Patients with diabetes mellitus

During a short-term high protein diet an increase in GFR and RPF has been demonstrated in most studies of type 1 diabetic patients with normo- and microalbuminuria [26-29], while a short-term low protein diet induces a decline in GFR of 10 % in these patients, although RPF remains unchanged [30-33].

In patients with diabetic nephropathy, however, no change in GFR in response to a high protein diet has been observed [34]. The setting of severe renal injury with maximal perfusion of residual renal tissue has been suggested in this setting. Three studies, using valid markers of GFR, have previously investigated the short-term impact of dietary protein restriction in diabetic nephropathy [35-37]. However, in two randomised crossover trials, neither Bending et al. [35] nor Pinto et al. [37] demonstrated any significant changes in GFR, measured by a continuous infusion technique with timed urine collections, during 3 weeks of dietary protein restriction [achieved 0.64 g/kg/day] in 10 type 1 diabetic patients with diabetic nephropathy. Nevertheless, diabetic cystopathy, a common feature in patients with diabetic nephropathy, often leads to major errors in urine collections [38], and may have blurred the results in these two studies.

In a prospective controlled trial with concealed randomisation, Hansen et al. [36] demonstrated a reversible decline in GFR (51Cr-EDTA plasma clearance) and albuminuria in 14 type 1 diabetic patients with diabetic nephropathy during short-term (3-5 weeks) treatment with a low protein diet (recommended 0.6 g/kg/day). Correspondingly with a decrease in dietary protein intake of 0.4 g/kg/day, there was a reversible decline in GFR and albuminuria of approximately 8 % and 29 %, respectively. These changes were independent of glycaemic control, energy intake and blood pressure. The initial decline in GFR during dietary protein restriction was greater in patients with elevated GFR, as demonstrated in the MDRD study [39]. Interestingly, the antiproteinuric effect of dietary protein restriction was obtained during antihypertensive treatment [mostly with ACE-inhibitors] and was associated to the degree of dietary protein restriction, suggesting at least partly independent but additive effects of these two treatment modalities on albuminuria (see below).

In conclusion, short-term dietary protein restriction induces a parallel reduction in GFR in both healthy subjects and diabetic patients with normo- and microalbuminuria. Although controversial, recent data highly suggests an equivalent decline in GFR and albuminuria during dietary protein restriction in type 1 diabetic patients with diabetic nephropathy. Studies in patients with non-diabetic nephropathies have similarly demonstrated an acute decline in GFR and proteinuria after the initiation of dietary protein restriction [40], and further suggested an additive effect of dietary protein restriction and ACE inhibition [enalapril] on proteinuria [41;42], independently of the action on GFR.

Implications of short-term renal effects of dietary protein restriction

The short-term renal effects of dietary protein restriction may have considerable implications in clinical practice and trials. The short-term renal effects of dietary protein restriction theoretically may offset the potential long-term beneficial effect of this treatment on the progression of kidney disease, especially if the trial is of short duration (less than two to three years) and the rate of progression in kidney disease is slow [39].

Renal mechanisms of dietary protein intake

The exact mechanisms by which dietary protein restriction modulates kidney function are unclear, but both haemodynamic and non-haemodynamic factors seem to be modified by dietary protein restriction in chronic renal diseases.

The majority of animal studies have demonstrated a decline in glomerular capillary hydraulic pressure and renal plasma flow during dietary protein restriction due to renal vasoconstriction, located primarily at the site of the afferent arteriole [43-45]. Recently, it has been hypothesised that short-term dietary protein restriction may contribute to an improvement of impaired autoregulation of GFR [36] seen in patients with diabetic nephropathy [46;47]. However, although changes in the tubuloglomerular feedback system, renal synthesis of prostaglandin's, hormonal factors, endothelium-derived relaxing factor and the renin-angiotensin system [48], have been suggested as mediators of the haemodynamic response to protein intake, data are still controversial.

A considerable number of non-haemodynamic effects of dietary protein restriction have been identified [49]. Diminished proteinase activity in glomeruli and tubules, associated with renal hypertrophy characterised by accumulation of cellular protein and extracellular matrix, seen in several models of glomerulosclerosis [49-51], is stimulated during dietary protein restriction [52], while renal overproduction of TGF-^, a key mediator of progressive matrix accumulation and tissue fibrosis [53;54] is reduced during dietary protein restriction in several models of renal disease [55-57]. Recent data by Peters et al. [16] demonstrated that single therapy with maximal effective doses of enalapril, losartan, and dietary protein restriction significantly reduced glomerular TGF-P production to a similar degree (45 %) in experimental glomerulonephritis. However, when either maximal doses of enalapril or losartan were combined with low-protein feeding a further reduction in TGF-P production of approximately 15 % was demonstrated. The reduction in TGF-P over-expression was associated with a decrease in proteinuria and glomerular matrix accumulation. These data highly suggest that dietary protein restriction acts on pathways in addition to blocking of the renin-angiotensin system as mentioned above. Previous studies in experimental renal failure support these findings [15;58].

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