Mycophenolate Mofetil, Carnitine and PDE5 Inhibitor, Three Potential Treatments for Resistant Proteinuria Slowing Diabetic Nephropathy Deterioration

Overview

Diabetes mellitus (DM) is a growing disease and it is a public health concern, and projections of its future effect are alarming. About one third of those affected will develop diabetic nephropathy at 20 years after diagnosis. Of these patients, 20% will develop clinically end-stage renal disease ESRD, requiring renal replacement therapy (RRT). Patients with type 2 diabetes account for most patients with end stage renal disease (ESRD) and RRT. To the best of the investigators knowledge, the effects of MMF on diabetic nephropathy in patients with DM type II were not studied so far. Therefore, the purpose of this pilot study is to evaluate the effects of Mofetil Mycophenolate (MMF) on proteinuria and progression of kidney disease of diabetic origin, in patients at high risk for progressive renal failure in whom other treatment modalities are insufficient or had failed.

The pathophysiology of the diabetic nephropathy was initially considered to be merely secondary to a non-immune mechanism, specifically due to metabolic (hyperglycemia) and hemodynamic (glomerular capillary hypertension - mechanical stretching) factors. However, our understanding of the pathophysiological processes that lead to diabetic nephropathy and its progression is now clearer and involved not only a non immune mechanism, but also immune-mediated and inflammatory mechanism. Activation of the immune system, with the participation of a chronic inflammatory state, plays a central role in the pathogenesis of diabetic nephropathy. Evidence for the involvement of the immune system in the pathogenesis of diabetic nephropathy was derived from the elevated levels of proinflammatory cytokines such as IL-1, IL-6, IL-18, and TNF-α. These factors are important predictors of the development of diabetic nephropathy, and recently it was shown that these inflammatory cytokines play a determinant role in the development and progression of the microvascular diabetic nephropathy. The first published study that showed the implication of the inflammatory cytokines in the pathogenesis of the diabetic nephropathy was in 1991. Mycophenolate Mofetil (MMF) is an immunosuppressant drug, used to prevent rejection, especially acute rejection in various organ transplantations, mainly kidney transplantation since 1995. In the last decade there are increasing reports describing the beneficial use of MMF in immune- mediated and auto-immune disorders such as Systemic Lupus Erythematosus, IGA nephropathy and other glomerulopathies. Unfortunately, the potentially beneficial effects of MMF on diabetic nephropathy were not examined in clinical DM and is limited to diabetic rats. In a recent study, Utimura et al. have demonstrated that MMF largely prevented the development of albuminuria and glomerular injury in experimental diabetic nephropathy. The beneficial effect of MMF was not related to its action on glomerular hemodynamic or improvement of metabolic control, but probably related directly to its immunosuppressive and anti-inflammatory properties.