Can a Calorie-Restricted Diet Improve Long-Term Progressive Kidney Function Decline?

Studies have found that there may be a benefit in implementing a calorie restriction diet in patients with type 2 diabetes to improve glomerular hyperfiltration and kidney function. 

Centrally located obesity is a major cause of type 2 diabetes. Moreover, obesity and diabetes are connected to kidney dysfunction, supported by glomerular hyperfiltration, a risk factor for accelerated kidney function loss. A recent study has found that 6 months of calorie restriction with adequate nutrition in patients with type 2 diabetes, abdominal obesity, and normal kidney function saw an improvement of insulin sensitivity and a significant reduction in GFR. This reflects the improvement of glomerular hyperfiltration. This study aims to assess whether and how calorie restriction may promote protection against long–term progressive kidney function decline and the improvement of the risk of micro – and macrovascular complications in patients with overweight or obesity and type 2 diabetes. 

This study was a single-center, parallel, prospective, randomized, open-label, blinded endpoint trial of 103 patients. Patients with type 2 diabetes 40 years or older with a body mass index of ≥ 27 kg/m², serum creatinine <1.2 mg/dL, and urinary albumin excretion ≤ 300 mg/24h. The main exclusion criteria included concomitant non–diabetic kidney disease, ischemic kidney disease, and uncontrolled diabetes. The patient’s ability to maintain a calorie restriction for 24 months was assessed at screening through the Binge Eating Disorder Scale (BES) and the Assessment of Motivation for Change – Nutrition questionnaires. Patients were randomly assigned (1:1) to either 25% calorie restriction or continued on their standard diet for 24 months. Patients completed a 7 – day food diary, which was used to assess compliance in their respective study groups. The primary outcome was GFR change at six months versus baseline. The primary analysis was comparing 6-month GFR changes in the two diet groups. Other outcomes included changes in albuminuria and albumin fractional clearance, HbA1c, blood pressure, regression from or progression of micro– and macrovascular complications. All statistical analyses were by modified intention–to–treat. Change in GFR at six months was assessed by ANCOVA. Within-group comparisons were assessed by paired t-tests, repeated – measures, ANOVA, or the McNemar test. Two-sided P values were seen statistically significant at <0.05. 

At six months, GFR measures decreased significantly by 5.16 ± 10.03 mL/min (from 105.4±20.8 mL/min to 102.2±18.8 mL/min, P=0.001) with calorie restriction, and by only 0.98±9.71 mL/min (from 105.6±19.8 mL/min to mL/min to 105.0±20.4 mL/min, P=0.497) with a standard diet. The between-group difference in the changes in GFR was statistically significant (P=0.044). From month 6 to study end, chronic GFR decline was statistically significant with a standard diet (0.28±0.67 mL/min/month, P=0.009), but not significant with calorie restriction (0.16±0.59 mL/min/month P=0.075). Additionally, between-group differences were not significant. Median albuminuria and albumin fractional clearance decreased minimally at six months, and they came back up to baseline levels in calorie restriction patients. These variables progressively increased in standard diet patients. There was a significant difference between groups in six–month changes in fractional clearance (0.58±0.87 to 0.39±0.54 with calorie restriction and 0.58±0.74 to 0.98±1.92 with standard diet) (P<0.05). Of the 78 patients with normoalbuminuria at inclusion, one on calorie restriction (2.4%) and three on standard diet (88.1%) progressed to microalbuminuria. Among the 25 patients with microalbuminuria, one on calorie restriction regressed to normoalbuminuria (8.3%). One patient per group progressed to macroalbuminuria. HbA1c levels fell on calorie restriction versus baseline and standard diet (p <0.01; p<0.05, respectively). Patients on calorie restriction saw a significant decrease in mean systolic and diastolic blood pressure at six months with (P<0.05 and P=0.053, respectively), 80 patients without retinal involvement at inclusion had one fundoscopy evaluation on follow up. Of these patients, two calorie restriction patients developed retinopathy compared to 1 on a standard diet. Among the 23 patients with retinal involvement at inclusion, two on standard diet regressed to no retinopathy. Of the 17 patients without evidence of macular involvement at inclusion, one on calorie restriction and two on standard diet progressed to maculopathy. Among the seven patients with maculopathy at inclusion, one patient on calorie restriction had regression of macular alterations. 

This study found that in patients with overweight or obesity and type 2 diabetes, measured GFR declined significantly after six months of calorie restriction compared to a standard diet. Furthermore, GFR changes at six months were significantly different between groups. After short–term improvement of hyperfiltration, the GFR stabilized in the long–term treatment with calorie restriction. At the same time, it continued to decline in the long-term treatment with the standard diet. The short–term decline in GFR as a result of calorie restriction was related to an additional improvement of fractional albumin clearance, HbA1c levels, and blood pressure compared to a standard diet. 

Additionally, albuminuria stabilized in patients receiving calorie restriction but progressed in patients receiving a standard diet. Altogether, these findings confirmed the hypotheses that the short–term decline in GFR after calorie restriction was related to an improvement in glomerular hyperfiltration and thus led to long–term nephroprotection. Additionally, the short–term improvement of hyperfiltration and then stabilization of the GFR in calorie restriction patients was like previously observed acute reductions seen with RAAS inhibitors and SGLT2 inhibitors. Calorie restriction could become a vital treatment option and medications to slow the progressive renal function decline and cardiovascular morbidity commonly seen in patients with type 2 diabetes. This easy–to–implement intervention’s benefits can help significantly optimize the treatment of these patients. Further studies should be done with larger patient populations to assess further the benefits of calorie restriction on patients with type 2 diabetes. 

Practice Pearls: 

• Compared to a standard diet, calorie restriction led to improved glomerular hyperfiltration and nephroprotection in patients with type 2 diabetes. 
• Calorie restriction also led to improved risk factors for kidney and cardiovascular events.  
• Calorie restriction can be seen as an easy–to–implement treatment therapy for patients with type 2 diabetes to slow renal function decline and limit cardiovascular morbidity. 

Ruggenenti, Piero, et al. “Long-Term Kidney and Systemic Effects of Calorie Restriction in Overweight or Obese Type 2 Diabetic Patients (C.RE.S.O. 2 Randomized Controlled Trial).” Diabetes Research and Clinical Practice, February 24, 2022, p. 109804., https://doi.org/10.1016/j.diabres.2022.109804.  

Amanda Roberts, PharmD Candidate, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences Institute of Public Health