EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Protein energy wasting is a highly prevalent and clinically significant complication in patients receiving maintenance hemodialysis, affecting approximately 30% to 50% of this population worldwide. Protein energy wasting is associated with substantially increased risk of all-cause and cardiovascular mortality, reduced functional capacity, impaired immune function, and poor quality of life. The pathogenesis of protein energy wasting is multifactorial and involves reduced dietary intake, chronic inflammation, metabolic acidosis, dialysis-related nutrient losses, hormonal and metabolic disturbances, and comorbid disease burden. This narrative literature review synthesized contemporary evidence (2020-2025) on the epidemiology, pathophysiology, assessment, and nutritional management of protein energy wasting in patients receiving hemodialysis. We highlighted limitations of traditional biochemical markers such as serum albumin and emphasized the importance of multidimensional nutritional assessment using validated clinical tools, including the Subjective Global Assessment and Malnutrition-Inflammation Score, complemented by objective body composition techniques. We also discussed current guideline-recommended targets for protein and energy intake, as well as real-world barriers to achieving these targets. We reviewed and examined evidence supporting oral nutritional supplementation as first-line therapy, along with indications for intradialytic parenteral nutrition in selected patients with severe or refractory protein energy wasting, and the role of micronutrient management, vitamin D repletion, and targeted trace element supplementation. Emerging adjunctive strategies, including omega-3 fatty acids, gut microbiome modulation, and exercise–nutrition synergy, were also addressed. Overall, effective management of protein energy wasting requires early identification, individualized dietary strategies, and integration within multidisciplinary dialysis care models. Future research should prioritize pragmatic trials focused on hard clinical outcomes and personalized approaches to nutritional therapy in this high-risk population.

Key words : Intradialytic parenteral nutrition, Malnutrition–inflammation complex, Oral nutritional supplementation, Protein-energy wasting

Introduction
Protein energy wasting (PEW) represents a pervasive and life-threatening complication affecting 30% to 50% of patients on maintenance hemodialysis globally, with higher prevalence observed in elderly populations, women, and individuals with diabetes mellitus or cardiovascular comorbidities.^1,2 As defined by the International Society of Renal Nutrition and Metabolism, PEW is a state of decreased body protein and energy reserves, manifested through reductions in visceral and somatic protein, adipose tissue, and serum protein concentrations, and functions as both a marker and mediator of poor outcomes in end-stage renal disease.³
Large prospective cohort studies have consistently demonstrated that PEW independently predicts 1.5- to 3.5-fold increased risks of all-cause and cardiovascular mortality after adjustment for age, dialysis vintage, comorbidity burden, and dialysis adequacy.^4,5 The mechanisms linking PEW to adverse outcomes extend beyond simple caloric deficit: loss of lean body mass directly impairs respiratory muscle function, immune competence, and wound healing capacity, while simultaneously exacerbating insulin resistance and endothelial dysfunction.⁶ Furthermore, the malnutrition-inflammation-atherosclerosis syndrome conceptualizes PEW not as an isolated nutritional disorder but as an integrated pathophysiological cascade wherein chronic inflammation drives both muscle catabolism and accelerated vascular disease.⁷ This paradigm shift underscores that nutritional interventions in patients on hemodialysis must target not only substrate delivery but also the underlying inflammatory milieu.

Pathophysiological Mechanisms Underlying Nutritional Deterioration
The pathogenesis of PEW in patients on hemodialysis reflects a complex interplay of reduced nutrient intake, metabolic derangements, dialysis-related losses, and inflammation-mediated catabolism, a constellation termed “malnutrition-inflammation complex syndrome.”⁸

Anorexia and reduced oral intake
Uremic toxin accumulation (eg, indoxyl sulfate, p-cresyl sulfate) directly suppresses appetite via hypothalamic signaling pathways and induces early satiety through delayed gastric emptying.⁹ Concomitant factors, including dysgeusia, xerostomia, depression, socioeconomic constraints, and overly restrictive dietary prescriptions, further compromise dietary adherence. Notably, contemporary evidence has challenged the historical emphasis on stringent phosphorus and potassium restriction; emerging data have suggested that excessively restrictive diets may inadvertently precipitate protein-energy malnutrition without commensurate reductions in hyperphosphatemia-related mortality.¹⁰

Chronic inflammation and catabolic signaling
Persistent low-grade inflammation, driven by bioincompatible dialysis membranes, endotoxin translocation from gut dysbiosis, vascular access complications, and comorbid conditions, elevates proinflammatory cytokines (interleukin 6, tumor necrosis factor α, C-reactive protein) that activate the ubiquitin-proteasome and caspase-3 proteolytic pathways, accelerating skeletal muscle breakdown.¹¹ These cytokines concurrently suppress insulin-like growth factor-1 signaling and mechanistic target of rapamycin-mediated protein synthesis, creating a sustained negative nitrogen balance resistant to nutritional supplementation alone.

Metabolic acidosis
Even mild metabolic acidosis (serum bicarbonate <22 mmol/L), prevalent in 15% to 30% of patients on hemodialysis despite dialysis correction, stimulates branched-chain amino acid oxidation and suppresses albumin synthesis.¹² Recent trials have demonstrated that bicarbonate supplementation to maintain levels ≥24 mmol/L preserves lean body mass and improves physical function independent of dialysis adequacy.¹³

Dialysis-related nutrient losses
Each hemodialysis session removes 8 to 12 g of amino acids and small peptides, equivalent to 10% to 15% of daily protein requirements.¹⁴ Additional losses of water-soluble vitamins (B1, B6, C, folate) and trace elements (zinc, selenium) occur with each treatment, cumulatively contributing to micronutrient depletion over time.¹⁵

Nutritional Assessment: Beyond Serum Albumin
Accurate identification of PEW requires multidimensional assessment integrating anthropometric, biochemical, dietary, and functional parameters, as no single parameter suffices for diagnosis.¹⁶

Limitations of conventional biomarkers
Serum albumin, long considered to be the gold standard, has shown poor specificity in hemodialysis populations due to confounding by inflammation (negative acute-phase reactant), volume overload (hemodilution), and liver synthetic function.¹⁷ Prealbumin (transthyretin) has demonstrated shorter half-life and greater sensitivity to short-term nutritional changes but remains similarly confounded by inflammation and thyroid status.¹⁸ Consequently, both markers should be interpreted alongside inflammatory indices rather than in isolation.

Validated clinical tools
The Subjective Global Assessment predicts mortality with hazard ratios of 2.1 to 3.4 in multiple hemodialysis cohorts.¹⁹ The Malnutrition-Inflammation Score has shown superior prognostic accuracy compared with albumin alone (area under the curve of 0.78 vs 0.65).²⁰

Body composition analysis
Bioelectrical impedance analysis, particularly multifrequency and segmental techniques, provides objective quantification of lean tissue mass, fat mass, and extracellular water.²¹ The lean tissue index independently predicts mortality; values <13 kg/m² in women and <15 kg/m² in men confer a 2.3-fold higher mortality risk.²² Dual x-ray absorptiometry and computed tomography offer research-grade precision but are limited by cost and accessibility.²³ Current KDIGO and ESPEN guidelines endorse combined Subjective Global Assessment/Malnutrition-Inflammation Score screening supplemented by bioelectrical impedance analysis for longitudinal monitoring.^24,25

Dietary Protein and Energy Targets: Evidence and Implementation Challenges
Guidelines recommend protein intake of ≥1.2 g/kg/day and energy intake of 30 to 35 kcal/kg/day for stable hemodialysis patients.^26,27 Nevertheless, 40% to 60% of these patients consume below these thresholds.²⁸ A 2023 multicenter trial showed that liberalizing phosphorus intake to 1200 mg/day increased protein consumption without worsening serum phosphorus or mortality.²⁹ In elderly HD patients, mild overweight may confer survival advantage (the “obesity paradox).”³⁰

Oral Nutritional Supplementation: Efficacy and Practical Considerations
Meta-analyses have demonstrated that oral nutritional supplements providing 20 to 30 g protein and 300 to 400 kcal can increase serum albumin, prealbumin, and body weight over 3 to 6 months.^31,32 Intradialytic supplementation exploits an anabolic window.³³ A 2022 randomized control trial has shown the ability for significant gains in lean body mass and functional capacity.³⁴ Adherence limitations remain substantial,³⁵ although personalization improves outcomes.³⁶ Cost-effectiveness analyses support use of oral nutritional support, with NNT8-12 to prevent hospitalization.³⁷

Intradialytic Parenteral Nutrition: Targeted Application
Intradialytic parenteral nutrition is reserved for patients with severe PEW unresponsive to oral strategies.³⁸ Randomized control trials have demonstrated improvements in albumin and body weight, with omega-3–enriched formulations reducing inflammatory markers.³⁹ The NIPPN trial found benefit only in selected high-risk subgroups, supporting restrictive indications.⁴⁰

Micronutrient Management: Beyond Routine Supplementation
Hemodialysis accelerates losses of water-soluble vitamins.⁴¹ Vitamin D deficiency affects >80% of patients,⁴² and adjunctive cholecalciferol improves musculoskeletal outcomes. Zinc and selenium deficiencies are common in patients on hemodialysis, warranting targeted rather than universal supplementation.⁴³

Emerging Adjunctive Strategies
Omega-3 fatty acids reduce inflammation and dyslipidemia, with ongoing trials assessing effects on muscle mass.⁴⁴ Probiotics reduce uremic toxins and inflammatory markers.⁴⁵ Exercise combined with protein supplementation yields synergistic anabolic effects, particularly when performed intradialytically.⁴⁶

Multidisciplinary Integration: The Critical Success Factor
Dialysis units that have structured dietitian involvement have shown superior nutritional and clinical outcomes. Integrated models combining screening, early supplementation, body composition monitoring, and coordinated care are most effective.⁴⁷ Telehealth nutrition services have shown non-inferiority to in-person care.⁴⁸

Knowledge Gaps and Future Directions
Unresolved questions include optimal protein targets in elderly patients, long-term safety of liberalized phosphorus diets, comparative efficacy of intradialytic parenteral nutrition versus high-dose oral nutritional support, and personalized micronutrient strategies. Large pragmatic trials and implementation research are urgently needed.⁴⁹

Volume: 24 Issue: 6 July 2026 - Supplement - 2

FULL TEXT