T2D. Smooth spline curves for the estimation of risk of all-cause and cardiovascular death showed the classic obesity paradox, with reduced mortality as BMI increased in non-diabetics; for T2D patients this pattern was lost. After adjustment for age and sex, hazard ratios for low-weight and obesity were: 2.04 [95% confidence intervals (CI) 1.50-2.78, P < 0.001] and 0.76 (95% CI 0.58-0.99, P = 0.04), respectively, for non-T2D patients; and 1.30 (95% CI 0.77-2.19, P = 0.32) and 0.99 (95% CI 0.78-1.26, P = 0.95), respectively, for T2D patients. Multivariate analyses for mortality (including BMI as a continuous variable) were significant for non-diabetic patients only. CONCLUSIONS: In patients with HF, but without T2D, the obesity paradox was present; however, T2D removed this phenomenon. Advice about weight loss for obese diabetic patients with HF requires further research.

Aging and Heart Rate in Heart Failure: Clinical Implications for Long-term Mortality.

OBJECTIVE: To assess the relationship between resting heart rate and long-term all-cause mortality in ambulatory patients with heart failure (HF) relative to age, considering that although heart rate has been strongly associated with mortality in HF, the influence of age on target heart rate is incompletely characterized. PATIENTS AND METHODS: Consecutive patients in sinus rhythm referred to an ambulatory HF clinic of a university hospital between August 1, 2001, and March 31, 2012, were included. Unadjusted and adjusted Cox regression analyses were performed to assess heart rate as a prognostic marker, both as a continuous variable and after categorization into quintiles. Smooth spline estimates and hazard ratios (HRs) were plotted for 2 age strata (<75 years vs ≥75 years) for each individual heart rate. RESULTS: A total of 1033 patients were included (766 men [74.2%]; mean age, 65.1±12.6 years). During a mean follow-up of 4.6±3.3 years (median, 3.8 years [25th-75th percentile, 1.9-6.9]), 476 patients (46.1%) died. Mortality was associated with a statistically greater heart rate in the total cohort (HR, 1.18; 95% CI, 1.11-1.26; P<.001). From a clinical viewpoint, this means an 18% increased risk for every 10-beats/min elevation in heart rate. The same characteristics were present in the relationship between heart rate assessed after 6 months and long-term mortality (HR, 1.30; 95% CI, 1.20-1.42; P<.001). Overall, the prognostic importance of heart rate in ambulatory patients with HF was largely influenced by patient age. Remarkably, in the elderly population (≥75 years), heart rate below 68 beats/min conferred an increased risk of death, whereas in younger patients, mortality exhibited a declining slope at even the lowest heart rates. CONCLUSION: Our research, if applicable to the prospective management of patients with ambulatory HF, suggests that patients aged 75 years or older have the best outcomes with target heart rates of 68 beats/min; however, younger patients may benefit from lower heart rates, even below 55 beats/min.

Renal function largely influences Galectin-3 prognostic value in heart failure.

BACKGROUND: Galectin-3 (Gal-3) has been associated with cardiac remodeling and heart failure (HF) prognosis. Renal function is also a well known HF prognostic indicator. The link between renal insufficiency, HF, and Gal-3 is not completely elucidated. METHODS AND RESULTS: We explored the association between Gal-3 and renal function in a cohort of 876 consecutive ambulatory patients with HF (mean age: 68 years; mean left ventricular ejection fraction [LVEF]: 36%), 52.2% had HF etiology of ischemic heart disease. Circulating Gal-3 was highly correlated with estimated glomerular filtration rate (eGFR), calculated with either the chronic kidney disease-epidemiology (CKD-EPI) equation (r = -0.64) or the CKD-EPI-cystatin-C equation (r = -0.59) and with Cystatin-C levels (r = 0.70), after adjusting for age, sex, New York Heart Association (NYHA) functional class, LVEF, and HF etiology (all p<0.001). Patients were stratified by CKD-EPI-eGFR (ml/min/1.73 m(2)), as follows: ≥ 60 (n = 218), 30 to 59 (n = 434), and <30 (n = 224). In these strata, Gal-3 significantly increased (median [IQR]: 12.3 [10.4-15.6]; 16.1 [13-19.8]; and 24.5 [20-33.8] ng/ml, respectively; trend p < 0.001). This was independent of NYHA functional class (I-II and III-IV) and LVEF (<45% and ≥ 45%). Gal-3 was associated with mortality in univariate analyses, but after adjusting for CKD-EPI-eGFR, the hazard ratios were 1.10 (95% CI: 0.89-1.34, p = 0.39) for all cause death, and 0.90 (95% CI: 0.68-1.21, p = 0.50) for cardiovascular death. Similar results were obtained with eGFRs calculated with the CKD-EPI-cystatin-C equation. CONCLUSION: Circulating Gal-3 was highly associated with renal function in outpatients with HF. The value of Gal-3 for HF prognosis declined after adjusting for renal function.