Pistachio Consumption in Patients With Chronic Kidney Disease

Effects of Short-Term Pistachio Consumption on Phosphorus, Parathyroid Hormone, Fibroblast Growth Factor 23, and Malondialdehyde Concentrations in Patients With Chronic Kidney Disease: A Randomized Crossover Trial

Standard chronic kidney disease (CKD) guidelines frequently restrict nut intake due to concerns regarding their phosphorus and potassium content. While uncontrolled phosphorus loading exacerbates secondary hyperparathyroidism, vascular calcification, and mortality, overly restrictive diets can preclude the intake of essential cardioprotective nutrients. Phytate (myo-inositol hexaphosphate), abundant in fiber-rich foods like pistachios, acts as a natural inhibitor of calcium salt deposition, potentially mitigating vascular calcification. Crucially, the phosphorus in nuts is largely organically bound as phytate, which resists enzymatic cleavage in the human gastrointestinal tract, significantly reducing its intestinal bioavailability. Given these properties, moderate pistachio consumption may offer cardiovascular benefits without compromising mineral metabolism. This study aims to evaluate the short-term effects of pistachio supplementation on circulating and urinary phosphorus, parathyroid hormone (PTH) in patients with CKD. This study is an open-label, randomized, controlled crossover clinical trial involving patients with stage 4 and 5 (non-dialysis) CKD. All participants will undergo a 1-week run-in period to initiate a standardized pre-dialysis renal diet (protein 0.8 g/kg/day, potassium 39 mg/kg/day, phosphorus 12 mg/kg/day). Following the run-in, participants will be randomized (1:1 ratio) to one of two 4-week dietary sequences of Pistachio Diet period (30 g/day of pistachios) or Control Diet period. The sequences will be separated by a 4-week washout period. Venous blood and 24-hour urine samples will be collected and serum biomarkers: Phosphorus, potassium, PTH, FGF23, MDA, fasting glucose, creatinine, lipid profile, high-sensitivity C-reactive protein (CRP), and alkaline phosphatase and urinary phosphorus, sodium, uric acid, and potassium will be measured.

Introduction Cardiovascular diseases (CVD) remain the leading cause of mortality in patients with chronic kidney disease (CKD), and targeted nutritional management plays a critical role in mitigating CVD risk in this population. While extensive epidemiological evidence underscores the cardioprotective benefits of nut consumption, dietary guidelines for patients with CKD typically mandate strict phosphorus and potassium restriction. Consequently, nut intake is frequently discouraged in this group. This restriction stems from the impaired renal capacity to excrete excess phosphorus and potassium; unmitigated dietary phosphorus loading can exacerbate secondary hyperparathyroidism, renal osteodystrophy, vascular calcification, and overall cardiovascular morbidity and mortality. Conversely, overly restrictive phosphorus diets often precipitate inadequate intake of essential cardioprotective nutrients.

Phytate (phytic acid or myo-inositol hexaphosphate) is a naturally occurring compound abundant in fiber-rich foods, including whole grains, legumes, and nuts. It acts as an effective dietary inhibitor of calcium salt deposition, thereby mitigating risks associated with nephrolithiasis and vascular calcification. Nuts are rich sources of both dietary fiber and phytate, with pistachios standing out among the highest botanical sources-averaging 1,562 mg (range: 0.29-2.83 g) of inositol phosphate per 100 g. Accumulating evidence indicates that pistachio consumption may attenuate cardiovascular risk through anti-inflammatory, antioxidant, and lipid-lowering mechanisms, alongside favorable effects on blood pressure.

Crucially, the majority of phosphorus in unprocessed nuts is organically bound as phytate, 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 systemically bioavailable. Given these favorable phytochemical profiles, moderate pistachio consumption by patients with CKD could potentially improve specific cardiovascular risk factors without adversely altering mineral metabolism. Nevertheless, interventional data evaluating the clinical safety and efficacy of nut consumption in CKD populations remain sparse. This study aims to evaluate the short-term effects of incorporating pistachios into the diets of patients with CKD on circulating and urinary phosphorus levels, as well as 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 crossover clinical trial. Eligible patients with stage 4 and 5 non-dialysis CKD presenting to the nephrology clinic will be informed of the study objectives, and written informed consent will be obtained prior to enrollment.

Prior to randomization, all participants will undergo a 1-week run-in period. During this phase, 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). The primary purpose of this run-in phase is to ensure participant adherence to the dietary protocol and to stabilize baseline metabolic parameters before the initiation of the experimental periods.

Eligibility Criteria

Inclusion 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 renal transplantation).
• 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 Protocol

Participants will be randomized in a 1:1 ratio to one of two dietary sequences:

1. Pistachio-Supplemented Diet: A pre-dialysis renal diet providing targeted macronutrient and mineral allotments (protein: 0.8 g/kg/day, potassium: 39 mg/kg/day, phosphorus: 12 mg/kg/day supplemented with 30 g/day of pistachios. A low-sodium guideline will be maintained.
2. Control Diet: The identical baseline renal diet without pistachios, isoenergetically substituted with 60 g of white bread and one tablespoon of olive oil.

Randomization sequences will be generated using Random Allocation Software (RAS) with 1:1 allocation. Owing to the nature of the nutritional intervention, the trial is open-label and unblinded. Comprehensive verbal and written instructions regarding the dietary regimens will be provided prior to each intervention period.

Trial Design and Follow-Up

Participants will follow their assigned diet for 4 weeks, followed by a 4-week washout period. Subsequently, they will cross over to the alternative diet for a second 4-week period. Participants will be instructed to maintain stable physical activity levels throughout 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 by counting and weighing returned pre-portioned packaging (30 g per packet).

Biochemical Assessments

Venous blood samples (10 mL) will be drawn after a 12-hour fast at baseline and upon completion of each 4-week intervention period. Serum will be immediately separated and stored -80∘C until analysis. Concurrently, 24-hour urine collections will be obtained at the end of the run-in period, after wash-out period baseline, and at the end of each 4-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 plasma glucose, creatinine, lipid profile, high-sensitivity C-reactive protein (CRP), and alkaline phosphatase. Urinary analyses will measure phosphorus, sodium, uric acid, and potassium 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 calculated and compared with an independent t-test between the two sequences, which should not have a significant difference. Also, the equality of the Sequence effect will be tested by calculating the difference between periods 1 and 2 for each participant and then comparing it with an independent t-test. Linear Mixed Model will be used for the main analysis.

Inclusion 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 renal transplantation).
• 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.