B-type natriuretic peptide/ferritin ratio as a predictor of the risk of developing acute renal injury in acute decompensated heart failure

Abstract

OBJECTIVES: Acute decompensated heart failure (ADHF) is a clinical condition that requires urgent diagnosis and treatment. Patients present with pulmonary capillary wedge pressure, pulmonary arterial pressure, and venous pressure elevation. Along with the progressive deterioration observed in the clinical picture, impairment or deterioration of kidney function may also occur. In this study, we evaluated the B-type natriuretic peptide (BNP)/ferritin ratio as a predictor of the risk of developing acute renal injury (ARI) in ADHF.

METHODS: A total of 157 patients with a diagnosis of ischemic dilated cardiomyopathy for more than 6 months that presented to our clinic with ADHF were included in this cohort study. After the treatment protocol was applied, the sample was divided into two groups as patients with and without ARI. The BNP and ferritin levels were examined along with the routine blood parameters (BNP), and the BNP, ferritin, and BNP/ferritin values were compared between the groups.

RESULTS: ARI was present in 34.3% (n = 54) of the patients, who were also found to have higher BNP (892.76 vs. 817.54), lower ferritin (86.78 ± 57.2 vs. 105.46 ± 38.3), and higher BNP/ferritin (10.48 ± 2.14 vs. 7.89 ± 1.89). The multivariate logistic regression analysis revealed the BNP/ferritin ratio as an independent risk factor for ARI (odds ratio = 3.19; 95% CI, 1.92-6.54; P = 0.001). Using the receiver operating characteristic curve, a cutoff value of 9.32 for BNP/ferritin ratio had a sensitivity of 81.8% and a specificity of 93.5% (area under the curve 0.842, P < 0.001) for the prediction of ARI.

CONCLUSION: The BNP/ferritin ratio is a new parameter that can be used to draw attention to the severity of the treatment and renal function in ADHF cases in emergency situations.

Introduction

Acute decompensated heart failure (ADHF) can manifest with a wide range of clinical signs from mild pulmonary edema to cardiogenic shock. After discharge from the hospital, 20% of patients require hospitalization again within the 1^st month and 50% within the first 6 months, and the 2-month mortality is reported as 20%.[1],[2] While diuretics are known to have positive effects in short and medium terms, mortality and morbidity outcomes related to their long-term use have not yet been clarified. It has been recommended that BUN and creatinine values be monitored every 1–2 days during hospitalization, regardless of clinical condition.[3] In addition, the previously used renin-angiotensin-aldosterone system (RAAS) blockers prepare a sensitive environment for renal damage. As the risk of developing renal failure increases, in-hospital mortality significantly increases.[4]

B-type natriuretic peptide (BNP) is a heart hormone secreted by cardiac myocytes in the ventricles in response to pressure changes that occur when heart failure develops or worsens. BNP levels are associated with the severity and prognosis of heart failure.[5]

Anemia in heart failure, despite having a multifactorial etiology, is considered to be caused by complex interactions between poor renal function and bone marrow response and is associated with worse symptoms and higher mortality.[6],[7] It has been shown that anemia has higher prevalence in patients with congestive heart failure, it is associated with rehospitalization due to decompensation and cardiac mortality, and it is related to poorer survival in the short term in cases of acute heart failure.[8],[9] The correlation of mortality in heart failure with renal function, BNP, and ferritin that is an indicator of anemia also suggests the presence of a relationship between renal functions and BNP and ferritin. Thus, in this study, in patients with acute heart failure, we examined the relationship between acute renal injury (ARI) risk and BNP and ferritin, and a third combined parameter, i.e., the ratio of BNP/ferritin, which, to our knowledge, has not been previously investigated in the literature.Acute decompensated heart failure (ADHF) can manifest with a wide range of clinical signs from mild pulmonary edema to cardiogenic shock. After discharge from the hospital, 20% of patients require hospitalization again within the 1^st month and 50% within the first 6 months, and the 2-month mortality is reported as 20%.[1],[2] While diuretics are known to have positive effects in short and medium terms, mortality and morbidity outcomes related to their long-term use have not yet been clarified. It has been recommended that BUN and creatinine values be monitored every 1–2 days during hospitalization, regardless of clinical condition.[3] In addition, the previously used renin-angiotensin-aldosterone system (RAAS) blockers prepare a sensitive environment for renal damage. As the risk of developing renal failure increases, in-hospital mortality significantly increases.[4]

Material and Methods

The study was conducted following the ethical guidelines of the declaration of Helsinki after receiving approval from the Institutional Ethics Committee. Ethical approval for the present study was obtained from Atatürk University Medical Faculty Clinical Research Ethics Committee (No: 07/25) Date: June 26, 2020. Data were obtained from the patients who were evaluated in the emergency service of our institution, where 100–150 patients applied daily. Patients who presented to the emergency department of our center with ADHF between November 2019 and June 2020 were included in the study. The diagnoses of the patients were determined in the emergency department by a cardiologist or specialist emergency physician experienced in echocardiography. These patients were observed in the cardiology intensive care unit after their first treatment in the emergency department. Patients with end-stage renal failure (estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m²), those receiving iron supplements, pregnant and lactating women, those with malignant cancer, hematological problems, or acute coronary syndrome, with cardiac arrest and hemodynamic impairment, those with a left ventricular ejection fraction of >40%, or right heart failure, obese patients (body mass index >30), patients aged >75, and those with liver dysfunction were excluded. Patients with a diagnosis of ischemic dilated cardiomyopathy for more than 6 months that presented to our clinic with ADHF were included in our study. As a result, 157 patients were divided into two groups as those with and without ARI risk according to the rifle criteria. In the Rifle criteria, the risk of ARI is defined as a 50% increase in the serum creatinine level and a consequent 25% decrease in GFR or urine excretion decreasing below 0.5 mL kg/h for more than 6 h.[10] To identify renal dysfunction, the changes in the highest renal parameters of patients observed during a hospitalization period of at least 3 days were taken into consideration. An echocardiographic evaluation was performed in the left lateral decubitus position with a 3.5 MHz transducer using the cardiovascular ultrasound system. Ejection fraction was calculated using the modified Simpson method.

Serum glucose, creatinine, and lipid profile were determined by the standard methods. Complete blood counts were obtained with an automated blood cell counter. Blood urea nitrogen, total protein, and albumin values were analyzed using test kits according to the manufacturer's instructions.

The Statistical Package for the Social Sciences software version 20 for Windows was used for the statistical analysis of all data (SPSS, Inc.,Chicago, IL). Categorical variables were expressed as percentages, and the Chi-square test and Fisher's exact test were used for comparisons. Continuous variables were calculated as mean value ± standard deviation, and the Shapiro–Wilk test was conducted to check the normality of the distribution of variables. Student's t-test was used to compare the continuous variables with normal distribution, and the Mann–Whitney U-test to compare those that did not show normal distribution. Relationships of two different variables with each other were made using Spearman or Pearson correlation analysis. Spearman rank test was performed to define the correlation of ARI with BNP, ferritin and BNP/ferritin ratio. Calibration was evaluated through the Hosmer-Lemeshow goodness-of-fit test with groups (P = 0.32). Univariate and multivariate logistic regression analyses were performed to calculate the odds ratio (OR) of the ARI risk factors. The variables found significant in the univariate analysis (P < 0.05) and several variables confirmed to be significant in clinical practice were included in the multiple logistic regression analysis (model summary; Nagelkerke R²: %53). The ability of the model to distinguish between patients with and without the risk of ARI was also analyzed based on the receiver operating characteristic (ROC) curve.

Results

A total of 157 ADHF patients with ischemic etiology were included in this study. The basic clinical and laboratory features of the patients are given in [Table 1]. Kidney damage consistent with ARI was detected in 54 (34.3%) patients. The ARI group was older, and their hypertension rate was higher. Heart failure duration was similar between the ARI and non-ARI groups. There was no significant difference between the groups in terms of vital signs. The basal creatinine value was higher in the group with ARI but not at a statistically significant level, while eGFR was significantly lower in the same group. In addition, in the group with ARI, troponin I, BNP, and BNP/ferritin ratio were high, and the ferritin value was lower compared to the non-ARI group.

Table 1. Baseline characteristics and laboratory findings of the study population

The univariate logistic regression revealed that age, hypertension, eGFR, troponin I, BNP, ferritin, and BNP/ferritin ratio were associated with ARI (P < 0.05 for all). In the multivariate analysis, the BNP/ferritin ratio (OR = 3.19; 95% confidence interval [CI], 1.92–6.54; P = 0.001), ferritin (OR = 0.72; 95% CI, 0.89–0.53; P = 0.028), BNP (OR = 1.13; 95% CI, 1.01––1.73; P = 0.043), and age (OR = 3.02; 95% CI, 1.83–9.62; P = 0.001) remained significant predictors for the development of ARI in patients after ADHF [Table 2]. Furthermore, ARI had a positive correlation with age (r = 0.384, P < 0.001) and hypertension (r = 0.424, P < 0.001).

Table 2. Univariate and multivariate logistic regression analyses for the risk of developing acute renal injury

According to the ROC analysis of the ability of the investigated parameter to predict ARI risk, the sensitivity and specificity values were calculated as 73.2 and 86.4%, respectively, for BNP at the optimal cutoff value of 624.84; 71.2 and 79.5%, respectively, for ferritin at the optimal cutoff value of 53.48 and 81.8 and 93.5%, respectively, for the BNP/ferritin ratio at the optimal cutoff value of 9.32. The area under the curve value was found to be 0.779 for BNP, 0.754 for ferritin, and 0.842 for the BNP/ferritin ratio [Figure 1].

Figure 1. Receiver operating characteristic curves for B‑type natriuretic peptide, ferritin and B-type natriuretic peptide/ferritin ratio in predicting the risk of acute renal injury development

×

Figure 1

Close

Discussion

Deterioration of renal function is directly linked to poor prognosis in patients with ADHF. The underlying causes of renal function deterioration are multifactorial, and some are associated with the cardiological effects of aggressive diuretic therapy to resolve congestion and with tubular damage caused by reduced ejection fraction. Early detection of deterioration of renal function is important for detecting end-organ damage.[11] Aghel et al., evaluating ADHF cases, found that the number of presentations to the hospital was higher among the patients with worsening renal function than in those with normal renal function.[12] Other researchers indicated the need for investigating markers to determine kidney damage in an early and sensitive manner due to heterogeneity of the group of patients with renal dysfunction.[13],[14] In other studies, various biomarkers, such as cystatin C, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 were reported to be prognostic indicators of early-stage renal damage in ADHF.[15],[16],[17] An absolute increase in creatinine in approximately 20% of individuals hospitalized with ADHF also suggests that renal failure is a common morbidity in this patient population.[18],[19]

In the ADHERE registry, a linear relationship was found between BNP concentrations and the in-hospital mortality of ADHF patients.[20] The efficacy of predicting outcomes in patients with chronic renal failure has been evaluated in several studies, and a positive correlation has been found between high-serum BNP levels and mortality and renal disease progression in most cases.[21] Similarly, in our study, the relationship of BNP with cardiac and renal dysfunction was observed to be an indicator of the risk of renal dysfunction in ADHF.

The anemia and iron deficiency have been shown to be independent predictors for poor prognosis in heart failure, decrease the quality of life, and increase the risk of mortality and hospitalization.[3] Iron deficiency etiopathogenesis is considered to be complex and multifactorial, with the most discussed causes being inflammatory activation, malnutrition, intestinal edema, renal dysfunction, hemodilution, diabetes, impaired bone marrow function, use of RAAS inhibitors, and occult gastrointestinal bleeding.[22] In our study, similar to BNP, a low ferritin level was found to be an indicator of renal dysfunction in ADHF, which supports previous studies reporting the close relationship between ferritin and cardiac and renal functions.

Limitations

The main limitation of the study is that it is retrospective and single center. Our information about recurrent problems is limited because some patients do not come to follow-up.

Conclusion

We determined that elevated BNP and reduced ferritin could be evaluated in combination as the BNP/ferritin ratio to predict the risk of ARI in patients with ADHF in a stronger manner than either parameter alone.

Institutional review board approval was obtained from the Atatürk University Board of Ethics on Clinical Studies Ethics Committee (Date: June 26, 2020, Number: 07/25).

Küçüksu Z. and Öztürk M. performed the measurements, Ceyhun G. and Aydın Ş.S. were involved in planning and supervised the work, Ceyhun G. processed the experimental data, performed the analysis, drafted the manuscript and designed the figures. Özkoç M., Altınkaya O., Ateş A., aided in interpreting the results and worked on the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

None Declared.

None

References

1. Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M, IMPACT‐HF Investigators and Coordinators. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: Results of the Initiation management predischarge: Process for assessment of carvedilol therapy in heart failure (IMPACT‐HF) trial. J Am Coll Cardiol 2004;43:1534‐41.
2. Binanay C, Califf RM, Hasselblad V, O’Connor CO, Shah MR, Sopko G, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: The ESCAPE trial. JAMA 2005;294:1625‐33.
3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2128‐200.
4. Fonarow GC, Adams KF Jr., Abraham WT, Yancy CW, Boscardin WJ, ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in‐hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis. JAMA 2005;293:572‐80.
5. Torre‐Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201‐6.
6. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, et al. Anemia and mortality in heart failure patients a systematic review and meta‐analysis. J Am Coll Cardiol 2008;52:818‐27.
7. O’Meara E, Murphy C, McMurray JJ. Anemia and heart failure. Curr Heart Fail Rep 2004;1:176‐82.
8. Consuegra‐Sánchez L, Núñez J, Fácila L, Bertomeu V, Robles R, Llácer A. Prognostic impact of anemia in acute heart failure. Rev Invest Clin 2006;58:279‐84.
9. Sánchez‐Torrijos J, Gudín‐Uriel M, Nadal‐Barangé M, Jacas‐Osborn V, Trigo‐Bautista A, Giménez‐Alcalá M, et al. Prognostic value of discharge hemoglobin level in patients hospitalized for acute heart failure. Rev Esp Cardiol 2006;59:1276‐82.
10. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure – Definition, outcome measures, animal models, fluid therapy and information technology needs: The second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004;8:R204‐12.
11. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589‐96.
12. Aghel A, Shrestha K, Mullens W, Borowski A, Tang WH. Serum neutrophil gelatinase‐associated lipocalin (NGAL) in predicting worsening renal function in acute decompensated heart failure. J Card Fail 2010;16:49‐54.
13. Schmidt‐Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, et al. Dual action of neutrophil gelatinase‐associated lipocalin. J Am Soc Nephrol 2007;18:407‐13.
14. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase‐associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231‐8.
15. Campbell CY, Clarke W, Park H, Haq N, Barone BB, Brotman DJ. Usefulness of cystatin C and prognosis following admission for acute heart failure. Am J Cardiol 2009;104:389‐92
16. Maisel AS, Mueller C, Fitzgerald R, Brikhan R, Hiestand BC, Iqbal N, et al. Prognostic utility of plasma neutrophil gelatinase‐associated lipocalin in patients with acute heart failure: The NGAL EvaLuation Along with B‐type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. Eur J Heart Fail 2011;13:846‐51.
17. Jungbauer CG, Birner C, Jung B, Buchner S, Lubnow M, Bary C, et al. Kidney injury molecule‐1 and N‐acetyl‐beta‐D‐glucosaminidase in chronic heart failure: Possible biomarkers of cardiorenal syndrome. Eur J Heart Fail 2011;13:1104‐10.
18. Fonarow GC, ADHERE Scientific Advisory Committee. The acute decompensated heart failure national registry (ADHERE): Opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med 2003;4 Suppl 7:S21‐30.
19. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen‐Solal A, Aguilar JC, et al. The euro heart failure survey programme‐‐ a survey on the quality of care among patients with heart failure in Europe. Part 1: Patient characteristics and diagnosis. Eur Heart J 2003;24:442‐63.
20. Fonarow GC, Peacock WF, Phillips CO, Givertz MM, Lopatin M, ADHERE Scientific Advisory Committee and Investigators. Admission B‐type natriuretic peptide levels and in‐hospital mortality in acute decompensated heart failure. J Am Coll Cardiol 2007;49:1943‐50.
21. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y, Schwartz D. Anemia, chronic renal disease and congestive heart failure‐‐the cardio renal anemia syndrome: The need for cooperation between cardiologists and nephrologists. Int Urol Nephrol 2006;38:295‐310.
22. Çavuşoğlu Y, Altay H, Çetiner M, Güvenç TS, Temizhan A, Ural D, et al. Iron deficiency and anemia in heart failure. Turk Kardiyol Dern Ars 2017;45:1‐38.