Prognostic value of glomerular filtration changes versus natriuretic response in decompensated heart failure with reduced ejection.

BACKGROUND: Glomerular filtration rate (GFR) and natriuretic response to diuretics represent important treatment targets in acute decompensated heart failure (ADHF). METHODS AND RESULTS: Consecutive ADHF patients (n = 50) with ejection fraction ≤ 45% and clinical signs of volume overload received protocol-driven decongestive therapy. Serum creatinine (Cr), cystatin C (CysC), and ß-trace protein (ßTP) were measured on admission and three subsequent days of treatment. Worsening renal function (WRF) was defined as a ≥ 0.3 increase in absolute biomarker levels or ≥ 20% decrease in estimated GFR. Consecutive 24-hour urinary collections were simultaneously performed to measure Cr clearance and natriuresis. Serum Cr, CysC, and ßTP were strongly correlated at admission (ρ = 0.788-0.909) and during decongestive treatment (ρ = 0.884-888). Moreover, derived GFR estimates correlated well with Cr clearance (ρ = 0.820-0.908). Nevertheless, WRF incidence differed markedly according to Cr- (26%-30%), CysC- (46%-54%), or ßTP-based definitions (31%-48%). WRF by any definition was not associated with all-cause mortality or ADHF readmission, in contrast to stronger natriuresis per loop diuretic dose [hazard ratio 0.20 (95% confidence interval 0.06-0.64); P = .007]. CONCLUSIONS: Serial measurements of CysC/ßTP, compared with serum Cr, more frequently indicate WRF during decongestive treatment in ADHF. However, adverse clinical outcome in such patients might be better predicted by the natriuretic response to diuretic therapy.

Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue?

BACKGROUND: Recently, a lot of research has focused on the discovery of novel renal biomarkers. Among others, the urinary kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) have been proven to be promising biomarkers in a wide variety of renal pathologies. However, little is known about the normal concentrations in urine of healthy subjects. Therefore, the goal of our study is to establish reference values for urinary KIM-1, NGAL, N-acetyl-ß-D-glucosamidase (NAG), and cystatin C in a healthy population, taking into account possible effects of age and gender. METHODS: We collected urine samples from 338 healthy, nonsmoking subjects between 0 and 95 years old. Subjects with elevated α1-microglobulin values were excluded. Next to the urinary concentrations of KIM-1, NGAL, NAG, and cystatin C, we measured urinary creatinine and specific gravity to correct for urinary dilution. The possible effect of age and gender on the four urinary biomarkers was investigated, and the reference values were established. RESULTS: For the absolute urinary concentrations of the biomarkers, age had a significant effect on all the biomarkers, except for cystatin C, whereas gender significantly affected all four of them, except for NAG. The normalization of biomarkers for creatinine and specific gravity had an effect on the correlation between the biomarkers on one hand and age and gender on the other. CONCLUSIONS: In conclusion, age and gender had different effects on KIM-1, NGAL, NAG, and cystatin C. Based on this knowledge, age- and gender-specific reference values for KIM-1, NGAL, NAG, and cystatin C were established.

The association between urinary kidney injury molecule 1 and urinary cadmium in elderly during long-term, low-dose cadmium exposure: a pilot study.

BACKGROUND: Urinary kidney injury molecule 1 is a recently discovered early biomarker for renal damage that has been proven to be correlated to urinary cadmium in rats. However, so far the association between urinary cadmium and kidney injury molecule 1 in humans after long-term, low-dose cadmium exposure has not been studied. METHODS: We collected urine and blood samples from 153 non-smoking men and women aged 60+, living in an area with moderate cadmium pollution from a non-ferrous metal plant for a significant period. Urinary cadmium and urinary kidney injury molecule 1 as well as other renal biomarkers (alpha1-microglobulin, beta2-microglobulin, blood urea nitrogen, urinary proteins and microalbumin) were assessed. RESULTS: Both before (r = 0.20; p = 0.01) and after (partial r = 0.32; p < 0.0001) adjustment for creatinine, age, sex, past smoking, socio-economic status and body mass index, urinary kidney injury molecule 1 correlated with urinary cadmium concentrations. No significant association was found between the other studied renal biomarkers and urinary cadmium. CONCLUSIONS: We showed that urinary kidney injury molecule 1 levels are positively correlated with urinary cadmium concentration in an elderly population after long-term, low-dose exposure to cadmium, while other classical markers do not show an association. Therefore, urinary kidney injury molecule 1 might be considered as a biomarker for early-stage metal-induced kidney injury by cadmium.

Endurance Exercise Intervention Is Beneficial to Kidney Function in a Rat Model of Isolated Abdominal Venous Congestion: a Pilot Study.

In this study, the effects of moderate intense endurance exercise on heart and kidney function and morphology were studied in a thoracic inferior vena cava constricted (IVCc) rat model of abdominal venous congestion. After IVC surgical constriction, eight sedentary male Sprague-Dawley IVCc rats (IVCc-SED) were compared to eight IVCc rats subjected to moderate intense endurance exercise (IVCc-MOD). Heart and kidney function was examined and renal functional reserve (RFR) was investigated by administering a high protein diet (HPD). After 12 weeks of exercise training, abdominal venous pressure, indices of body fat content, plasma cystatin C levels, and post-HPD urinary KIM-1 levels were all significantly lower in IVCc-MOD versus IVCc-SED rats (P < 0.05). RFR did not differ between both groups. The implementation of moderate intense endurance exercise in the IVCc model reduces abdominal venous pressure and is beneficial to kidney function.

Urinary Sodium Profiling in Chronic Heart Failure to Detect Development of Acute Decompensated Heart Failure.

OBJECTIVES: This study sought to determine the relationship between urinary sodium (Una) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization. BACKGROUND: No data are available on the longitudinal dynamics of Una concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization. METHODS: Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot Una samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in Una concentration. Patients were followed for the development of the clinical endpoint of AHF. RESULTS: A total of 80 chronic HF patients (71 ± 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 ± 7%) prospectively submitted weekly pre-diuretic first void morning Una samples for 30 weeks. A total of 1,970 Una samples were collected, with mean Una concentration of 81.6 ± 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l Una [n = 39]) and low (73 mmol/l Una [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 ± 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower Una concentrations (F[1.80] = 24.063; p < 0.001). The discriminating capacity of Una concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, Una concentration dropped (Una = 46 ± 16 mmol/l vs. 70 ± 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (Una = 71 ± 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation. CONCLUSIONS: Overall, Una concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower Una concentration and exhibited a further drop in Una concentration during the week preceding hospitalization. Ambulatory Una sample collection is feasible and may offer additional prognostic and therapeutic information.

Selective abdominal venous congestion to investigate cardiorenal interactions in a rat model.

Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman's space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion.

Selective abdominal venous congestion induces adverse renal and hepatic morphological and functional alterations despite a preserved cardiac function.

Venous congestion is an important contributor to worsening renal function in heart failure and the cardiorenal syndrome. In patients, it is difficult to study the effects of isolated venous congestion on organ function. In this study, the consequences of isolated abdominal venous congestion on morphology and function of the kidneys, liver and heart were studied in a rat model. Twelve sham-operated (SHAM) male Sprague Dawley rats were compared to eleven inferior vena cava-constricted (IVCc) rats for twenty-one weeks. Abdominal venous pressure was significantly higher in the IVCc versus SHAM group (p < 0.0001). Indices of liver and kidney weight, function and morphology, inflammation as well as collagen deposition were significantly increased in the IVCc compared to SHAM group, (p < 0.05). Echocardiographic and hemodynamic parameters were largely unaffected by abdominal venous congestion. In this rat model of isolated abdominal venous congestion, retrogradely conducted glomerular hypertension without a concomitant change in glomerular filtration rate was observed. Adverse short-term hepatic morphological alterations were developed which explain the observed organ function dysfunction. Importantly, cardiac function remained comparable between both groups. This study provides relevant insight in the pathophysiology of abdominal congestion on organ function.

Effect of pH on the stability of kidney injury molecule 1 (KIM-1) and on the accuracy of its measurement in human urine.

BACKGROUND: Urinary KIM-1 is a novel biomarker for tubular kidney damage, however little is known about its stability. The goal of this study is to examine the effect of urinary pH on the stability of KIM-1. METHODS: Urine samples were collected from 45 volunteers. Samples were aliquoted, adapted to different pH values (range 4 to 9) and stored at -80°C. After thawing, each aliquot was divided into two, of which one was used to measure KIM-1 (human tim-1/kim-1/Havcr Elisa kit; R&D systems) at the same pH at which it was stored, while the other was readapted to pH 7 before measurement. RESULTS: KIM-1 values of aliquots of the same sample are stable when stored at pH 6, 7 and 8 whereas at lower and higher storage pH, KIM-1 levels decrease significantly. When samples are readjusted to a neutral pH just before KIM-1 measurement, there are no longer significant differences between KIM-1 in aliquots stored at different pH values. CONCLUSIONS: No effect of urinary pH on the stability of KIM-1 was seen. However, the only commercially available human tim-1/kim-1/Havcr Elisa kit of RD systems is pH dependent and we therefore suggest samples should be adjusted to neutral pH before measurement.