Plasma N-terminal pro-brain natriuretic peptide level as a marker of adverse outcome in patients with co-existing diabetes, chronic kidney disease and heart failure

Implication for health policy/practice/research/medical education: Measuring N-terminal pro–B-type natriuretic peptide (NT-proBNP) level in patients with coexisting chronic kidney disease, diabetes and heart failure may predict the risk of adverse outcomes consisting, the need for dialysis, re-hospitalization and mortality. Please cite this paper as: Soliman AR, Ahmed RM, Yousry A, Abdelaziz TS, Selem AH. Plasma N-terminal pro-brain natriuretic peptide level as a marker of adverse outcome in patients with co-existing diabetes, chronic kidney disease and heart failure. J Renal Inj Prev. 2021; 10(3): e20. doi: 10.34172/jrip.2021.20. O rig in al

re-hospitalization and death in the setting of common clinical scenario of coexisting CKD and heart failure.

Study population
This study is a prospective observational study that was conducted in the emergency department of two large teaching hospitals during the period from November 2016 to April 2017.
One hundred and twenty adult patients who were diagnosed with heart failure were included in the study. CKD was defined based on an estimated glomerular filtration rate (eGFR) of ≤60 mL/min. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate the GFR of the study subjects.

CKD stages
According to the Kidney Disease Improving Global Outcomes (KDIGO) guideline, CKD was classified into 5 stages. All patients were subjected to the following assessments; A complete medical history and clinical examination including thorough cardiac examination was performed.
NT-proBNP level, serum creatinine, and transthoracic echocardiography were tested at the time of recruitment and after 6 months.
Additionally, serum potassium, C-reactive protein (CRP), serum troponin and HbA1c (for diabetic individuals) were measured in patients at baseline. Rehospitalization, need for dialysis and mortality were recorded for every patient. The planned follow-up period was 6 months.

Inclusion criteria
Patients with DM or CKD (GFR <60 mL/min) who have were admitted to the intensive care unit (ICU) at both hospitals from November 2016 to April 2017 with clinical presentation of congestive heart failure were eligible for study entry.

Exclusion criteria
We excluded patients who underwent cardiopulmonary resuscitation, pregnant females, patients on hormonal therapy or contraceptives, and patients with acute coronary syndrome, poor echocardiography image quality, atrial fibrillation, or valvular heart disease.

Echocardiographic study
Transthoracic echocardiography was done to estimate left ventricular ejection fraction (EF) and left cardiac chambers dimensions and volumes.

Determination of NT-proBNP
Anticoagulant-free venous blood samples have been assayed for NT-proBNP using a commercial enzyme-linked immunosorbent assay (ELISA) kit, employing an anti-serum specific to the amino terminal (Biomedica Gruppe, Germany).

Ethical issues
The research adhered to fundamentals of Declaration of Helsinki. The Ethical and Research Committee of the National Research Centre approved the protocol for this study, approval number NRC-REC-1214. The study has been conducted in Zagazig University hospitals and Cairo University hospitals. All participants agreed to take part in the study and signed a declaration of informed consent.

Statistical analysis
For comparisons between groups, normally distributed data were analysed using independent t test. Non-normally distributed were analysed using the Mann-Whitney U test. To compare continuous variables between >2 groups, we used one-way ANOVA or the Kruskal-Wallis equality-ofpopulations rank test according to the data distribution. Spearman's correlation analysis was performed to explore variables with a significant correlation with proBNP. A model to predict hospitalization or mortality was created using logistic regression analysis. STATA software version 13.1 was used.

Study population
The baseline characteristics were generally comparable between the studied groups with regard to age and gender (most of the study participants were male). Most patients had left ventricular hypertrophy (LVH) and a comparable EF and CRP level, but all of these results were statistically not significant (Table 1).
When analysing the results, patients were classified into three groups; • Group 1: patients with diabetes mellitus and no CKD • Group 2: patients with both diabetes and CKD • Group 3: patients with CKD, no diabetes Hypertension (HTN) was more prevalent, and severe heart failure was only encountered in patients with both DM and CKD with heart failure. Diabetic patients with normal kidney function had significantly lower serum potassium and serum uric acid levels than patients with CKD, but serum uric acid potassium and were statistically non-significant between groups 2 and 3 ( Table 1).

Baseline NT-proBNP and troponin levels
At the time of ICU admission, baseline NT-proBNP and troponin levels were elevated in patients with CKD as compared to patients with diabetes alone. This finding was statistically significant regarding proBNP (P = 0.0001). However, when we compared groups 2 and 3 (both had CKD, the mean value of either markers was statistically not significant across both groups) ( Table 2).

NT-proBNP levels after six months of follow-up in the studied groups
CKD patients with diabetes had significantly higher levels of proBNP than patients with CKD alone after six months of follow-up, as shown in Table 2.

Changes in NT-proBNP from recruitment till completion of follow-up period
ProBNP levels were significantly increased from baseline to the end of the follow-up period in DM patients with normal kidney function (group 1; P ≤ 0.001). However, in patients with CKD (group 2 and group 3), NT-proBNP levels were significantly decreased at the end of followup (P = 0.02 and P = 0.002, respectively). In group 2 (DM with CKD), six patients required hemodialysis. They had very high initial levels of NT-proBNP, which tended to decrease at the end of follow-up, however this finding was statistically non-significant as shown in Table 3 (P > 0.05).

Levels of NT-proBNP and its relation to EF% and left ventricular diastolic dysfunction grade
The levels of NT-proBNP were significantly higher in patients with a left ventricular EF% less than 50% (HF with reduced ejection fraction; HFREF) than in patients with a left ventricular EF% more than 50% (HF with preserved ejection fraction; HFPEF) at both baseline and after follow-up. In addition, NT-proBNP levels were significantly correlated with the grade of left ventricular diastolic dysfunction (LVDD). ProBNP levels were significantly elevated in patients with severe diastolic dysfunction than in those with milder grades (Table 4).

Factors associated with higher NT-proBNP levels
Higher NT-proBNP levels were affected by gender, older age at enrolment, the presence of HTN, lower GFR, LVDD grade, increasing NYHA (New York Heart Association) stage, and higher serum troponin and creatinine levels ( Table 5).

Re-hospitalization
Re-hospitalization was encountered more in group 2 (17%) in comparison to 9.8% and 11.1% in groups 1 and 3, respectively (Table 1). Among several factors included in the study, baseline proBNP predicts re-hospitalization. Increasing NYHA class, EF, and the follow-up serum creatinine level had a significant ability to predict rehospitalization ( Table 6).

Mortality
Increased mortality was noticed in patients in group 2 (both DM and CKD) followed by group 3 (CKD only), but this result was statistically not significant as seen in Table 1. Baseline NT-proBNP was a determinant of mortality. The stage of NYHA classification and EF% were significant predictors of mortality in our study (P < 0.05) ( Table 7).

Discussion
Both DM and CKD are increasingly recognized as serious, worldwide public health concerns, since there is a strong correlation of diabetes and CKD with cardiovascular disease (CVD) (6,7). NT-proBNP has been linked to both type 2 DM and renal disease patients, while NT-proBNP was a useful prognostic marker, in addition to BNP and troponin T for short-term follow-up (<3 years) of CKD patients with cardiac disease (8,9). Among our patients, HTN was more prevalent in diabetic patients who developed CKD (group 2). HTN in patients with diabetes or CKD was found to accelerate vascular complications in this population and to predispose individuals to cardiac diseases (10)(11)(12).
Among our patients, baseline NT-proBNP was elevated in patients who have CKD (group 2 and group 3) than in those without CKD. Left ventricular (LV) functional or structural abnormalities result in elevated levels NT-proBNP in patients with CKD (13). This finding is in agreement with a study by Hickman et al, which demonstrating increased prevalence of heart failure with declining eGFR (14). The rise in NT-proBNP levels is proportional to kidney function deterioration (15). However, cut-off values for elevated NT-proBNP patients with CKD are not completely known (2).
NT-proBNP levels were significantly elevated from baseline to the completion of the follow-up in DM patients with normal kidney function, while in patients with CKD (group 2 and group 3), proBNP levels were significantly decreased after six months of follow-up. However, group 2 still had a significantly higher proBNP level than group 3.
One explanation is possibly along with progression of diabetes, the diabetic group might develop silent ischemia  or some degree of left ventricular diastolic dysfunction. This development could explain the increase in proBNP levels at the end of the follow-up period in comparison to patients in groups 2 and 3 who usually show symptoms earlier and may have started anti-failure treatment at an earlier stage, reflected by the improvement of proBNP levels at the end of the follow-up period. Participants in the CKD groups were also given increasing doses of diuretics compared to patients in group 1. Diuretics decrease the secretion of proBNP peptide from ventricular myocardial wall, through releasing stress off the ventricular walls. In addition, in diabetic patients who develop CKD, hyperglycemia spontaneously improves over time even without hypoglycemic medications by the effect of decreased insulin clearance with GFR reduction. Moreover, according to a literature review, diabetes mellitus was found to contribute independently to high plasma NT-proBNP levels (16).
In diabetes complicated with CKD, which necessitates dialysis, the proBNP levels increase substantially. Furthermore, their proBNP level tended to decrease by the end of the follow-up. Dialysis therapy decreases the levels of NT-proBNP probably due increased clearance and achieving better volume control (17). A large study demonstrated that NT-proBNP levels obtained before dialysis could predict mortality in patients receiving haemodialysis (HD) (18). A higher proBNP level was significantly related to a lower GFR and higher serum creatinine level but not to diabetes in our study. It was also significantly related to female gender, older age at enrolment, the presence of HTN, lower EF percentage, LVDD grade, NYHA stage, and troponin level. Studies have shown an inverse moderate, but significant correlation between eGFR and NT-proBNP concentrations (19).
Numerous studies reported a correlation between NT-proBNP values and cardiac failure severity as assessed by various parameters. These studies also found that age, body mass index (BMI), and eGFR were significant predictors of log NT-proBNP. The log NT-proBNP showed an inverse correlation with EF (15).
Mortality was higher in patients with DM complicated with CKD in our study. Moreover, among several factors included in the study, the baseline proBNP level did not show a strong ability to predict re-hospitalization or mortality. Only increasing NYHA class, percent of EF and follow-up serum creatinine levels were able to significantly predict re-hospitalization.
Additionally, the class of NYHA, percent of EF and rehospitalization were significantly predictors of mortality in our study (P < 0.05).
The combination of percentage reduction in NT-proBNP and the absolute values have been shown to predict outcome in hospitalised patients who have been admitted with decompensated congestive cardiac failure (20). Therefore, NT-proBNP may be a better marker in predicting death than BNP. This may be due to the longer half-life of NT-proBNP and its status as a more accurate index of LV hypertrophy (21).
The study has some limitations. The small size of this study should be borne in mind, and different numbers of patients were included in each group. Future studies on the current topic with more properly matched groups might be necessary.

Conclusion
This study showed that co-occurrence of CKD with diabetes in patients with heart failure and a high initial proBNP level is associated with a higher risk of worsening heart failure, higher rates of complications such as the need for dialysis, re-hospitalization and higher mortality.

Limitations of the study
This study is limited by the small participants' number. Validation of the findings will require a larger number of recruits.