KIDNEY FAILURE STABILIZES AFTER AN INCREASE OVER 2 DECADES Paolo Cravedi, Piero Ruggenenti, Giuseppe Remuzzi Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo - Mario Negri Institute for Pharmacological Research, Bergamo, Italy SUMMARY The level of proteinuria is one of the most important predictors for progressive renal function loss in kidney disease. Reduction of urinary protein levels by renin-angiotensin-system (RAS) inhibitors limits renal function decline in patients with non-diabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been reported. The increasing use of these drugs is possibly at the basis of the stabilization of rates of new cases of kidney failure reported to the US Renal Data System after a 2-decade period of progressive increases. RAS inhibition, however, may not be effective to the same degree in all patients. For those patients who do not reach a complete remission of proteinuria, treatment procedures to implement renoprotection should include strict blood pressure control (and metabolic control in diabetics), lowering of blood lipids, and lifestyle modifications. Early intervention may be important to maximize renoprotection, especially in diabetics. haemodynamic changes in response to nephron loss due to the original insult that, in turn, causes relentless injury of remaining intact nephrons (1). Enhancing intraglomerular capillary pressure impairs the size-selective function of the glomerular barrier and causes excessive protein ultrafiltration. Rather than simply a marker of damage, ultrafiltered proteins exert a toxic effect to the kidney through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis. This establishes a vicious circle in which changes in renal haemodynamics due to the loss of nephrons lead first to proteinuria and then to the loss of more nephrons (2). A recent study evaluated gene expression profile of renal proximal epithelial cells isolated from biopsies of proteinuric patients and control subjects. Interestingly, statistical analysis identified 168 genes which separate patients from controls and which favour tubular atrophy and interstitial fibrosis (3). This is confirmed by clinical studies that clearly showed proteinuria as a predictor of progression of renal failure in non-diabetic and diabetic renal disease (2). In the 274 patients with non-diabetic chronic nephropathies and clinical proteinuria included in the Ramipril Efficacy in Nephropathy (REIN) trial, urinary protein excretion was the only baseline variable that correlated with decline in glomerular filtration rate (GFR) and progression to end stage renal disease (ESRD) (4). Similar findings are now available for patients with type 2 diabetes (5). PROTEINURIA AS A MAJOR DETERMINANT OF CHRONIC KIDNEY DISEASE PROGRESSION A large number of experimental studies have demonstrated that chronic nephropathies share common pathogenetic mechanisms that contribute to renal disease progression, even independ- ently from the original cause (Figure 1). Progressive deteriora- tion of renal function is the result of compensatory glomerular BIODATA Prof. Giuseppe Remuzzi was appointed Professor of Nephrology and Director of the Division of Immunology and Organ Transplantation 1996 at Ospedali Riuniti of Bergamo, and Director of the Department of Nephrology and Dialysis of the same hospital in 1999. Since 1984, as director of the Negri Bergamo Laboratories and the affiliated Clinical Research Centre for Rare Diseases “Aldo e Cele Dacco” (both divisions of the Mario Negri Institute for Pharmacological Research), he coordinates a team of researchers studying human renal diseases and their corresponding experimental models from the perspective of pathophysiology and therapeutic intervention. KEY WORDS Kidney failure • Proteinuria • ACE inhibitor • Angiotensin receptor antagonist 100 Journal of Renal Care 2007 XXXIII 3