Pistachio Consumption in Patients With Chronic Kidney Disease

Introduction Cardiovascular diseases (CVD) remain the leading cause of mortality inpatients with chronic kidney disease (CKD), and targeted nutritional management plays acritical role in mitigating CVD risk in this population. While extensive epidemiologicalevidence underscores the cardioprotective benefits of nut consumption, dietary guidelinesfor patients with CKD typically mandate strict phosphorus and potassium restriction.Consequently, nut intake is frequently discouraged in this group. This restriction stemsfrom the impaired renal capacity to excrete excess phosphorus and potassium; unmitigateddietary phosphorus loading can exacerbate secondary hyperparathyroidism, renalosteodystrophy, vascular calcification, and overall cardiovascular morbidity andmortality. Conversely, overly restrictive phosphorus diets often precipitate inadequateintake of essential cardioprotective nutrients.Phytate (phytic acid or myo‐inositol hexaphosphate) is a naturally occurring compoundabundant in fiber‐rich foods, including whole grains, legumes, and nuts. It acts as aneffective dietary inhibitor of calcium salt deposition, thereby mitigating risksassociated with nephrolithiasis and vascular calcification. Nuts are rich sources of bothdietary fiber and phytate, with pistachios standing out among the highest botanicalsources‐averaging 1,562 mg (range: 0.29‐2.83 g) of inositol phosphate per 100 g.Accumulating evidence indicates that pistachio consumption may attenuate cardiovascularrisk through anti‐inflammatory, antioxidant, and lipid‐lowering mechanisms, alongsidefavorable effects on blood pressure.Crucially, the majority of phosphorus in unprocessed nuts is organically bound asphytate, which resists enzymatic cleavage in the human gastrointestinal tract,substantially reducing its intestinal bioavailability and systemic absorption. Therefore,a large proportion of phosphorus derived from natural nuts may not be systemicallybioavailable. Given these favorable phytochemical profiles, moderate pistachioconsumption by patients with CKD could potentially improve specific cardiovascular riskfactors without adversely altering mineral metabolism. Nevertheless, interventional dataevaluating the clinical safety and efficacy of nut consumption in CKD populations remainsparse. This study aims to evaluate the short‐term effects of incorporating pistachiosinto the diets of patients with CKD on circulating and urinary phosphorus levels, as wellas serum concentrations of parathyroid hormone (PTH), fibroblast growth factor 23(FGF23), and malondialdehyde (MDA).Methods This study is designed as an open‐label, randomized, controlled crossoverclinical trial. Eligible patients with stage 4 and 5 non‐dialysis CKD presenting to thenephrology clinic will be informed of the study objectives, and written informed consentwill be obtained prior to enrollment.Prior to randomization, all participants will undergo a 1‐week run‐in period. During thisphase, participants will initiate the standardized, modified pre‐dialysis renal diet(protein: 0.8 g/kg/day, potassium: 39 mg/kg/day, and phosphorus: 12 mg/kg/day). Theprimary purpose of this run‐in phase is to ensure participant adherence to the dietaryprotocol and to stabilize baseline metabolic parameters before the initiation of theexperimental periods.Eligibility CriteriaInclusion Criteria: ‐ Age ≥18 ‐ Stage 4 or 5 non‐dialysis CKD, defined as an estimated glomerular filtration rate(eGFR) <30 mL/min/1.73 m2 ‐ Exclusion Criteria: ‐ Unwillingness or inability to provide informed consent. ‐ History of renal replacement therapy (maintenance dialysis or renaltransplantation). ‐ Baseline hyperphosphatemia. ‐ Known allergy to pistachios. ‐ Pregnancy or lactation. ‐ Active malignancy under treatment. ‐ Consumption of <80% of the provided pistachio ration during the intervention period.Interventions and Dietary ProtocolParticipants will be randomized in a 1:1 ratio to one of two dietary sequences: 1. Pistachio‐Supplemented Diet: A pre‐dialysis renal diet providing targetedmacronutrient and mineral allotments (protein: 0.8 g/kg/day, potassium: 39mg/kg/day, phosphorus: 12 mg/kg/day supplemented with 30 g/day of pistachios. Alow‐sodium guideline will be maintained. 2. Control Diet: The identical baseline renal diet without pistachios, isoenergeticallysubstituted with 60 g of white bread and one tablespoon of olive oil.Randomization sequences will be generated using Random Allocation Software (RAS) with 1:1allocation. Owing to the nature of the nutritional intervention, the trial is open‐labeland unblinded. Comprehensive verbal and written instructions regarding the dietaryregimens will be provided prior to each intervention period.Trial Design and Follow‐UpParticipants will follow their assigned diet for 4 weeks, followed by a 4‐week washoutperiod. Subsequently, they will cross over to the alternative diet for a second 4‐weekperiod. Participants will be instructed to maintain stable physical activity levelsthroughout the study.Adherence and general clinical status will be monitored via weekly telephone calls.Compliance with the pistachio supplementation will be verified at clinical visits bycounting and weighing returned pre‐portioned packaging (30 g per packet).Biochemical AssessmentsVenous blood samples (10 mL) will be drawn after a 12‐hour fast at baseline and uponcompletion of each 4‐week intervention period. Serum will be immediately separated andstored ‐80∘C until analysis. Concurrently, 24‐hour urine collections will be obtained atthe end of the run‐in period, after wash‐out period baseline, and at the end of each4‐week period; total urine volume will be recorded, and aliquots will be stored at ‐80∘C.Serum biomarkers will include phosphorus, potassium, PTH, FGF23, MDA, fasting plasmaglucose, creatinine, lipid profile, high‐sensitivity C‐reactive protein (CRP), andalkaline phosphatase. Urinary analyses will measure phosphorus, sodium, uric acid, andpotassium concentrations.Data analysis will be performed using SPSS. To examine the carry‐over effect hypothesis,the sum of the measured values in periods 1 and 2 for each participant will be calculatedand compared with an independent t‐test between the two sequences, which should not havea significant difference. Also, the equality of the Sequence effect will be tested bycalculating the difference between periods 1 and 2 for each participant and thencomparing it with an independent t‐test. Linear Mixed Model will be used for the mainanalysis.