The aim of this systematic review is to evaluate the relationship between anosmia and dysgeusia and nutritional status in CKD patients, as well as to identify clinical interventions currently available to address these clinical conditions in this population.

This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines and following the PRISMA checklist,28 reported in Supplementary File 1.

The protocol of this systematic review was registered in the International prospective register of systematic reviews (PROSPERO) of the National Institute of Health Research (https://www.crd.york.ac.uk/prospero/) with protocol registration number: CRD42023469530.

For the present study, the research query was formulated utilizing the PICO model.29 The PICO model serves as a methodology employed by scholars to refine a research subject. It revolves around four core elements: patient or problem (P), intervention or indicator (I), comparison (C), and outcome (O). This review considered three components of the PICO methodology, adopting a PIO. The following aspects were therefore considered based on the approach: P: patients with CKD; I: identification of primary research studies describing olfactory and taste dysfunctions and malnutrition; O: evaluate the correlation between olfactory and taste dysfunctions and malnutrition and the impact of healthcare interventions in reducing these clinical conditions.

Between September 2023 and June 2024, a comprehensive and systematic bibliographic search was conducted in scientific databases, including PubMed, Cochrane Library, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Scopus and Web of Science. To achieve a targeted and precise search, we employed a combination of specific keywords and Mesh Terms (Medical Subject Headings), using the keywords “chronic kidney disease”, “olfactory dysfunctions”, “taste dysfunctions”, “Therapy”, “Treatment”, “Management”, “Malnutrition”, and their variations, opportunely combined by Boolean operators. Additionally, a manual search was conducted in Google Scholar to retrieve additional records in grey literature; full search algorithms are available in the data available statement (supplementary file 1). In the initial screening phase, two expert reviewers (SM and MS) independently assessed all titles and abstracts extracted from the electronic database searches. Utilizing the EndNote 20 software (https://endnote.com/), duplicates and non-relevant records were systematically eliminated. In instances of discordance, a third expert reviewer (MP) was consulted to facilitate consensus. For those studies deemed potentially relevant in the initial screening, full-text articles were obtained. Each of these was subjected to a rigorous independent assessment by the reviewers (SM and MS) in alignment with predetermined eligibility criteria. In situations where consensus was challenging, dialogues were initiated between the primary reviewers. If no agreement was reached, the adjudication of the third reviewer (MP), previously uninvolved, was sought to ensure an unbiased decision-making process.

In this study, we defined inclusion and exclusion criteria to align with the review's scope and methodology, ensuring the selection of pertinent and recent articles.

Inclusion criteria: 1. Primary study: Any type of experimental or observational study design, including qualitative and mixed-method studies; 2. Related to identify or treat anosmia or dysgeusia; 3. Participants: CKD patients.

Exclusion criteria: 1. Studies that do not meet the inclusion criteria; 2. Studies that focus on individuals without CKD; 3. Olfactory or taste dysfunctions caused by COVID-19 or diseases other than CKD.

The risk of bias and the methodological quality of the included articles were initially evaluated by two reviewers (GF and SMP). Conflicts were resolved by the involvement of a third review author (SM). To rigorously assess the methodological quality and relevance of the selected studies, we employed the JBI Critical Appraisal Tools.30 These tools, recognized for their precision in evaluating various research designs, provided a structured framework to discern the reliability and applicability of each study. By utilizing these instruments, we ensured that only the most robust and pertinent studies were incorporated into our systematic review.31 High-quality studies were identified on the basis of a previous meta-analysis32 in which studies with a JBI score higher than 70% were classified as having a high quality, those with a score between 69.9% and 50% as having a medium quality, and those with a score less than 50% as having a low quality. The result of this evaluation is reported in Supplementary File 1.

In this SR, the robustness of the evidence was ascertained using the framework established by the Oxford Centre for Evidence-Based Medicine (OCEBM) in 2011.33 The OCEBM's framework categorizes research into five distinct levels of evidence, contingent upon the study design and the quality of the research conducted. High-level studies, encompassing systematic reviews of randomized controlled trials and good quality individual trials, were assigned to the first evidence level. In contrast, research predominantly grounded in expert consensus or lacking empirical support was lowered to the fifth level. Intermediate-stage research, which includes but is not limited to less rigorous randomized controlled trials, cohort studies, and methodologies such as case series or case-control investigations, was allocated to the second, third, and fourth levels, respectively. Certain studies underwent a recalibration of their evidence level, either being elevated or diminished, influenced by parameters like methodological rigour, precision of findings, and the relevance of the results to the topic at hand.

Data from selected articles was extracted and reported in tables as follows: authors, year of publication, country, study design, populations, type of intervention and assessment of quality/bias.

The articles incorporated into this review were systematically categorized based on the type of interventions (prevention, education, clinical treatment). For each of these types of intervention classifications, the study methodologies and primary results were first reported through a narrative synthesis and subsequently in specific tables and graphs.

A total of 1949 records were identified, with 1783 articles were through electronic database searches (49 Cochrane Library, 166 PubMed, 22 CINAHL, 995 Scopus and 60 Web of Science, 491 Embase) and 166 articles were identified through ‘grey literature’ (Google Scholar). After removing 1548 duplicate articles, all titles were screened, and 401 articles were retained and evaluated for eligibility by reading the abstract. Of these, 370 studies were judged not relevant for various reasons, and the remaining 31 full text were evaluated; 24 studies were subsequently excluded as they did not meet the selection criteria for our research. The screening process ultimately included only seven studies. Two studies related to anosmia and five studies with dysgeusia, as represented in Fig. 1.

Fig. 1.

Prisma flow diagram.

(0.23MB).

The studies were conducted in various countries, including the United States (n=4),8,34–36 the United Kingdom (n=1),37 Australia (n=1),38 and Taiwan (n=1).39 In total, seven studies were included in this systematic review in line with our objectives. Among these, five studies8,36–39 assessed dysgeusia, while two studies34,35 focused on anosmia in CKD patients. Our analysis, based on the reviewed studies, involved a sample of 219 patients, with 67 included in the anosmia analysis (range 31–36) and 152 included in the dysgeusia analysis (range 7–145). The risk of bias, assessed using the framework proposed by JBI, demonstrated high quality of the included studies (range 75–100%), with an average score of 87.63%. Specifically, all studies exhibited high quality8,34–39; none of the selected studies were of medium or low quality.

Two studies34,35 investigated anosmia in CKD and end-stage renal disease (ESRD) patients, using the subjective global assessment (SGA) score to comprehensively evaluate nutritional status. The SGA score, ranging from 7 (indicating normal nutritional status) to 1–2 (indicating severe malnutrition status), provided an insightful assessment of nutritional levels. Additionally, the University of Pennsylvania Smell Identification Test (UPSIT) was employed to gauge olfactory function. The characteristics of these studies are reported in Table 1.

In the first study, a cohort study,34 the relationship between olfaction and nutrition was investigated, and an innovative intervention was introduced to enhance olfaction in ESRD patients. The study included 161 participants (36 CKD, 100 ESRD, and 25 controls) and revealed impaired odour identification in ESRD patients. The assessment of nutritional status using the SGA score demonstrated a reduction in odour identification scores associated with higher subjective global assessment scores, lower serum total cholesterol, and lower albumin concentrations. The subsequent pilot included seven ESRD patients self-administering 20μg intranasal theophylline daily for six weeks, resulting in improved olfactory function in 71% patients. This study underscores the need for further investigation into intranasal theophylline to enhance olfactory thresholds in ESRD patients.

The assessment of anosmia was also addressed by a second observational study,35 which enrolled 31 haemodialysis patients and 18 controls. Although no significant difference in olfactory function was observed between controls and “healthier” ESRD patients, those with lower smell scores exhibited significantly lower SGA scores and higher C-reactive protein levels. Intriguingly, neither smell scores nor nutritional status correlated with levels of the retained uraemic solution. This study supports the idea of impaired smell identification in ESRD patients, emphasizing that this impairment is not present in those with normal nutritional status.

We included a total of five studies on dysgeusia, comprising two cross-sectional studies,8,38 one cross-over study,38 one cohort study,40 and one RCT in double blind.36 The characteristics of this studies are shown in Table 2.

In two separate studies,36,37 researchers explored the potential significance of poor nutrient intake, particularly zinc deficiency, as a critical parameter for assessing malnutrition in dialysis patients.

In two studies, a double-blind randomized study36 aimed to determine the impact of zinc supplementation on taste perception in 15 haemodialysis patients. Seven patients received zinc sulphate (220mg) over six days, while the other eight received a placebo pill. The Visual Analog Scale was utilized to measure taste scores along with blood chemistry tests. The study revealed a disturbance in taste perception for sour taste in haemodialysis patients, and interestingly, this disturbance was not corrected by zinc supplementation. Despite previous evidence highlighting the importance of zinc in taste perception, none of the existing studies have proposed a persuasive mechanism to explain this phenomenon.

In a preceding study,37 designed as a cross-over study with 20 haemodialysis patients using zinc supplements (440mg) and placebos, researchers assessed taste acuity, serum zinc, zinc concentration in hair samples, and daily caloric intake. In contrast to the findings of Matson et al.,36 this study demonstrated that after zinc supplementation, taste acuity improved in 95% of patients, and hair zinc concentration increased in 85% of patients. Additionally, patients reported a significant improvement in appetite, and the average caloric intake increased in nineteen out of 20 patients. This seminal yet enduring study suggests that zinc supplementation proves highly beneficial in improving malnutrition among these patients.

In contrast to previous studies,36,37 a singular cross-sectional study38 aimed to investigate the potential association between taste alterations and the presence of malnutrition. The study encompassed 298 patients divided into two groups: the first group (n=145) underwent conservative non-dialysis management, while the second group (n=153) underwent renal replacement therapy. The researchers employed a 5-point Likert scale, termed iPOS-renal, ranging from none to overwhelming, to assess taste changes. Additionally, they evaluated various symptoms, including gastrointestinal symptoms, nausea, vomiting, diarrhoea, anorexia, constipation, and sore/dry mouth. Furthermore, the nutritional status was determined using the 7-point Subjective Global Assessment Tool, and biochemical parameters, such as serum urea, estimated glomerular filtration rate, and albumin, were also collected. Taste changes were reported by 38% of the 298 patients, and these changes were found to be associated with upper gastrointestinal symptoms and malnutrition in CKD patients. In a separate investigation,8 taste perception was assessed using a sensory questionnaire, which rated flavour intensity on a scale from 0 to 100. Unadjusted flavour intensity showed no discernible differences between dialysis patients and the control group. However, upon adjustment for deionized water taste, significant differences emerged between the groups (p=0.04), particularly for monosodium glutamate, sodium chloride, and sodium phosphate solutions. The study also noted significant differences in serum parameters, especially potassium, and sensory ratings. In the most recent study,39 researchers delved into whether gustatory function was correlated with frailty, utilizing both objective measures (taste strip kit) and subjective assessments (visual analogue scale). Among the 78 CKD patients involved, 14 patients were identified as frail (17.9%). The researchers employed three validated instruments: Edmond Frail Scale (EFS), FRAIL scale, and Study of Osteoporotic Fracture scale (SOF) and to assess frailty in patients. Their findings suggested that gustatory dysfunction might be a significant risk factor in CKD patients.

While the present review offers a comprehensive analysis of the available literature on anosmia in CKD patients, it is important to acknowledge certain limitations. Our study is inherently constrained by the limited number of studies available, particularly concerning anosmia. Additionally, many of the included studies had small sample sizes and lacked relevance to malnutrition. Despite these limitations, some studies underscore the importance of not underestimating symptoms such as anosmia and dysgeusia in haemodialysis patients. Furthermore, these symptoms may serve as indicators of nutritional status in both CKD and ESRD patients. Thus, while our study has its constraints, it emphasizes the significance of recognizing these symptoms and their potential implications for nutritional management in CKD and ESRD patients.