Renal insufficiency (RI) is a clinical syndrome characterized by impaired kidney metabolic function resulting from diverse etiologies, leading to disruptions in the body’s metabolites, fluid balance, electrolytes, and acid–base homeostasis (1). RI is categorized into chronic renal insufficiency and acute renal insufficiency (2). However, inconsistent terminology in renal function and disease classification has prompted standardized nomenclature: chronic renal insufficiency is now termed chronic kidney disease (CKD) per Kidney Disease Improving Global Outcomes (KDIGO) conference consensus (3, 4), while acute renal insufficiency is defined as acute kidney injury (5–7). CKD encompasses pathologies such as glomerulonephritis, diabetic nephropathy, and end-stage renal disease (8, 9), and is staged 1–5 based on severity, progressing from mild functional impairment to renal failure requiring dialysis or transplantation. Projections indicate that by 2040, kidney disease will rank as the fifth leading cause of reduced life expectancy globally (4, 8).

Amino acids (AA) and their derivatives are ubiquitously utilized as dietary supplements in clinical and nutritional contexts, exerting profound influences on renal physiology and homeostasis. RI is associated with dysregulated serum AA concentrations, though evidence suggests moderate dietary AA intake may confer therapeutic benefits (1). Studies indicate that AA infusion protects renal function through mechanisms such as replenishing depleted AA, enhancing renal plasma flow (RPF), and improving estimated glomerular filtration rate (10–12). The kidneys also contribute significantly to protein metabolism: in healthy individuals, 97–98% of filtered AA and peptides undergo tubular reabsorption. In CKD patients, however, inflammatory states and metabolic acidosis disrupt AA and protein metabolism. Progressive CKD further alters filtration and reabsorption, exacerbating AA wasting and proteinuria (13, 14).

AA and their derivatives, as fundamental components of proteins and peptides, serve as critical dietary supplements with profound implications for renal health (15). AA exhibits multifaceted roles in nutrition, therapy, and medicine, frequently acting as a primary active ingredient in nutritional formulations (16). Biomarkers, such as albumin (ALB), total protein (TP), and transferrin (TRF), are indispensable for evaluating nutritional status in patients with RI, while also serving as predictors of disease progression and clinical outcomes (17). Despite their therapeutic potential, excessive intake of most AA supplements, particularly amino acids like glutamine and arginine, which are essential for tumor cell proliferation, may induce adverse effects (18). In RI patients, prolonged high-dose AA administration can disrupt amino acid homeostasis, leading to nitrogen accumulation and exacerbating renal damage (19).

Preclinical studies have demonstrated that AA supplementation improves glomerular filtration rate (GFR) in RI models, yet clinical trials report inconsistent outcomes. This discrepancy is compounded by substantial heterogeneity in study design, including variations in AA formulations, intervention durations, and patient baseline characteristics (20, 21). Notably, while AA metabolism is intricately linked to nutritional status, current research has underemphasized key nutritional parameters—such as ALB, TP, TRF, and body mass index (BMI)—which are central to assessing both nutritional adequacy and renal disease trajectories (17). Existing literature further highlights conflicting evidence regarding AA’s effects on these markers: divergent results have been reported for ALB, TP, and TRF in RI populations undergoing AA interventions. Although animal studies suggest renoprotective and nutritional benefits, the clinical evidence base remains fragmented, characterized by a lack of systematic quantitative synthesis, especially of high-quality randomized controlled trials (RCTs), hindering clarity on AA’s clinical applicability and optimal dosing strategies in RI (11, 22, 23). To address this gap, we conducted a bibliometric analysis to map research trends and a meta-analysis of RCTs to (1) evaluate AA effects on renal function: blood urea nitrogen (BUN), RPF, GFR, uric acid (UA), and nutritional parameters; (2) identify intervention modifiers through subgroup analyses; and (3) delineate unresolved evidence gaps for future inquiry. This integrated approach aims to quantify the clinical benefits of AA in renal protection and nutritional efficacy, providing robust evidence to inform clinical practice.

Researchers with high citation rates or prolific publication outputs exert significant influence on the trajectory of scientific inquiry within a field, making their identification critical to understanding its leadership (39). This analysis identifies Kalantar-Zadeh Kamyar and Zidek Walter as pivotal contributors to advancing knowledge on AA interventions in RI. Understanding national and institutional contributions to research in this field will help researchers to seek collaborations between universities or international institutions to advance the field (40). For instance, the University of California System emerged as the most productive institution in this domain, underscoring its leadership in AA-related renal research.

Keyword and term analyses derived from article titles and abstracts reveal thematic priorities (41). Recurrent terms such as chronic kidney disease risk progression oxidative stress chronic renal failure inflammation renal failure expression and metabolism highlight a sustained focus on elucidating mechanisms underlying renal injury and failure progression. Density visualization emphasized chronic kidney disease and oxidative stress as dominant themes, while temporal trends identified biomarkers as an emerging keyword, reflecting intensified efforts to discover novel CKD biomarkers in recent years.

In terms of the development of research, the first study evaluating AA in RI was published in 1973, which showed that intravenous AA produced favorable effects in patients with acute renal insufficiency (42). Subsequent milestones include an RCT in 1982 comparing standard AA with essential amino acids (EAA) in renal impairment (43, 44), which solidified EAA supplementation as a sustained research priority in RI through 2000. Post-2000, investigations increasingly targeted CKD management, with recent emphasis on AA formulations to improve renal function and nutritional status in CKD and dialysis populations (11, 18). Notably, the role of AA in preventing cardiac surgery-associated acute kidney injury has emerged as a prominent focus, supported by high-quality clinical trials (10, 12, 45, 46).

Renal function indices were altered to varying degrees in patients with different types of RI compared to normal subjects. In normal physiology, intravenous AA administration elevates GFR via activation of renal functional reserve. However, this compensatory mechanism diminishes as CKD progresses to end-stage renal disease (47). Stevens et al. identified a sustained decline in GFR as a predictor of adverse outcomes in CKD (48). Seki et al. linked elevated BUN to accelerated renal deterioration in advanced CKD (stages 3–5) (49). Jiang et al. postulated that AA supplementation enhances RPF, thereby exerting renoprotective effects (50). Hyperuricemia and urinary stone formation, driven by elevated UA, are recognized risk factors for CKD progression (51, 52). Dysregulated AA metabolism contributes to hyperuricemia in CKD patients; AA supplementation may correct this imbalance and reduce UA levels, even in advanced disease (11, 53). This meta-analysis synthesizes evidence supporting AA’s potential renal benefits. For instance, there was a numerical increase in RPF in 3 of the 3 studies (11, 21, 36), and UA levels were reduced in 2 of the 3 studies (11, 38). Consistent with preliminary results and preclinical studies. However, BUN levels were elevated in 4 of 5 studies (22, 23, 35, 36). Singer et al. noted that short-term AA infusion (75 g/day) in acute kidney injury patients significantly raised BUN by days 2–4 (p < 0.04) (50), likely due to increased protein catabolism. In stable CKD, elevated BUN is primarily attributed to excessive protein intake (51), and low-protein diets effectively mitigate this effect (52). Therapeutic strategies may thus require tailored approaches: high-dose AA infusion (150 g/day) for short-term acute kidney injury management versus long-term protein restriction in CKD to counteract BUN elevation (54, 55).

Nutrition serves as a cornerstone in CKD management (56). The kidneys are central to maintaining nutritional homeostasis, regulating AA balance partially through synthesis and catabolism (57). In therapeutic contexts, AA is primarily utilized in drug therapy to support protein synthesis (58). For patients with kidney injury, 9AA is generally used, which contains eight EAA and histidine in its composition, and the intervention in this study contained 9AA in all AA mixtures except arginine (59). EAA supplementation in CKD patients aids in preserving protein homeostasis (19), while biomarkers such as ALB, TP, TRF, and BMI are widely employed to assess nutritional status in CKD and HD populations (60). Protein depletion and malnutrition are prevalent in HD-treated CKD patients due to AA losses during dialysis (17). Murtas et al. demonstrated that CKD disrupts AA kinetic metabolism, impairing protein anabolism, a phenomenon exacerbated by HD-induced AA depletion (11). Conversely, Erkan et al.’s retrospective study found no significant improvement in ALB levels with daily 1.1% AA solution use in PD patients over 12 months (61). This meta-analysis corroborates prior findings, revealing no statistically significant impact of AA therapy on ALB, TP, TRF, or BMI in RI patients (17, 62). The lack of significant nutritional parameter changes may be attributed to (1) Intervention heterogeneity: Included studies utilized diverse AA formulations (e.g., L-arginine, variable EAA compositions) and short intervention durations (7/9 studies ≤3 months), potentially blunting effects on slow-turnover biomarkers like ALB (half-life: 2–3 weeks) (63). (2) CKD-associated catabolic states: Uremic toxin accumulation, chronic inflammation, and dialysis-induced AA losses (up to 800 g/year in HD patients) counteract the anabolic effects of supplementation, with 60.2% of participants in the population included in this article receiving dialysis treatment (22, 64). These findings underscore a critical limitation: standalone nutritional parameters may not capture AA efficacy in complex RI populations, necessitating integrated assessments of inflammation, metabolic markers, and patient-centered outcomes. For CKD patients, especially those who need dialysis, supplemental AA therapy should be supplemented with attention to the nutritional status of the patients and appropriate nutritional supplements, while focusing on the changes in renal function indices for a protein-restricted diet or other effective measures. Future studies should further explore the effects of different AA types, dosages, and treatment durations on nutritional indicators to optimize the treatment regimen.

This study has several limitations. In the bibliometric analysis, reliance solely on the Web of Science database may introduce selection bias, as inclusion of additional repositories (e.g., Scopus, MEDLINE) could yield divergent results. Furthermore, the search strategy encompassed studies involving AA structural derivatives, potentially capturing marginally relevant literature. For the meta-analysis, heterogeneity in eligibility criteria, control interventions, AA treatment components (e.g., dosage, formulation), and patient subtypes (e.g., CKD stages, dialysis modalities) limits the generalizability of pooled results. Such variability underscores the need for standardized protocols in future trials to enhance comparability.

Bibliometric analysis suggests that the keywords oxidative stress, inflammation, risk, and progression aim to shed light on possible mechanisms of RI. Keyword trends focused on CKD and new biomarkers, findings that reiterated the importance of chronic kidney disease progression and mechanisms. The meta-analysis yielded a multifaceted therapeutic landscape for AA supplementation: while it exhibited promising effects by enhancing RPF and reducing UA levels, these advantages were counterbalanced by sustained elevation in BUN and lack of significant alterations in nutritional parameters. This suggests that the renal impacts of AA are context-dependent, influenced by factors such as patient population, intervention duration, and formulation composition, and thus warrant nuanced interpretation and judicious clinical consideration. Clinically, these findings underscore the need to balance observed improvements in GFR and UA against potential risks associated with BUN elevation when integrating AA supplementation into therapeutic regimens.