Neprilysin inhibition and chronic kidney disease

Abstract

Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD)

Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD.

Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin – angiotensin – aldosterone (RAAS) system.

Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF).

The idea of ​​blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema.

Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria.

Key words: neprilysin, natriuretic peptides, sacubitril/valsartan, hypertension, heart failure, CKD

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Taste disorders in patients with end-stage chronic kidney disease

Abstract

The authors aimed to explore taste distortion in patients with chronic kidney disease (CKD). One hundred and four patients were divided into a control group and a study group. The data was collected through a questionnaire and was statistically analyzed. The results showed that 28.7% of respondents had a loss of taste (96.60% CKD patients). There was a statistically significant correlation between the duration of treatment and taste loss, between patients’ age and taste impairment, and between patients’ age and the sense of a metallic taste in the mouth. Distortion in the sense of taste is an oral manifestation characteristic of CKD patients.

KEYWORDS: CKD, hemodialysis, metallic taste, oral manifestations, taste disorders.

Introduction

As a result of their treatment patients with end-stage chronic kidney disease commonly display characteristic oral manifestations such as taste alteration, taste loss, dry mouth, etc. [1,2,3,4,5]. They are usually the consequence of metabolic and physiological disturbances inherent to the disease. Dental literature provides evidence of the relationship between the duration of the dialysis treatment and the development of oral lesions [1, 6]. In a 2012 survey Asha [7] reported that high levels of urea, dimethyl and trimethyl amines and low levels of zinc might be associated with decreased taste perception in uremic patients. The cause of a metallic taste in uremic patients was reported to be due to urea content in the saliva and its subsequent breakdown to ammonia and carbon dioxide by bacterial urease [7]. Taste disorders (dysgeusia) are also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is a decrease in taste sensitivity [8, 9, 10].

Dysgeusia (taste disorder) is a taste disturbance associated with the distorted perception of taste or a persistent sense of taste in the absence of taste stimuli. These changes could lead to food aversion, reduced food intake and nutritional deficiencies, ultimately causing weight loss and in more severe cases malnutrition, weakness, fatigue [8]. The nutritional status is subsequently affected as there are reports of a correlation between taste distortion and low levels of serum albumin, creatinine, protein and sodium intake, chest measurements and the increased need for enteral nutrition. Furthermore, latest studies show that altered taste perception is associated with 17% higher rate of mortality, although not with increased rate of hospitalization [9].

There are objective methods for testing taste impairment. Gustometry involves the use of various substance, such as citric acid, caffeine, sucrose and others, where after each taste stimulus the oral cavity is to be rinsed. Another method of research is electrogustometry, which applies current of low-intensity (μA) over the dorsum of the tongue, designed to activate trigeminus nerve endings [11, 12]. Subjective test methods include questionnaires, interviews, etc. They are suited for patients who have undergone a long-term dialysis treatment, mostly due to their dependence on the dialysis machine, the observation of a strict diet and the negative impact on the mental equilibrium of patients. Recent years have seen the development of much used validated screening questionnaires [10, 11].

 

Objective

To explore distortion of the taste sense in patients with end-stage chronic kidney disease (CKD) on renal replacement therapy (RRT).

 

Material and methods

The clinical study was approved by the Research Ethics Committee at the Medical University of Varna with Protocol No. 55/ 16 June 2016. It involved 104 patients (61 female patients – 58.65% and 43 male patients – 41.35%), aged 46.9 ± 21.2 years (with the youngest participant being 19 years old and the oldest – 80 years old). The patients were divided into 2 groups: a Control group, involving 34 participants without any common diseases and a Study group of 70 patients in end-stage chronic kidney disease. The Study group patients were provisionally divided according to the duration of their chronic dialysis treatment into 2 subgroups:   5-year Treatment group and Over 5-year Treatment group.

All participants signed an Informed Consent after being informed in detail of the purpose and terms of participation in the study. The data was collected through a questionnaire, consisting of a basic section (name of participant, gender, and age) and three questions related to the subjective sense of taste, experienced by the CKD patients:

  1. Can you feel any loss of taste?
  2. Can you feel a metallic taste in your mouth?
  3. Can you feel any taste alteration?

The answering options needed to be either Yes or No. The accurate and truthful representation of the data collected was entrusted to the good faith of patients.

The statistical evaluation of results was carried out using SPSS software package for epidemiological and clinical data analysis (V. 17.00). Non-parametric statistical methods were applied to verify statistical hypotheses (chi-square test for independence), as well as cross tabulation, calculating relative distributions, graphical representation of data, etc.

 

Results

The analysis of question 1 (Can you feel any loss of taste?) showed that 28.70% of respondents had returned the unfavorable answer Yes, where 96.60% belonged to the Study group of CKD patients and only 1 patient from Control group responded positively. The remaining 71.30% of patients had marked No as an answer to that question. According to expectations, the negative answer was provided by 97.10% of representatives of the Control group and by only 58 CKD patients (20%). The chi-square test of independence  incorporating Yates’s  correction for continuity showed that there was a statistically significant correlation between the patients’ group and the taste loss perception ( χ2 (1, n = 101) = 14.78, p <0.001, phi = 0,41).

It was interesting to observe that to question 2 (Can you feel a metallic taste in your mouth?) positive answer was given solely by CKD patients (22 respondents, 21.20% of all patients surveyed) (Table 1).

More than 1/3 of CKD patients (31.40%) confirmed that they felt a metallic taste in the mouth. This percentage is relatively high in the CKD group since taste buds adapt slowly and depend on the concentration of dissolved ions in the saliva, produced as by-products as a result of the treatment of patients. As expected, no participant from the Control group responded positively to this question.

The statistical analysis of the dependence between patients’ group and the subjective perception of a metallic taste confirmed the presence of a statistically significant correlation (χ2 (1, n = 104) = 11.734, p = 0.001, phi = 0.36).

Similar results were obtained in the distribution of the answers to question 3 (Can you feel any taste alteration?). More than half of all respondents (61.50%) replied negatively, whereas 38.50% (40 patients) gave a positive answer. The relative proportion of CKD patients who indicated Yes as an answer was 52.90%, as opposed to 47.10% who replied with a No . Within the Control group the Yes/No distribution was 8.80%/ 91.20%, respectively. The positive answer was selected by 92.50% of CKD patients and by only 7.50% of participants from the Control group. It is safe to conclude that the sense of taste alteration can be manifested also in healthy patients however less frequently and among fewer of them. Taste detection thresholds vary widely across individuals. They are determined not only by the concentration of the food substance but also by food temperature. The data obtained confirmed that CKD patients experienced change in taste as a typical oral manifestation.

The chi-square test of independence  incorporating Yates’s  correction for continuity showed that there was a statistically significant correlation between the patients’ group and the subjective perception of loss of taste (χ2 (1, n = 104) = 16.93, p <0.001, phi = 0.43) (Figure 1).

 

As shown in Fig. 1 none of the patients in the Control group felt a metallic taste in the mouth and only 8% (1 or 2 patients) reported taste alteration or a loss of taste. When using subjective methods for measuring taste, the distinctions in the intensity of separate tastes can be elusive for a person to detect. It is well known that at least 30% change in the concentration of a substance is often needed in order to register a difference in the intensity of gustatory stimuli [13, 14]. Certain flavors are known to alter the taste sense itself, for example, acids can reduce the sweetness of sucrose, fructose, and NaCl dulls sweet taste sensitivity [15].

The nature of kidney disease and its treatment cause different substances in various quantities to dissolve in the oral fluids, which in turn trigger the trigeminal chemoreceptor cells and stimulate the microvilli on the taste buds. The mechanisms are not fully grasped. This accounts for the research into other factors that may lead to taste distortions in CKD patients:

Duration of treatment: The results showed that the duration of the disease did not affect taste alteration and the subjective perception of a metallic taste in the mouth (χ2 (1, n = 70) = 0, p = 1.00, and χ2 (1, n = 70) = 0.066, p = 0.797, respectively). However, there was a statistically significant correlation between the duration of treatment and the subjective perception of taste loss: χ2 (1, n = 70) = 5.84, p = 0.02, phi = 0.326.

When examining the dependencies between taste alteration and the sense of a metallic taste, a very strong statistically significant correlation was established: χ2 (1, n = 70) = 25.922, p <0.001, phi = 0.639. The analysis revealed that CKD patients most often associated taste change with a metallic taste. As seen in Table 2, all patients (100%) who responded positively to the question 3 (Can you feel any taste alteration?) also admitted having a metallic taste in the mouth.

Gender: The results indicated that there was no statistically significant correlation between the patient’s gender and the subjective perception of a metallic taste: χ2 (1, n = 70) = 2.6, p = 0.11. The same applied for the dependency between the patient’s gender and the subjective sense of taste alteration: χ2 (1, n = 70) = 3.38, p = 0.07.

Age: The effects of patients’ age on the subjective perceptions of taste were also examined. Patients were divided into groups according to WHO age classification [16]. The results from the chi-square test of independence revealed strong statistically significant correlations between the Age group and taste alteration (χ2 (1, n = 70) = 39.528, p <0.001, phi = 0.751), as well as between the Age group and the sense of a metallic taste (χ2 (1, n = 70) = 42.319, p <0.001, phi = 0.778). The results obtained by cross-tabulation showed that 88.30% of patients, who reported any taste distortion, were young or middle-aged. All 10 patients in older age had not registered any taste alteration. Similar results were observed on the correlation between the Age group and the sense of a metallic taste. 95.50% patients, who experienced a metallic taste in the mouth, were young or middle-aged. Likewise, none of the older patient had reported of a metallic taste. Such dependencies, which are often observed for certain phenomena of the visual system, can be explained with age-related transformations and are due to the central neuronal interactions [17, 16].

 

Discussion

Taste receptors belong to the group of contact chemoreceptor cells. They play an important role in the selection of food and the regulation of the digestive system [18]. It is well known that nutritional status has a significant impact on the overall health and the quality of life in patients with systemic diseases [19]. This shifts the scientific interest towards the study of taste distortion in CKD patients, who exhibit variations in the type and concentration of ions dissolved in the saliva as a result of the disease and chronic dialysis treatment. There are further studies on the low level of zinc in the blood and the taste impairment in CKD patients, undergoing hemodialysis, which cannot be corrected through interventional treatment methods [20].

The correlation between the subjective sense of taste distortion in CKD patients and that of Control group patients proved the critical role of kidney disease as a contributing factor for taste alteration: (χ2 (1, n = 104) = 16.93, p <0.001 , phi = 0.43). It was established that the duration of treatment did not affect taste sense, ether metallic or altered taste (χ2 (1, n = 70) = 0.066, p = 0.797). However, over time CKD patients reported a loss of taste (χ2 ( 1, n = 70) = 5.84, p = 0.02, phi = 0.326).

Strong statistically significant relationships were observed between patients’ age and taste alteration (χ2 (1, n = 70) = 39.528, p <0,001, phi = 0.751), and between their age and the sense of a metallic taste (χ2 (1, n = 70) = 42.319, p <0.001, phi = 0.778). CKD patients at a younger or middle age proved to be more sensitive to taste alterations compared to older patients.

 

Conclusions

Taste impairment is regarded as a characteristic oral manifestation observed in CKD patients.  Since the mechanism behind taste receptors has not been fully grasped, research interest should be directed towards the effects of taste distortion on the body’s digestive cycle and subsequently on nutritional deficiencies. The issue is particularly relevant owing to its relationship to the quality of life of CKD patients.

 

References

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