ORIGINAL ARTICLE Subclinical functional and structural renal abnormalities predict new onset type 2 diabetes in patients with primary hypertension F Viazzi 1 , G Leoncini 1 , LE Derchi 2 , E Baratto 1 , G Storace 1 , M Vercelli 3,4 , G Deferrari 1 and R Pontremoli 1 Recent studies suggest a close relationship between renal dysfunction and new onset diabetes (NOD). The aim of the study was to investigate the association between subclinical functional and structural renal abnormalities and NOD in primary hypertension (PH). This observational prospective study (9.1±2.2 years follow-up) includes 231 consecutive untreated non- diabetic patients with PH and without overt nephropathy. The primary end point was NOD. Albuminuria (albumin to creatinine ratio, ACR), glomerular filtration rate (eGFR), and renal structure and hemodynamics (ultrasound scan and Doppler) were evaluated at baseline. During 2106 person-years of follow-up, 10 patients developed diabetes (incidence rate 4.7/1000 person- years). Patients with NOD showed a higher body mass index, serum uric acid, serum creatinine and ACR, and lower eGFR and renal volume (RV) to resistive index (RI) ratio (RV/RI) at baseline, as compared with the 221 controls that did not develop diabetes. When all renal variables were taken into consideration, RV/RI was the only variable significantly related to diabetes (hazard ratio 1.04, P ¼ 0.0342). Patients in the lowest tertile of RV/RI were more likely to develop diabetes (10.4 vs 2.6 vs 0%, P ¼ 0.0044). For each s.d. decrease of RV/RI, the risk of NOD increased by 68% (P ¼ 0.0012). Subclinical functional and structural renal abnormalities are independent predictors of diabetes in PH. Journal of Human Hypertension (2013) 27, 95--99; doi:10.1038/jhh.2012.5; published online 16 February 2012 Keywords: renal resistive index; arterial stiffness; insulin resistance; primary hypertension; diabetes INTRODUCTION The alarming increase in the incidence of diabetes and the consequent social and economic burden on public health services call for greater efforts to prevent or delay this condition. Developing new, simple markers to be used in clinical practice is therefore a crucial issue. Patients with hypertension are a subgroup at an increased risk of developing diabetes, nevertheless the underlying pathogenetic mechanisms have not yet been elucidated. Longitudinal studies have consistently shown that early signs of renal damage bear an incidence of cardiovascular (CV) events that is even greater than that of end stage renal disease. 1 The association between impaired renal function and unfavorable CV outcome is due, at least in part, to the relationship between renal damage and increased incidence of diabetes. Although elevated urinary albumin excretion has been con- sidered mostly a consequence of diabetes, several findings have recently suggested that urinary albumin excretion may also precede and predict the development of type 2 diabetes. 2-5 Furthermore, decreases in glomerular filtration rate (eGFR) have recently been linked to insulin resistance 6 and future development of diabetes. 7,8 Finally, in addition to being a well- known concomitant of metabolic syndrome (MS), mild hyperur- icemia has been proposed as a marker of decreased kidney function. Recent studies have also suggested that increased serum uric acid (SUA) levels are associated with excessive risk of incident type 2 diabetes in the general population 9 and in primary hypertension (PH), regardless of the presence of MS and other potential confounders. 10 The increasing evidence indicating common pathogenetic mechanisms between renal damage and type 2 diabetes prompted us to look at early kidney abnormalities as potential predictors of diabetes in patients with PH. SUBJECTS AND METHODS Patient population A total of 231 consecutive, untreated patients with PH attending the outpatient clinic of our institution were included in the present study. Recruitment took place between January 1997 and June 1999; median follow-up was 9.1 years ( ± 2.2). Exclusion criteria were: age o18, evidence of neoplastic, hepatic, and/or renal disease (defined as serum creatinine X124 mmol l À1 in males and X106 mmol l À1 in females or overt proteinuria), chronic heart failure (New York Heart Association (NYHA) class III and IV), diabetes (presence of hypoglycemic drugs or fasting plasma glucose X7.0 mmol l À1 ), severe obesity (defined as body weight 4150% of ideal body weight), severe hypertension (X180/110 mm Hg) and disabling diseases such as dementia or the inability to cooperate. Out of 295 patients seen at our clinic within the above-mentioned time range, 274 (all Caucasian Europeans) fulfilled the inclusion criteria and agreed to participate in the study. Hypertension was defined as an average blood pressure (BP) X140/ 90 mm Hg on at least three different occasions, or by the presence of antihypertensive treatment. Essential hypertension was diagnosed by the attending physician once complete medical history, physical examination and routine biochemical analyses of blood and urine had been obtained from each patient. Further investigation was carried out only when abnormalities were found in these Received 23 August 2011; revised 15 December 2011; accepted 16 January 2012; published online 16 February 2012 1 Department of Cardionephrology and Department of Internal Medicine, University of Genoa, Azienda Ospedaliera Universitaria San Martino, Genoa, Italy; 2 Cattedra di Radiologia R, University of Genoa, Genoa, Italy; 3 Registro Tumori della Regione Liguria, SS Epidemiologia Descrittiva, IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy and 4 DISSAL Dipartimento Scienze della Salute, University of Genoa, Genoa, Italy. Correspondence: Dr F Viazzi, Department of Cardionephrology and Department of Internal Medicine, University of Genoa, Azienda Ospedaliera Universitaria San Martino, Viale Benedetto XV 6 - 16132 Genoa, Italy. E-mail: francesca.viazzi@unige.it Journal of Human Hypertension (2013) 27, 95 - 99 & 2013 Macmillan Publishers Limited All rights reserved 0950-9240/13 www.nature.com/jhh