22nd Camillo Golgi Lecture
The kidney in diabetes: dynamic pathways of injury and repair

The natural history of diabetic nephropathy has been changing in the last decades; in addition to development and progression, the natural history now also includes the possibility of regression. The clinical manifestations of diabetic nephropathy, proteinuria, decreased glomerular filtration rate and increasing blood pressure are similar in type 1 and type 2 diabetes, while these renal lesions underlying the functional abnormalities may differ. Indeed, in type 1 diabetes, although tubular, interstitial and arteriolar lesions are also present, the most important structural changes involve the glomerulus and these are closely correlated to albuminuria. In contrast, a substantial subset of type 2 diabetic patients, despite the presence of microalbuminuria or proteinuria, have normal glomerular structure with or without tubulo-interstitial and arteriolar abnormalities.

Several studies using light and electron microscopic morphometric analysis described the renal structural changes and the structural-functional relationships of diabetic nephropathy. This lecture will also focus on the early stages of the disease, especially on the predictive power of microalbuminuria and on the structural basis of this early functional abnormality. The kidney in diabetes is characterised by a constellation of lesions, comprising not only the well known Kimmelstiel-Wilson glomerular lesions, mesangial expansion and glomerular basement membrane thickening, but also changes in the structure of podocytes, arterioles, tubules, interstitium and in the glomerular-tubular junction.

These topics will be discussed, documenting the contribution of research kidney biopsy studies to the understanding the natural history, pathogenesis and pathophysiology of diabetic nephropathy. The renal lesions of diabetic nephropathy have been considered irreversible; indeed diabetic glomerulopathy is also called ‘glomerulosclerosis’, which implies the presence of permanent scar tissue. Evidence will be presented documenting the dramatic reversal of the established lesions of diabetic nephropathy in humans. Thus, studies in non uremic pancreas transplant recipients have clearly shown that both glomerular and tubulo-interstitial lesions can be reversed when long-term normoglycemia is maintained. These studies demonstrated the remarkable intrinsic capability of the kidney to engineer major architectural remodeling, switching from extracellular matrix production in excess of removal to removal exceeding production.

Thus, upon removal of the pathogenic environment, processes of healing emerge which reveal a cellular machinery pre-programmed to recapitulate normal renal structure. Further studies of these processes hold great promise for disease prevention and treatment.

Paola Fioretto