Di Iorio 2003.

Study characteristics
Methods	Study design: parallel RCT Study duration: not reported Study follow‐up period: 24 months
Participants	Country: Italy Setting: single centre; renal outpatient clinic Patients with CrCl ≤ 25 mL/min/1.73 m2 (CKD stage 4) receiving low protein diet (0.6 g/kg/day) for 6 to 12 months and ESA for 6 to 12 months Number: very low protein diet group (10); low protein diet group (10) Mean age ± SD (years): very low protein diet group (57 ± 17); low protein diet group (52 ± 15) Sex (M/F): very low protein diet group (6/4); low protein diet group (6/4) Exclusion criteria: bleeding or diseases potentially affecting ESA response (i.e. neoplastic diseases, infectious diseases, severe malnutrition)
Interventions	Very low protein diet group Prescribed protein intake: 0.3 g protein/kg/day + keto‐analogues and essential amino acids (Alfa Kappa 1 tablet/5 kg body weight) Calculated protein intake: 0.5 ± 0.01 g/kg/day at 12 months Low protein diet group Prescribed protein intake: 0.6 g protein/kg/day Calculated protein intake 0.79 ± 0.02 g/kg/day at 12 months Co‐interventions Sodium restriction Iron supplementation (maintain transferrin saturation > 20% and serum ferritin 100 to 500 mg/dL) Antihypertensive therapy (maintain blood pressure < 140/90 mmHg) 2 to 3 g/day of sodium bicarbonate, folic acid and vitamin B12 supplements Phosphate binders (maintain serum phosphate levels < 5.5 mg/dL)
Outcomes	ESKD: end point was GFR ≤ 7 mL/min/1.73 m2 or development of uraemic complications requiring haemodialysis GFR measured by CrCl Body weight at 12 months
Notes	Three patients in each group had diabetic kidney disease 3 month run‐in period before randomisation to verify stability of Hb coefficient All participants required to restrict dietary sodium intake Primary outcome was % reduction in ESA dose Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and lack of blinding may influence patient management
Blinding of outcome assessment (detection bias): End or change in GFR End of change in GFR	Low risk	Outcome was based on laboratory outcome and unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias): Need to start dialysis Need to start dialysis	Unclear risk	No information provided on criteria used to commence dialysis
Incomplete outcome data (attrition bias) All outcomes	Low risk	All included participants accounted for
Selective reporting (reporting bias)	Low risk	Reported on expected outcomes (death, dialysis, GFR, body weight)
Other bias	Unclear risk	Insufficient information to permit judgement