Authors: Kamyar Iravani, Tahereh Fereydoonnezhad, Aida Doostkam, Leila Malekmakan
Categories: Research, Chronic kidney disease, Olfactory impairment, Dialysis, Olfactory training, Curcumin
Source: BMC Nephrology
Authors: Kamyar Iravani, Tahereh Fereydoonnezhad, Aida Doostkam, Leila Malekmakan
Olfactory impairment is often considered a minor complication of chronic kidney disease (CKD), carrying important consequences for nutrition, safety, and overall quality of life. While several therapeutic strategies have been introduced in other populations, their effectiveness in the context of CKD remains poorly understood. This systematic review aimed to evaluate current evidence on the treatment of olfactory impairment in CKD patients, including those undergoing dialysis or kidney transplantation (KT).
A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science. Studies were included if they assessed therapeutic interventions targeting olfactory impairment in CKD patients. Data on study design, population, olfactory assessments, interventions, and outcomes were extracted and quality-assessed using the Effective Public Health Practice Project (EPHPP) tool.
Eight studies, published from 1987 to 2023, involving 469 CKD patients were included, spanning pre-dialysis, hemodialysis (HD), peritoneal dialysis (PD), and KT populations. Olfactory impairment was highly prevalent across all groups, affecting odor identification and discrimination. While KT offered the most complete recovery, dialysis had mixed effects, with limited improvement in olfactory thresholds. Among treatments, intranasal theophylline and curcumin showed partial efficacy, while olfactory training demonstrated the most consistent improvements in subjective and objective measures.
Olfactory impairment in CKD is a complex complication. Among available approaches, olfactory training stands out as a promising, non-pharmacologic option. Future clinical trials are essential to validate and refine treatment strategies tailored to the distinct metabolic and neurological challenges of CKD.Incorporating routine screening and targeted mannagement of olfactory impairment into nephrology practice may enhance overall patient care, nutritional status, and quality of life.
Not applicable
Olfactory impairment refers to a diminished sense of smell, which can arise from peripheral abnormalities, such as increased odor detection thresholds or disruptions in central olfactory processing, leading to reduced odor identification and discrimination [1]. Olfactory performance can range from normal to partially reduced (hyposmia) or wholly lost (anosmia). It is estimated that over 50% of individuals aged between 65 and 80 years suffer from olfactory impairment, with the prevalence increasing to 75% in those aged over 80 years [2, 3]. Remarkably, less than 25% of those with olfactory dysfunction are aware of their condition until formally tested [4]. Olfactory impairment is linked with both food aversion and anorexia, which contribute to poor nutritional status, fatigue, weakness, and malnutrition factors that significantly increase morbidity and mortality in patients [5, 6].
Beyond age-related decline, olfactory impairment may result from infections (e.g., COVID-19), trauma, chronic sinusitis, neurodegenerative diseases, tumors, exposure to medications and toxins, as well as chronic conditions like chronic kidney disease (CKD) [4, 7, 8].
In CKD, multiple pathophysiological mechanisms contribute to olfactory dysfunction, including uremic toxicity, nerve damage, malnutrition, and inflammation intensified by oxidative stress [9]. Evidence suggests that neuronal damage caused by renal failure plays a key role, with uremic toxins, oxidative stress, neuro-inflammation, and blood-brain barrier abnormalities disrupting the olfactory epithelium, bulb, and central processing pathways. Additionally, vascular calcification and endothelial dysfunction in CKD may further impair olfactory function by reducing cerebral blood flow [10].
Managing olfactory impairment typically involves a range of therapies tailored to its cause and severity, including olfactory training, pharmacological treatments, and surgical interventions for structural issues [11]. However, current evidence is insufficient to establish targeted therapeutic strategies for CKD-related olfactory dysfunction. While general treatments such as olfactory training and pharmacological interventions are commonly used, their efficacy in CKD remains poorly understood.
This systematic review aims to assess and evaluate therapeutic strategies specifically designed to address olfactory impairment in CKD patients.
This systematic review was conducted following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [12] and was registered on PROSPERO (CRD42025638124).
Studies were included if they investigated the treatment of olfactory disorders in patients diagnosed with CKD. Studies were original research articles (such as clinical trials, observational studies, or cohort studies) published in English literature. They examined therapeutic interventions, clinical outcomes, or management strategies related to olfactory dysfunction. Studies were excluded if they did not meet these eligibility criteria or the full text was unavailable. To ensure a focused and systematic approach, the eligibility criteria for this review were defined using the PICO framework as follows [13]: Population (P): studies involving patients diagnosed with CKD, including all stages (from early-stage CKD to ESRD) and those undergoing treatments such as dialysis or kidney transplantation (KT). Intervention (I): Any therapeutic or management strategy to address olfactory disorders, including pharmacological therapies, surgical interventions, dialysis, rehabilitation techniques, or lifestyle modifications. Comparison (C): studies with or without a comparison group. Comparators could include alternative treatments, placebo, or standard care. Outcome (O): primary outcomes included improved olfactory function, as measured by clinical assessments or patient-reported outcomes. Secondary outcomes included associations between olfactory scores and biochemical indicators such as serum urea and dialysis adequacy (Kt/V) and comparisons of olfactory performance across different treatment modalities.
A comprehensive search was conducted in PubMed, Scopus, and Web of Science to identify relevant studies on managing olfactory disorders in patients with CKD from inception till 5th of January 2025. The search strategy in PubMed combined Medical Subject Headings (MeSH) and free-text synonyms to ensure a thorough and sensitive search. In Scopus and Web of Science, due to the absence of MeSH terms, the search was conducted using only free-text keywords and their synonyms. Our search strategy included the following (Disosmia) OR (Dysosmia) OR (Hyposmia) OR (Odour) OR (Odour) OR (Olfactory) OR (Smell) OR (Anosmia) AND (Dialysis) OR (Renal Failure) OR (Chronic Kidney Disease) OR (Kidney Failure) OR (Kidney Transplant) OR (Renal Replacement Therapy) OR (End-stage Renal Disease). Additionally, the reference lists of the included studies were manually screened to identify any relevant articles that were not captured in the database search. Table 1 demonstrates the syntax used for each database.
Table 1Search strategy syntaxDatabaseSearch SyntaxPubMed(Disosmia OR Dysosmia OR Hyposmia OR Odour OR Odor OR Olfactory OR Smell OR Anosmia) AND (Dialysis OR Renal Failure OR Chronic Kidney Disease OR Kidney Failure OR Kidney Transplant OR Renal Replacement Therapy OR End-stage Renal Disease)ScopusTITLE-ABS-KEY (Disosmia OR Dysosmia OR Hyposmia OR Odour OR Odor OR Olfactory OR Smell OR Anosmia) AND TITLE-ABS-KEY (Dialysis OR Renal Failure OR Chronic Kidney Disease OR Kidney Failure OR Kidney Transplant OR Renal Replacement Therapy OR End-stage Renal Disease)Web of ScienceTS = (Disosmia OR Dysosmia OR Hyposmia OR Odour OR Odor OR Olfactory OR Smell OR Anosmia) AND TS = (Dialysis OR Renal Failure OR Chronic Kidney Disease OR Kidney Failure OR Kidney Transplant OR Renal Replacement Therapy OR End-stage Renal Disease)
All identified records were imported into EndNote, and duplicates were removed. Two reviewers independently screened the titles and abstracts (K.I. and T.F.) based on the eligibility criteria. Full-text articles were obtained for potentially relevant studies and assessed for inclusion. Disagreements were resolved through discussion or consulting two other reviewers (L.M. and A.D.). After the initial screening, the full-text articles of eligible studies were thoroughly reviewed to verify their compliance with the inclusion criteria. Studies that failed to meet the final eligibility standards were excluded.
A standardized data extraction form was developed to collect the following information from included Study characteristics (author, year, study design), Population characteristics (sample size, CKD stage, demographic data), Intervention details (type, duration, and dosage), Outcomes measured (e.g., improvement in olfactory function, quality of life). Two reviewers (K.I. and T.F.) performed data extraction independently, resolving discrepancies through consensus.
The quality of the included studies was evaluated using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. This tool assesses six selection bias, study design, confounders, blinding, data collection methods, and withdrawals/dropouts [14].
Two independent reviewers (K.I. and T.F.) conducted the assessments, resolving disagreements through discussion or consultation with two other reviewers (L.M. and A.D.). Each study received an overall rating of strong, moderate, or weak, ensuring a systematic evaluation of study quality and risk of bias.
To evaluate the strength of the overall evidence for each key outcome, we employed the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Two reviewers (K.I. and T.F.) independently assessed each intervention–outcome pair across five risk of bias, inconsistency, indirectness, imprecision, and publication bias. Certainty of evidence was then classified as high, moderate, low, or very low, in accordance with GRADE methodology. We summarized these evaluations in a Summary of Findings (SoF) table created using the GRADEpro GDT tool (see Table 3).
A total of 886 records were initially retrieved through the search process (Fig. 1). Following the elimination of 377 duplicates and a detailed screening of titles, abstracts, and full texts, eight studies met the inclusion criteria for this systematic review. Key characteristics and findings from these studies are outlined in Table 2.
Fig. 1PRISMA flow chart. PRISMA, preferred reporting items for systematic reviews and meta-analyses
Table 2Summary of included studiesAuthor (s) name, year of publication, countryObjectiveStudy typeNumber of participantsAge, mean (SD)Grouping categoryOlfactory assessment methodsTherapeutic interventionKey findingsQuality^*^ assessmentConrad et al., USA, 1987Evaluated olfactory performance in HD patients compared to healthy controlsCase-Control26 (10 control, 16 ESRD patients)patients: 18–68, 40.6 ± 3.5/ Control: 33.0 ± 2.5HDYes/No Odour IdentificationdialysisOlfactory scores declined significantly post-dialysis (p < 0.001).strongCorwin, USA, 1989Evaluated odor identification in HD patients compared to healthy controlsCase-Control30 (15 control, 15 ESRD patients)patients: 17–68, 41.7 ± 3.8/Control: 23–65, 40.5 ± 3.4HDYes/No Odour IdentificationdialysisDialysis patients showed reduced odor identification, which worsened after dialysis.strongGriep et al., Belgium, 1997Evaluated olfactory function in ESRD patientsCross-sectional101(16PD, 38HD, 19CRF, 28KT)CAPD:35–81, 64.0 ± 13.1; HD:37–88, 64.3 ± 13.0; CRF:24–81, 63.7 ± 13.7HD/PD/KTDetection Threshold (Isoamyl Acetate)dialysis, KTDialysis had no effect, but transplant restored normal olfactory function.strongLandis et al., Switzerland, 2011Assessed olfactory function in HD patients before and after a single dialysis session.Case-Control52 (24 healthy individuals, 20HD, 8PDpatients: HD:61 ± 3, PD:59 ± 4 /Control: 57 ± 2HD/PDSniffin’ Sticks (TDI), VASdialysisOlfactory function declined post-dialysis, with greater impairment in HD patients.strongKoseoglu et al., Turkey, 2017Assessed olfactory performance in non-diabetic CKD patientsCase-Control107 (24 healthy individuals, 38HD, 15PD, 30ND-CKD)patients: 19–73, 53/ Control: 38–75, 44HD/PDSniffin’ Sticks (TDI)dialysisDialysis patients had better olfactory scores than non-dialyzed CRF patients (p = 0.020).ModerateNigwekar et al., USA, 2017Evaluated intranasal theophylline in ESRD patients with olfactory dysfunction,Pilot clinical trial7 ESRD patientsnot reportedPharmacological interventionUPSITIntranasal theophyllineTheophylline improved odor identification in 71% of ESRD patients.weakIacono et al., Italy, 2022Evaluated olfactory function in CKD patientsCross-Sectional235(55 healthy individuals, 50KT, 49HD, 30PD, 51ND-CKD)patients: >18, 59.3 ± 14.6 / Control: >18, 53.9 ± 13.5HD/PD/KTOf VAS, Sniffin’ Sticks (TDI)dialysis, KTTDI scores were significantly lower in HD, PD, and ND-CKD vs. HS and KT (p < 0.001).strongMalekmakan et al., Iran, 2023Conducted a placebo-controlled, double-blind trial assessing curcumin’s effect on olfactory dysfunction in CKD patientsRCT58CKD(20curcumin, 19 training, 19controlpatients: 18–60(56.0 ± 2.2) Control: 18–60(55.7 ± 3.1)Olfactory Training/ Pharmacological interventionIran-SIT, QOD, Self-AssessmentCurcumin therapy and olfactory trainingOlfactory training was more effective than curcumin in improving smell function in CKD patients.StrongAbbreviations: CKD = Chronic Kidney Disease; HD = Hemodialysis; PD = Peritoneal Dialysis; KT = Kidney Transplant; CRF = Chronic Renal Failure; ND-CKD = Non-Dialyzed CKD; UPSIT = University of Pennsylvania Smell Identification Test; Iran-SIT = Iran Smell Identification Test; QOD = Questionnaire of Olfactory Disorders; TDI = Threshold, Discrimination, Identification (Sniffin’ Sticks test); VAS = Visual Analog Scale; ESRD = End-Stage Renal Disease; RCT = Randomized Controlled Trial. *: The quality measured using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool [14]. Each study received an overall rating of strong, moderate, or weak, ensuring a systematic evaluation of study quality and risk of bias
This review includes eight studies published between 1987 and 2023, encompassing 469 individuals with CKD. The study populations included individuals at various stages of CKD, ranging from pre-dialysis to hemodialysis (HD), peritoneal dialysis (PD), and KT. Study designs comprised three case-control, three cross-sectional, one randomized controlled trial (RCT), and a pilot clinical trial. The ages of participants across the studies ranged from 17 to 88 years.
Olfactory function was assessed using validated tools across the included studies. The most commonly used method was the Sniffin’ Sticks test, which evaluates Threshold, Discrimination, and Identification (TDI) scores (3 studies). This was followed by the University of Pennsylvania Smell Identification Test (UPSIT) or its localized version, the Iran Smell Identification Test (Iran-SIT) (3 studies). Two older studies used a binary Yes/No odor identification paradigm.
The results have been organized by population into various treatment modalities to enhance clarity and comprehension, as Hemodialysis (six studies), Peritoneal Dialysis (four studies), Kidney Transplantation (two studies), Pharmacological interventions (two studies), and Olfactory Training (one study). It should be noted that a single study may involve multiple treatment modalities, and thus, a single study can be categorized into more than one group.
Six studies have explored the impact of HD on olfactory function [15–20], producing mixed findings. While earlier research observed no improvement or even worsening in olfactory performance following HD, more recent studies suggest partial reversibility, particularly in odor threshold sensitivity.
In an early controlled study, Conrad et al. (USA, 1987) [15] employed a yes/no odor recognition task to evaluate olfactory performance in chronic HD patients. Compared to healthy controls, HD patients demonstrated chronic and acute olfactory deficits, with performance significantly declining after dialysis (mean score dropped from 78.40% to 72.67%, p < 0.001). These findings were reinforced by Corwin (USA, 1989) [19], who used a similar yes-no identification paradigm and found that olfactory discrimination worsened post-dialysis despite reductions in uremic toxin levels. Interestingly, despite the expected reduction in uremic toxin levels, the observed decline in olfactory performance after dialysis suggests that toxin clearance alone may not fully explain olfactory dysfunction. This finding points to the potential role of dialysis-related physiological changes in contributing to sensory impairment.
Griep et al. (Belgium, 1997) [16] evaluated olfactory function in HD patients using isoamyl acetate detection thresholds. Olfactory performance was significantly impaired in HD patients compared to healthy controls (p < 0.0005), with no significant improvement observed after dialysis (p = 0.140). A negative correlation between odor perception and serum urea levels (r=–0.38, p = 0.009) indicated that the dysfunction may reflect a chronic uremic effect rather than acutely reversible through dialysis.
In contrast, Landis et al. (Switzerland, 2011) [17] assessed olfactory function in HD patients before and after a single dialysis session. Olfactory performance improved significantly one hour after dialysis (t = 3.4, p = 0.003), with a 14.5% increase in odor identification scores and a 9.1% improvement in acetic acid thresholds. Despite these functional gains, no significant correlation was found between urea levels and olfactory outcomes across identification, acetic acid, or n-butanol thresholds. This suggests that the observed improvements were not directly related to urea clearance.
Similarly, Koseoglu et al. (Turkey, 2017) [18] assessed non-diabetic CKD patients. They found that those on HD had better olfactory performance than non-dialyzed patients, with higher TDI scores (25.5 vs. 22.5, p = 0.020) and improved odor thresholds (p = 0.029). However, no significant difference was observed in odor discrimination or identification, indicating that peripheral sensitivity may benefit from HD while central olfactory processing remains impaired. Additionally, no negative correlation was seen between creatinine levels and TDI scores, suggesting that olfactory function was independent of serum creatinine concentration in this study.
Iacono et al. (Italy, 2022) [20] conducted a large cross-sectional case-control study to evaluate olfactory function in patients across various renal replacement therapies. Among patients undergoing HD, 75.5% exhibited olfactory impairment, with a mean TDI score of 26.1 ± 5.5, indicating hyposmia. Compared to healthy controls and KT, HD patients showed significantly lower odor identification (9.6) and discrimination scores (9.9), while odor threshold scores (6.7) were relatively preserved. Significantly, TDI scores negatively correlated with serum urea (β=–0.03, p < 0.001) and positively with dialysis adequacy (Kt/V) (β = 0.01, p = 0.054), suggesting a link between uremic toxin burden and olfactory decline.
Collectively, these six studies [15–20] underscore that olfactory dysfunction is highly prevalent in HD patients, particularly in odor identification and discrimination domains. Earlier studies highlighted post-dialysis deterioration or stasis, while newer evidence suggests partial functional recovery, especially in odor threshold sensitivity.
Four studies have investigated the effects of PD on olfactory function, revealing varying degrees of impairment and highlighting the role of chronic uremia and metabolic stability.
Griep et al. (USA, 1997) [16] evaluated odor detection thresholds across renal replacement therapies and found that PD patients had significantly impaired odor perception compared to healthy controls (p = 0.001), with performance similar to HD patients (p = 0.779). No acute improvement in olfaction was observed. A significant correlation between blood urea and odor detection (r = − 0.44, p = 0.046) suggested that chronic uremic exposure, rather than short-term clearance, drives sensory dysfunction in PD patients.
Landis et al. (Switzerland, 2011) [17] compared PD, HD, and healthy controls using the Sniffin’ Sticks test. PD patients showed moderate olfactory impairment, with identification scores (9.6 ± 0.2) and threshold scores (acetic 14.4 ± 0.4; n-butanol: 7.5 ± 0.5) lower than controls but better than HD patients. No correlation with urea levels was found.
Koseoglu et al. (Turkey, 2017) [18] examined olfactory function in non-diabetic CRF patients. They reported that those on PD had a higher mean TDI score (27.5) compared to non-dialyzed patients (p = 0.020), along with better odor threshold scores (p = 0.029). No significant differences were observed in odor discrimination or identification. Overall, PD patients performed similarly to HD patients, indicating that neither modality fully restores olfactory function, though some peripheral sensitivity may be preserved.
Iacono et al. (Italy, 2022) [20] provided the most recent and comprehensive data, reporting that 93.3% of PD patients had an olfactory impairment, with a mean TDI score of 23.7—the lowest among all treatment groups. Odor threshold, discrimination, and identification scores were significantly reduced, and threshold scores were the poorest overall. PD was identified as an independent predictor of olfactory dysfunction (p < 0.001), and subjective self-assessments did not correlate with TDI scores (p = 0.293), indicating low patient awareness. These findings suggest that PD may be associated with more profound olfactory deficits, possibly due to less effective toxin clearance than other modalities.
Overall, while PD may offer slightly better olfactory outcomes than HD in some studies, significant dysfunction remains prevalent, underscoring the need for targeted interventions.
Two studies evaluated olfactory outcomes in KT recipients compared to other renal replacement therapies.
Griep et al. (USA, 1997) [16] reported that KT patients demonstrated near-normal odor detection thresholds and significantly better olfactory perception than both HD and PD patients (p < 0.0005). Their scores were statistically indistinguishable from healthy controls (p = 0.83), reinforcing that normalizing renal function can reverse olfactory deficits.
In a large cross-sectional study, Iacono et al. (Italy, 2022) [20] found that KT recipients had significantly better olfactory performance than patients on HD, PD, or pre-dialysis CKD patients. Their mean TDI score was 31.6 ± 3.6, closely resembling healthy controls (32.3 ± 4.1), with no statistically significant difference between the two groups. This contrasts sharply with the lower scores seen in dialysis groups (e.g., HD: 26.1 ± 5.1, PD: 23.7 ± 4.8). Only 34% of KT recipients showed olfactory impairment, compared to over 75% in dialysis patients.
These results suggest that KT offers the most complete recovery of olfactory function among renal replacement therapies, likely due to sustained toxin clearance and systemic normalization.
In addition to observational studies, two investigations assessed the potential of pharmacologic therapies to improve olfaction in CKD.
Nigwekar et al. (USA, 2017) [21] performed a proof-of-concept trial on seven ESRD patients with olfactory dysfunction, administering intranasal theophylline (20 mg daily per nostril) for 6 weeks. Five of seven participants (71%) showed improvement in odor identification, with mean scores increasing by 5.0% ± 3.5% and up to 10.7% ± 4.2% in some cases. Three patients improved by one olfactory category (e.g., severe to moderate hyposmia). Although changes in odor threshold were less consistent, the treatment was well tolerated with no adverse events. These findings support theophylline as a promising peripheral-targeting intervention for olfactory dysfunction in CKD patients.
Malekmakan et al. (Iran, 2023) [9] conducted a placebo-controlled, double-blind trial assessing curcumin’s effect on olfactory dysfunction in CKD patients. Participants receiving curcumin (500 mg twice daily for 12 weeks) demonstrated significant improvements in QOD scores (p = 0.045) and self-rated olfactory function (p = 0.047). However, improvement in Iran-SIT scores was not statistically significant (p = 0.066). Notably, 20% of patients in the curcumin group reached normosmic levels post-treatment. While curcumin’s impact was less pronounced than olfactory training, it outperformed placebo, indicating a potential therapeutic role via anti-inflammatory mechanisms.
In summary, both theophylline and curcumin show promise for improving olfactory CKD, with curcumin offering anti-inflammatory benefits. More extensive trials are needed.
Malekmakan et al. (2023) [9] evaluated olfactory training in CKD patients using a structured 12-week program involving repeated exposure to four different lavender (flowery), lemon (fruity), cinnamon (spicy), and eucalyptus (resinous). Patients were instructed to inhale each scent twice daily for 20 s. The training group showed significant improvements across all outcomes. The Iran-SIT score increased from 15.3 ± 4.9 to 18.8 ± 2.7 (p = 0.001), QOD scores improved from 19.0 ± 10.4 to 12.2 ± 9.9 (p = 0.003), and self-assessment scores rose from 6.8 ± 1.8 to 8.2 ± 3.1 (p = 0.027). Additionally, 36.8% of patients achieved normosmia post-intervention, compared to none at baseline. Among all groups, olfactory training produced the strongest and most consistent improvements, highlighting its effectiveness as a non-pharmacologic treatment for olfactory dysfunction in CKD.
The overall certainty of the evidence for each intervention–outcome pair is summarized in Table 3. Using the GRADE framework, we rated the certainty as moderate for olfactory training, low for curcumin and kidney transplantation, and very low for intranasal theophylline and dialysis-related outcomes. Downgrading was primarily due to limitations in study design (e.g., observational or uncontrolled trials), small sample sizes, inconsistent findings, and imprecise effect estimates.
Table 3GRADE summary of findings for interventions targeting olfactory dysfunction in CKD patientsInterventionOutcomeNo. of studies (Participants)Certainty of evidence (GRADE)CommentsOlfactory trainingImprovement in olfactory function1 study(19 participants) Moderate Significant improvement in objective and subjective measures; downgraded due to small sample size and single trial.Curcumin supplementationSubjective and objective olfactory change1 study(20 participants) Low Subjective improvement observed; objective score (Iran-SIT) not statistically significant; downgraded for imprecision.Intranasal theophyllineImprovement in odor identification1 study(7 participants) Very Low Uncontrolled pilot trial with very small sample; downgraded for risk of bias, imprecision, and indirectness.Dialysis (HD/PD)Change in olfactory function6 studies(245 participants) Very Low Mixed and inconsistent findings; mostly observational designs; downgraded for risk of bias and inconsistency.Kidney transplantationRecovery of olfactory function2 studies(78 participants) Low Consistently better outcomes than dialysis, but based on observational designs; downgraded for indirectness and bias.GRADE = Grading of Recommendations, Assessment, Development and Evaluation. Certainty High = very confident; Moderate = further research may change estimate; Low = limited confidence; Very low = very uncertain estimate
This systematic review aimed to explore therapeutic strategies for olfactory impairment in patients with CKD. Across eight studies involving 469 participants, we found that olfactory dysfunction is highly prevalent among individuals with CKD, particularly those undergoing dialysis. Kidney transplantation was consistently associated with the most complete recovery of olfactory function, while dialysis demonstrated mixed and often limited improvements. Among the available therapeutic interventions, intranasal theophylline and curcumin showed partial efficacy, whereas olfactory training produced the most consistent and clinically meaningful improvements. These findings highlight both the burden of olfactory dysfunction in CKD and the potential of targeted therapeutic approaches.
Olfactory impairment is also well-documented in various non-renal contexts, such as sinonasal disease, viral infections, trauma, and neurodegeneration [22]. Several therapies have been introduced for these conditions and may have potential in CKD. These include topical corticosteroids [23], which reduce local inflammation with minimal systemic absorption; vitamin A, used to stimulate olfactory epithelial regeneration [24]; and zinc supplementation, known to benefit patients with zinc-deficiency–related anosmia [25]. More novel strategies, such as omega-3 fatty acids [26] and platelet-rich plasma (PRP) nasal injections, have shown promise in promoting olfactory recovery by reducing inflammation and supporting the repair and regeneration of damaged neural tissue [27]. Additionally, acupuncture has emerged as a potential adjunct therapy in patients with persistent post-viral anosmia [28]. While none of these therapies have been directly studied in CKD, their underlying mechanisms (e.g., oxidative stress modulation, neuroplasticity, epithelial repair) closely align with the proposed pathophysiology of CKD-related olfactory loss. Further clinical trials are needed to evaluate targeted treatments for olfactory impairment in CKD patients.
This review included eight studies covering pre-dialysis, HD, PD, KT, and behavioral or pharmacologic interventions. Olfactory impairment was prevalent across all groups. Most studies reported deficits in odor identification and discrimination. At the same time, threshold sensitivity was relatively preserved or partially reversible, suggesting that some components of the olfactory pathway may remain functionally intact and could potentially respond to targeted interventions.
When compared with previous studies conducted in CKD populations, our findings are largely consistent. Observational research has repeatedly shown that olfactory dysfunction is highly prevalent in advanced CKD and ESRD, often affecting over 70% of patients, and is closely linked to malnutrition and impaired quality of life [1, 21, 29]. Evidence regarding dialysis remains some reports have documented modest short-term improvements immediately after hemodialysis [17], whereas others have described persistent dysfunction despite regular HD or PD sessions [16, 18, 20], highlighting the variability also observed in our review. By contrast, kidney transplantation consistently emerges as the most effective intervention, restoring olfactory performance to levels comparable with healthy controls [20, 29, 30]. Pharmacologic approaches such as intranasal theophylline and oral curcumin remain underexplored in CKD, with only small-scale or pilot trials available, whereas olfactory training, already validated in non-renal populations [31], has shown encouraging preliminary results in CKD patients [9]. These consistencies and discrepancies highlight both the robustness of certain findings, such as the benefit of transplantation, and the need for further trials to clarify the role of dialysis and interventional therapies [29, 30].
The relationship between HD, PD, and olfactory recovery remains complex. Earlier studies reported no improvement or worsening post-dialysis, challenging the assumption that short-term toxin clearance is sufficient for sensory recovery. This research has indicated a deterioration in olfactory function following HD interventions. Although a decrease in uremic toxin levels is anticipated, the observed reduction in olfactory capabilities post-HD implies that the removal of toxins alone might not fully account for olfactory dysfunction. This outcome highlights the possible influence of physiological alterations induced by dialysis in the progression of sensory deficits. Furthermore, this suggests that the impairment could be a manifestation of a chronic uremic condition, rather than an acute issue rapidly reversible by dialysis [16, 20]. We consider this is likely attributable to sustained injury within the nervous system, resulting from the continued accumulation of uremic toxins. Even with more stable metabolic profiles, PD patients did not show consistent olfactory improvement, indicating that other factors may be involved. Recent studies suggest that improvements in dialysis adequacy may lead to clinically relevant gains in odor detection, reinforcing the importance of dialysis quality in sensory outcomes [20].
In addition to observational findings, this review incorporated interventional studies that provide promising evidence for potential therapeutic approaches. Among the pharmacological interventions explored, intranasal theophylline showed promising results in improving odor identification in CKD patients. The underlying mechanism is thought to involve the activation of epithelial ion channels and membrane transporters through increased intracellular cyclic AMP and cyclic GMP levels. These signaling molecules stimulate vacuolar proton-pumping ATPases, which are highly expressed in the olfactory epithelium and play a critical role in proton secretion required for odor detection. This pathway highlights theophylline’s potential as a targeted therapy for olfactory dysfunction in CKD [21]. Curcumin, a potent antioxidant and anti-inflammatory agent, improved quality-of-life and subjective olfactory scores, though objective improvements were less pronounced [9]. Among all interventions, olfactory training yielded the most promising outcomes. This low-cost, non-invasive behavioral approach significantly improved subjective and objective olfactory measures based on repeated exposure to familiar odourants. Over one-third of participants regained normosmia within just 12 weeks [9].
These results underscore that olfactory dysfunction in CKD is common and potentially treatable, particularly if proactively identified. The underlying causes of olfactory dysfunction in CKD appear to go beyond just uremic toxin build-up, involving factors like inflammation, impaired nerve regeneration, and disrupted cognitive integration. This may help explain why combining treatments such as peripheral stimulants like theophylline, anti-inflammatory agents like curcumin, and behavioral approaches like olfactory training could be more effective than any single strategy alone.
From a clinical perspective, routine olfactory assessment could be easily implemented in dialysis units using validated tools such as the Sniffin’ Sticks or UPSIT. Patients reporting anorexia, unexplained weight loss, or reduced food enjoyment may particularly benefit from early screening. Many studies found that patients were often unaware of their olfactory deficits, underscoring the need for proactive screening rather than relying on self-reported symptoms. Given its low cost and favorable safety profile, olfactory training may also represent a practical first-line approach, especially in resource-limited settings.
This review has some limitations. Small sample sizes and varied study designs limited the validity of several included studies. The limited sample sizes are likely due to insufficient research on olfactory dysfunction in CKD, emphasizing the critical need for further investigation. However, it is essential to underline that interpreting data derived from these limited studies requires extreme caution when considering their applicability and generalizability to the vast ESRD population. So, these results should be regarded as preliminary and hypothesis-generating, rather than broadly conclusive. Additionally, there is a notable challenge in the heterogeneity of tools and methodologies employed across various studies to assess olfactory function. This variability can impede direct comparisons and the generalizability of findings. Also, the overall quality and design of available studies present a considerable limitation. The majority of included research consists of observational studies (only one Randomized Controlled Trial in our review), which inherently carries a higher risk of bias and confounding., None of the studies investigated combined or sequential treatment approaches. Furthermore, few studies explored the biological markers associated with olfactory recovery. Another limitation of this review is that we did not search additional databases such as Embase, CINAHL, or the Cochrane Library, nor did we include grey literature sources. Although our search across PubMed, Scopus, and Web of Science captured a wide range of relevant studies, the exclusion of these additional sources may have limited the comprehensiveness of the evidence base. These gaps limit the strength of current conclusions and present clear directions for future inquiry.
Future studies should focus on longitudinal and randomized trials to better understand prevalence, progression, and response to treatment. Therapeutic trials should explore both monotherapies and combination approaches, including promising non-CKD interventions like vitamin A, PRP, omega-3 fatty acids, and acupuncture, tailored to the metabolic context of CKD. Significantly, these investigations should extend beyond simply assessing olfactory recovery also to evaluate its comprehensive impact on other clinically relevant outcomes. Such as nutritional status, overall quality of life, and patient safety, thereby providing a holistic understanding of the benefits of restoring olfactory function in CKD patients.
Olfactory impairment is a common and complex complication of CKD. Despite its impact on nutrition, safety, and emotional health, it frequently remains undiagnosed in clinical care. Encouragingly, emerging therapies, including pharmacologic agents and olfactory training, offer meaningful potential to restore smell and improve quality of life. Integrating olfactory assessment and treatment into routine nephrology care may help preserve a vital yet often neglected sense.
Our review provides clear insights into the clinical relevance of olfactory impairment in CKD patients. Nevertheless, it is imperative to recognize that the current evidence, while compelling, necessitates validation through additional well-designed, high-quality clinical trials. These studies are essential for confirming the effectiveness and long-term benefits of the interventions discussed herein, thereby providing a more solid foundation supported by comprehensive evidence.