Renal lesions in patients with type 2 diabetes: a puzzle waiting to be solved.

Three hundred sixty-six million people worldwide will be living with diabetes mellitus (DM) by 2030 ([1, 2]; http://www.idf.org/ global-diabetes-plan-2011-2021). Prospectively, 75–150 million of these patients will develop a diabetic nephropathy (DN) or a non-diabetic renal disease (NDRD), either isolated or superimposed on DN [3, 4]. To date, the differential diagnosis between ND and NDRD remains a challenge that nephrologists are trying to win [5]. DN is a widespread microangiopathic complication of DM eventually leading to end-stage renal disease over a variable number of years [6]. The natural history of DN, as originally depicted in patients with type 1 DM and later extrapolated to type 2 DM (T2DM), would comprise an early phase of microalbuminuria, which precedes overt nephropathy, characterized by macroalbuminuria and a progressive decline of glomerular filtration rate (GFR). Indeed, T2DM patients may present with overt proteinuria (and hypertension) already at the clinical onset of diabetic disease, or remain microalbuminuric without any progression to overt nephropathy, or even display renal insufficiency with minimal or absent proteinuria, this latter phenotype being increasingly recognized worldwide [7, 8]. In fact, the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study (pts number = 15 773), published in 2011 [7], found a 56.6% of non-albuminuric chronic renal failure among patients with T2DM. It is likely that treatments such as the use of drugs blocking the renin angiotensin system (RAS) system or modulating dyslipidaemia and an aggressive glucose monitoring have changed the natural history of renal damage in DM shifting the microangiopathic forms of the disease towards macroangiopathic forms [9–11]. As a matter of fact, non-albuminuric renal impairment in the RIACE study was correlated with a higher prevalence of cardiovascular disease (CVD) and female sex [7, 8]. These data suggest that T2DM patients with non-albuminuric renal impairment have a macroangiopathic phenotype and a higher CVD burden. Consequently, some questions would arise: do these patients suffer from heart disease or kidney disease? By definition, DN recognizes a microangiopathic damage characterized by the clinical appearance of microalbuminuria. Is the reduction of GFR without an increase of albuminuria sufficient to rule out the diagnosis of DN? Is the reduction of GFR a haemodynamic effect due to RAS inhibition? The large variability in the clinical presentation of renal involvement in patients with T2DM, along with the possibility of glomerulonephritides independent from DM, make kidney biopsy a prerequisite for a correct and thorough diagnosis. However, not all nephrologists agree on the usefulness of renal biopsy, first of all because they believe that biopsy, in spite of the variability of clinical presentations, cannot but diagnose DN in the vast majority of patients with T2DM, which would render it useless and unethical, second because of the risk of major complications (haematuria, perirenal haematoma, arterial embolization and very rarely nephrectomy) [12–14]. Therefore, DN is commonly identified only on the basis of confusing clinical and laboratory data, and such diagnosis may in several cases result in misleading. A diagnostic model to correctly identify a pure DN has been recently developed by Zhou et al. [15] as well as by Liang et al. [5]. In the first report, several clinical and laboratory parameters such as years with diabetes, systolic blood pressure values, glycosylated haemoglobin levels, the absence of haematuria and diabetic retinopathy were significantly correlated in a logistic regression analysis with pure DN with a sensitivity and specificity higher than 90%. In the second report, the authors evaluated the predictive role of clinical and laboratory data to