Diabetes Volume 66, January 2017 75 Piero Ruggenenti,1,2 Manuela Abbate,1 Barbara Ruggiero,1 Stefano Rota,2 Matias Trillini,1 Carolina Aparicio,1 Aneliya Parvanova,1 Ilian Petrov Iliev,1 Giovanna Pisanu,1 Annalisa Perna,1 Angela Russo,1 Olimpia Diadei,1 Davide Martinetti,1 Antonio Cannata,1 Fabiola Carrara,1 Silvia Ferrari,1 Nadia Stucchi,1 Giuseppe Remuzzi,1,2,3 and Luigi Fontana,4,5,6 on behalf of the C.RE.S.O. Study Group* Renal and Systemic Effects of Calorie Restriction in Patients With Type 2 Diabetes With Abdominal Obesity: A Randomized Controlled Trial Diabetes 2017;66:75–86 | DOI: 10.2337/db16-0607 In individuals with type 2 diabetes with abdominal obe- intake and concomitant treatments were similar between fi sity, hyper ltration is a risk factor for accelerated glo- the groups. CR was tolerated well. In patients with type OBESITY STUDIES merular filtration rate (GFR) decline and nephropathy. 2 diabetes with abdominal obesity, CR ameliorates In this academic, single-center, parallel-group, pros- glomerular hyperfiltration, insulin sensitivity, and other pective, randomized, open-label, blinded end point cardiovascular risk factors, effects that might translate trial, consenting patients with type 2 diabetes aged >18 into long-term nephro- and cardioprotection. years, with waist circumference >94 (males) or >80 (fe- males) cm, serum creatinine <1.2 mg/dL, and normoal- buminuria were randomized (1:1) with permuted blocks to Obesity, especially if centrally located (1), and diabetes (2) 6 months of a 25% calorie restricted (CR) or standard diet are both associated with renal dysfunction sustained by (SD). Primary outcome was measured GFR (iohexol plasma glomerular hyperfiltration (3,4), a risk factor for accelera- clearance). Analyses were by modified intention to treat. At fi ted loss of renal function and onset and progression of 6months,GFRsigni cantly decreased in 34 patients on CR fi and did not change appreciably in 36 on SD. Changes were nephropathy (5). Thus, glomerular hyper ltration might significantly different between the groups. GFR and body be one of the possible pathogenic links between obesity weight reduction were correlated. GFR reduction was and chronic kidney disease (CKD) (6,7). Finding that bari- fi larger in hyperfiltering (GFR >120 mL/min) than nonhy- atric surgery ameliorates glomerular hyper ltration asso- perfiltering patients and was associated with BMI, waist ciated with severe obesity (8) suggests that weight loss, in circumference, blood pressure, heart rate, HbA1c,blood addition to ameliorating a series of cardiovascular risk glucose, LDL-to-HDL cholesterol ratio, C-reactive protein, factors, might also affect the onset and progression of angiotensin II, and albuminuria reduction and CKD (5,8). This invasive procedure is, however, necessar- with increased glucose disposal rate (measured by ily restricted to a selected population at very high risk hyperinsulinemic-euglycemic clamps). Protein and sodium of obesity-related complications. Thus, calorie restriction 1IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche This article contains Supplementary Data online at http://diabetes Cliniche per le Malattie Rare “Aldo e Cele Daccò,” Bergamo, Italy .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0607/-/DC1. 2 Unit of Nephrology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, This article is featured in a podcast available at http://www.diabetesjournals.org/ Bergamo, Italy content/diabetes-core-update-podcasts. 3Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy P.R. and M.A. contributed equally to this research. 4Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy *A complete list of the of the C.RE.S.O. Study Group can be found in the 5Department of Medicine, Washington University in St. Louis, St. Louis, MO Supplementary Data online. 6CEINGE Biotecnologie Avanzate, Napoli, Italy © 2017 by the American Diabetes Association. Readers may use this article as Corresponding author: Giuseppe Remuzzi, [email protected]. long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals Received 11 May 2016 and accepted 24 August 2016. .org/content/license. Clinical trial reg. no. NCT01213212, clinicaltrials.gov. See accompanying article, p. 14. 76 Renal Effects of Calorie Restriction Diabetes Volume 66, January 2017 (CR) remains the principal method for inducing weight loss was measured with an oscillometric device (HEM-705CP; (9). However, no trial so far has formally tested the role of Omron, Tokyo, Japan) with the patient sitting after 15 min CR and weight loss on glomerular filtration, in particular by of rest. The average of three measurements, 2 minutes directly measuring the glomerular filtration rate (GFR) in apart, was recorded. Blood for laboratory assessments subjects with glomerular hyperfiltration and abdominal was sampled the morning after overnight fasting. UAE obesity (10). was measured in three consecutive overnight urine collec- Thus, we evaluated whether and to what extent mea- tions, and the median was recorded. sured GFR (11) could be affected by CR in the context of a GFR was measured by the plasma clearance of un- controlled, randomized clinical trial “Caloric REstriction labeled iohexol (11) after a single, intravenous injection in Subjects with abdominal Obesity and Type-2 diabetes of 5 mL iohexol solution (647 mg/mL Omnipaque 300; at increased risk” (C.RE.S.O). Nycomed Amersham Sorin, Milan, Italy). Participants with aGFR.120 mL/min (i.e., a GFR exceeding the upper limit fi RESEARCH DESIGN AND METHODS of normal range for measured GFR) were de ned as hyper- filtering, and those with a GFR #120 mL/min as nonhyper- This academic, single-center, parallel-group, prospective, filtering (5,14). The GFR was not normalized for the body randomized, open-label, blinded end point (PROBE) trial was surfaceareatoavoidtheconfoundingeffectofchangesin conducted at the Clinical Research Center (CRC) for Rare body surface area associated with diet-induced changes in Diseases of the IRCCS - Istituto di Ricerche Farmacologiche body weight (15,16), and absolute GFR values were consid- Mario Negri. Participants were identified among patients ered for the analyses. On the following day, the total-body referred to the outpatient clinics of the CRC and the glucose disposal rate (GDR) was assessed with hyperinsulinemic- diabetology units of Bergamo, Treviglio-Caravaggio, Romano euglycemic clamp (17). di Lombardia, and Seriate Hospitals, all in Italy. Participants were individuals with type 2 diabetes (American Diabetes Randomization and Masking Association criteria) aged .18 years old with abdominal Participants were randomly assigned (1:1) to 25% CR or obesity defined as waist circumference of .94 cm in men to continue on their already prescribed SD by a computer- and .80 cm in women (12), serum creatinine ,1.2 mg/dL, generated list of random permuted blocks prepared by a and urinary albumin excretion (UAE) ,20 mg/mininover- statistician (Giovanni Antonio Giuliano) of the CRC, who night urine collections. They had a stable body weight and was not involved in the analyses. All data assessors were calorie intake, and a stable diet with a standardized content masked to treatment allocation. in micro- and macronutrients and salt, according to guide- Intervention and Follow-up lines (13), and no systematic changes in blood pressure (BP), Intervention in the SD aimed to reinforce compliance glucose, and lipid-lowering medications during the previous with the recommended diet. Patients in the CR arm were 6 months. We excluded patients with primary, immune- provided with personalized dietary guidelines to decrease mediated, or ischemic kidney disease; urinary tract obstruc- their daily calorie intake by 25%. The nutrient composition tion or infection; concomitant therapy with renin-angiotensin recommended with both CR and SD interventions was system (RAS) inhibitors, steroids, or nonsteroidal anti- flexible to accommodate individual preferences but was inflammatory agents; heart failure; uncontrolled diabetes; designed to provide 45–50% of energy from carbohydrates, hypo- or hypernatremia from any cause; previous bariatric 30–35% from fat, and 15–20% from proteins, supply 100% surgery; depression; alcohol and drug abuse; pregnancy; of the daily recommended micronutrient intake, .20 g/day ineffective contraception; perimenopausal age; cancer or of fiber, and ,300 mg/day of cholesterol. Patients were chronic disease that might jeopardize study completion; encouraged to consume moderate and low glycemic index primary endocrinological diseases; poor compliance; or were and nutrient-dense foods (18). No particular lifestyle mod- unable to provide informed consent. The study conformed ification was introduced. Dietary prescriptions were based to the principles of the EU Clinical Trials Directive on energy intake at baseline, estimated by the subjects’ rest- (2001/20/EC), Good Clinical Practice, and the Declaration ing metabolic rate (RMR) using the Mifflin predictive equa- of Helsinki. The ethics committee of the local health agency tion (19), and results from the Physical Activity Recall (PAR) in Bergamo, Italy, approved the study. All patients provided and Total Daily Energy Expenditure (TDEE) questionnaire written informed consent. Data were recorded in dedicated (20). CR corresponded to a 25% calorie