Abstract Background and Aims Studies have demonstrated that chronic dialysis with residual kidney function (RKF) had better survival rates in comparison to those with diminished or absent RKF and are also further associated with improved cardiovascular outcomes. Thus, the strategic preservation of RKF following the initiation of hemodialysis or during transitional periods emerges as a crucial consideration. Compelling evidence suggests that more frequent hemodialysis may contribute to an accelerated decline in RKF, contrasting with the beneficial effects of a low-protein diet (LPD) supplemented with keto-analogues, which has been shown to delay the progression of kidney function decline in the chronic kidney disease (CKD) non-dialysis population. Our pilot study aims to investigate the impact of a stepwise incremental hemodialysis with LPD supplemented with keto-analogues approach on the preservation of RKF after the need to initiate dialysis. Method This open-label, randomized controlled trial (RCT) pilot study employed a 1:1 allocation ratio (Groups 1 and 2) and included 30 patients in CKD stage V non-dialysis, aged ≥18 years, with an eGFR of 5-10 ml/min/1.73 m² as per the CKD-EPI equation, and a urine output of ≥800 ml/day. Exclusion criteria comprised patients with active infection or inflammation, indicated by C-reactive protein (CRP) levels exceeding 10 mg/L, individuals with cancer, or those with a body mass index (BMI) ≥35 kg/m². Group 1 underwent once-weekly hemodialysis (HD) initiation lasting 4 hours, coupled with a low-protein diet (LPD) of 0.6 g/kg/day supplemented with keto-analogues (0.12 g/kg/day) on non-dialysis days and a regular protein diet (1.0 g/kg/day) on dialysis days. In contrast, Group 2 underwent twice-weekly HD initiation (4 hours each) and maintained a regular protein diet (1.0 g/kg/day) every day. A stepwise incremental approach to HD frequency (once to twice per week in Group 1 and twice to thrice per week in Group 2) was implemented if renal kidney function (RKF) fell below 3 ml/min/1.73 m², eqKt/V was ≤1.2/session, Kru was <3 mL/min, ultrafiltration rate exceeded 15 ml/kg/hour, serum potassium was >5.5 mEq/L, and serum phosphate or serum albumin were outside the ranges of >5.5 mg/dL and <3.5 g/dL, respectively. The study spanned a duration of 12 months. Results A total of 30 patients were enrolled in the study and randomized into Group 1 (N = 15) and Group 2 (N = 15). There were no significant differences in baseline characteristics, including age (58.0 ± 19.3 vs 61.9 ± 16.8 years; p = 0.638), BMI (24.0 ± 3.8 vs 23.5 ± 3.6 kg/m²; p = 0.751), eGFR (6.9 ± 1.4 vs 6.2 ± 1.9 mL/min/1.73 m²; p = 0.241), urine volume (2226 ± 729 vs 1690 ± 986 mL/day; p = 0.128), and serum albumin (3.8 ± 0.3 vs 3.6 ± 0.3 g/dL; p = 0.123). In both groups, urine volume decreased over 12 months but Group 1 exhibited significantly higher urine volumes compared to Group 2 at M6 (1697 ± 442 vs 1063 ± 480; p = 0.01), M9 (1453 ± 522 vs 918 ± 404; p = 0.02), and M12 (1119 ± 429 vs 768 ± 367; p = 0.03). Consistent with urine volume, there were significant differences in creatinine clearance (CCr) at M6 (3.9 ± 0.5 in Group 1 vs 2.7 ± 1.8 in Group 2; p = 0.05) and M9 (3.5 ± 0.3 in Group 1 vs 1.9 ± 0.9 in Group 2; p = 0.01). In Group 1, there was a need to increase the rate of dialysis to twice/week in 5 patients at average of 3.6 months after start of study. No significant differences in hospitalization, adverse effects, and patient survival were observed between the two groups. The body weight of all participant were well maintained and no sign of malnutrition. Conclusion Stepwise incremental HD initiated as once-weekly hemodialysis coupled with LPD with keto-analogue supplementation better preserved urine output and CCr compared with twice weekly HD on a regular protein diet. In a period of 12 months after initiation of dialysis, we demonstrated that this stepwise strategy was feasible.