Synergy of low nephron number and obesity: a new focus on hyperfiltration nephropathy

The 'hyperfiltration theory', originally postulated by Brenner's group more than 20 years ago, represented a revolutionary advance in defining the mechanisms responsible for the seemingly inexorable progression of renal insufficiency (1). Brenner's group and others demonstrated that rats submitted to renal ablation (more than five-sixths nephrectomy) developed proteinuria, glomerulosclerosis and progressive renal failure during the months following nephrectomy. They found that the functional and structural changes appearing in the remnant glomeruli correlated with the haemodynamic adaptations observed closely after renal ablation: increments in single nephron glomerular filtra- tion rate (GFR) mediated by preferential vasodilation of afferent glomerular arterioles, together with incre- ments in glomerular transcapillary hydraulic pressure and filtration fraction (1-3). Attenuation of these hae- modynamicadaptations by low protein diets or ACE inhibitors (that induce preferential vasodilation of effer- ent glomerular arteriole) largely prevents the appear- ance of glomerulosclerosis and renal failure. Brenner and collaborators postulated that 'maladaptive' haemodynamic changes in the remaining glomeruli after the reduction of renal mass below some critical level (by surgical ablation or any other type of renal disease) would represent a final common path for the progression of renal diseases independently of their original cause (1-3). The hyperfiltration theory encouraged a tremendous amount of investigations in the field of unspecific renal failure progression, and extensive renal ablation has remained as a definite model with which to investigate the mechanisms of progression and therapeutic interventions in many different types of nephropathies. However, the general applicability of hyperfiltration theory to humans has remained largely controversial. Some studies published in the 1990s showed that a significant number of patients submitted to extensive surgical removal of renal parenchyma developed proteinuria and progressive renal insufficiency, resem- bling the hyperfiltration nephropathy observed in experimental animals (4-6). Furthermore, renal biop- sies performed in a minority of these cases showed the typical findings of hyperfiltration nephropathy: glomerulomegaly with lesions of focal and segmental glomerulosclerosis (4). However, other patients with similar severe reductions in renal mass did not develop proteinuria or renal function decline over prolonged follow-up. Reasons for these discrepant evolutions were not apparent. Some authors emphasize the fact that many patients with remnant kidneys and mild renal insufficiency after surgery did not show progres- sion of renal insufficiency, casting serious doubts about the validity of simplistic translation of studies per- formed in rats to humans (7).