Progression of diabetic nephropathy

A valid determination of the rate of decline in GFR in patients with chronic renal disease requires a reliable method for the determination of GFR, repeated measurements of the GFR, and a follow-up of at least 2 years [59]. However, when short-term effects of intervention are likely, rate of decline in GFR is slow, and the hypothesised benefit of the intervention is proportional to the rate of decline in GFR without intervention, a time-to-event (ESRD/death) approach is favoured compared to a slope-based analysis [60]. If not accounted for in the design of the study, it would be expected that patients receiving a low protein diet would start dialysis later than patients with higher protein intake [61].

An ideal marker for the determination of GFR should be freely filtered through the glomerular capillary wall, biological inert, and neither secreted nor reabsorbed by the kidney tubules. 51Cr-EDTA or 125I-iothalamate has proved to be valid markers for the determination of the GFR [62], compared to serum creatinine and creatinine clearance. Creatinine clearance progressively overestimates GFR during deterioration of kidney function [63]. Furthermore, the generation of creatinine is influenced by muscle mass and dietary protein intake [64]. In studies dealing with the impact of dietary protein restriction, the effect of the intervention on renal creatinine handling invalidates serum creatinine as a measurement of renal function, as demonstrated in the MDRD study [65].

Impact of dietary protein restriction on the development of diabetic nephropathy

Persistent microalbuminuria precedes and predicts the development of diabetic nephropathy in both type 1 [66] and type 2 [67] diabetic patients. Two randomised and controlled trials have evaluated the beneficial effect of long-term dietary protein restriction on the course of urinary albumin excretion in type 1 [68] and type 2 [69] diabetic patients without diabetic nephropathy.

Dullaart et al. [68] performed a 2-year prospective and controlled trial with concealed randomisation in 30 type 1 diabetic patients with a mean urinary albumin excretion between 10 and 200 ^g/min. Fourteen patients were assigned to a low protein diet [pre-scribed 0.6 g/kg/day] and 16 patients were assigned to continue their usual protein diet. The average protein intake during the study was 0.79 g/kg/day in the low protein diet group and 1.09 g/kg/day in the usual protein diet group [p<0.001, between groups]. Although urinary albumin excretion decreased by 16 % in the low protein diet group during the study, this was not significantly different from the decrease of 5 % in the usual protein diet group. After adjustment for blood pressure and diabetes duration the low protein diet group had a decrease in urinary albumin excretion of 26 % during follow-up, compared to 5 % in the usual protein diet group [p<0.005, between groups]. Glomerular filtration rate [measured with 125I-iothalamate] decreased significantly in both diet groups during follow-up (non-significantly between groups).

Pijls et al. [69] performed a 1-year randomised, controlled and physician-blinded trial in type 2 diabetic patients with microalbuminuria or urinary albumin excretion >20 mg/24 h or diabetes duration of >5 years. Originally 160 patients were randomised, but due to loss to follow-up only data from 121 patients were analysed. Fifty-eight patients received a low protein diet [prescribed 0.8 g/kg] and 63 patients received their usual protein diet during follow-up. After 6 months, dietary protein intake slightly but significantly decreased by 0.05 g/kg in the low protein diet group, while an increase of 0.03 g/kg was demonstrated in the usual protein diet group (p<0.02, between groups). No significant change in dietary protein intake was seen between diet regimens after 12 months. Correspondingly, after 6 and 12 months, urinary albumin excretion was found to be 22 % (p<0.01) and 12 % (NS) lower in the low protein diet group compared to the usual protein diet group. After adjustment for diastolic blood pressure, urinary albumin excretion was 25 % (p<0.004) and 15 % (NS) lower in the low protein diet group after 6 and 12 months, respectively. Glomerular filtration rate, measured by creatinine clearance, remained unchanged in both diet groups during follow-up.

In conclusion, it is suggested by the studies of Dullaart et al. [68] and Pijls et al. [69] that dietary protein restriction may have a beneficial effect on the development of diabetic nephropathy in both type 1 and type 2 diabetic patients. However, adherence to a low protein diet was especially difficult to obtain in type 2 diabetic patients. Future studies have to confirm a beneficial impact of dietary protein restriction in these patients during treatment with blockers of the renin-angiotensin-system [70;71], now widely recommended.

Impact of dietary protein restriction on the progression of diabetic nephropathy

Three larger, long-term and controlled trials using valid markers of GFR (51Cr-EDTA [61;72] or 125I-iothalamate [73]) have evaluated the impact of dietary protein restriction on the progression of diabetic nephropathy in type 1 diabetic patients. Unfortunately, no similar studies have been performed in type 2 diabetic patients with diabetic nephropathy. However, in the Modification of Diet in Renal Disease (MDRD) study [40] 3 % of the patients had type 2 diabetes mellitus. This study tested the efficacy of dietary protein restriction upon the progression of various chronic renal diseases.

Walker et al. [72] performed a non-randomised, self-controlled trial in 19 type 1 diabetic patients with diabetic nephropathy. A period on a normal protein diet [achieved 1.13 g/kg/day] of 29 months was followed by a period on a low protein diet (achieved 0.67 g/kg/day) of 33 months. The rate of decline in GFR was 7.3 ml/min/year during a normal protein diet and 1.7 ml/min/year during a low protein diet (p<0.001). Similarly, there was a significant decline in urinary albumin excretion from 467 mg/24 h during a normal protein diet to 340 mg/24 h during a low protein diet (p=0.01). However, at baseline 9 patients were treated with antihypertensive drugs. In 9 of 19 patients, antihypertensive treatment was initiated or intensified during protein restriction, leading to a reduction in mean blood pressure from 106 to 102 mm Hg [72]. Blood pressure is a well-known progression promoter in diabetic nephropathy [74]. Previous studies in both diabetic and non-diabetic nephropathies have demonstrated a progressive, time dependent reduction in the rate of decline in GFR during long-term antihypertensive treatment [4;75;76] of unknown mechanism. This phenomenon may, in part, explain the findings in this self-controlled trial.

Zeller et al. [73] performed a prospective, controlled trial in 35 type 1 diabetic patients with diabetic nephropathy. Twenty patients were assigned to a low protein diet (pre-scribed 0.6 g/kg/day; achieved 0.72 g/kg/day) and followed for an average of 37 months, while 15 patients were assigned to continue their usual protein diet (achieved 1.08 g/kg/day; p<0.001, between groups) and were followed for 31 months. The rate of decline in GFR was 3.1 ml/min/year in the low protein diet group, while the decline in GFR was 12.1 ml/min/year in the usual protein diet group despite antihypertensive treatment, similar to what has been demonstrated during the natural course of diabetic nephropathy in patients not receiving antihypertensive treatment [77]. Approximately 25 percent of these patients, but none of the patients in the low protein diet group, had a follow-up of less than 10 months. Baseline proteinuria and mean blood pressure during follow-up were higher in the usual protein diet group (4.3 g/24-h and 106 mm Hg, respectively) as compared to the low protein diet group (3.1 g/24-h and 102 mm Hg, respectively), which could indeed have contributed to the accelerated decline in GFR in the usual protein diet group.

Recently, Hansen et al. [61] performed a 4-year prospective, controlled trial with concealed randomisation in 82 type 1 diabetic patients with progressive diabetic nephropathy (pre-study rate of decline in GFR >2 ml/min/year). Forty-one patients were assigned to a low protein diet (pre-scribed 0.6 g/kg/day) and 41 patients were assigned to continue their usual protein diet. The average dietary protein intake during protein restriction was 0.89 g/kg/day, compared to 1.02 g/kg/day in the control group (p=0.005, between groups). At entry and during follow-up, an equally number of patients in each diet group received antihypertensive treatment (>80 %), predominantly with ACE-inhibitors.

During follow-up blood pressure was similar in the two diet groups. An intention-to-treat analysis demonstrated that the rate of decline in GFR slowed equally in both diet groups during follow-up (3.9 ml/min/year in the usual group versus 3.8 in the low protein diet group). Although comparable in both diet groups during follow-up, blood pressure, albuminuria and haemoglobin A1c were independent risk factors for the deterioration of GFR. ESRD and death occurred in 27 % of patients in the control group as compared with only 1G % in the low protein diet group (p=G.G42). The relative risk of ESRD or death was G.23 (p=G.G1) for patients assigned to dietary protein restriction, compared with those assigned to the usual protein diet, after adjustment for the presence of cardiovascular disease at baseline. This finding is comparable to what has been previously demonstrated in patients with non-diabetic nephropathies [78;79]. The widespread use of ACE inhibitors and lack of adherence to the prescribed level of protein intake in the low protein diet group, may explain the lack of impact of diet intervention upon the rate of decline in GFR in this study, compared to the studies of Walker et al. [72] and Zeller et al. [73].

In the MDRD study [4G] 585 patients with chronic renal diseases were randomly assigned to a low protein diet (pre-scribed G.58 g/kg/day; achieved G.77 g/kg/day) or an usual protein diet (pre-scribed 1.3 g/kg/day; achieved 1.1 g/kg/day) for two years. At entry and during follow-up, an equally number of patients in each diet group received antihypertensive treatment (8G %), mainly with ACE-inhibitors. In the intention-to-treat analysis the projected decline in GFR was 1.2 ml/min/year less (NS) in the low protein diet group compared to the usual protein diet group. However, dietary protein restriction induced a biphasic decline in GFR, with a faster initial and a slower subsequent decline in GFR. The subsequent decline in GFR was 28 % less in the low protein diet group compared to the usual protein diet group (p=G.GG9).

In a meta-analysis by Pedrini et al. [78], it was suggested that dietary protein restriction slows the progression of diabetic nephropathy, since a low protein diet [<G.8 g/kg/day] significantly slowed the increase in urinary albumin excretion or the decline in GFR [relative risk G.56]. This analysis was based on 5 previously published studies [68;72;73;8G;81] in type 1 diabetic patients, including 3G patients with normo- and microalbuminuria [68]. However, the validity of this meta-analysis has been questioned [82].

In conclusion, these findings suggest that dietary protein restriction improves prognosis in type 1 diabetic patients with diabetic nephropathy independently of antihypertensive therapy. Whether a similar beneficial effect of dietary protein restriction is present in type 2 diabetic patients with diabetic nephropathy urgently needs to be elucidated.

Problems with long-term dietary protein restriction

Protein-caloric nutrition deficiency and adherence to the pre-scribed diet is two of the major problems during long-term dietary protein restriction.

Dietary protein regimens containing an iso-caloric protein intake of at least 0.6 g/kg/day have proved to attain nitrogen balance and maintain normal indices of nutrition during long-term therapy [83;84]. The recommended level of energy intake of 30 to 35 Kcal/kg/day [85] seems to be required to obtain the most sufficient use of the dietary protein in chronic renal disease [86]. Since mean values for various indices of nutritional status (body weight, serum albumin levels and mid-arm muscle circumference) remained within normal ranges during dietary protein restriction in the quoted long-term intervention studies [40;61;72;73], the obtained level of protein restriction appears to be save over a period of 2 to 4 years. However, during low protein diet in the MDRD study [40], small but significant declines in energy intake and various indices of nutritional status were observed throughout the study. Nevertheless, no difference in the rates of death or first hospitalisation was seen between diet groups.

Whether calorie deficiency per se has a beneficial effect on GFR is controversial [87-89]. Similarly, it has recently been suggested that vegetable proteins (regardless of their quantity) has a beneficial effect on renal haemodynamics compared to animal proteins [90]. At present, no data are yet available concerning the effects of vegetable proteins on the progression of chronic renal disease.

In a secondary analysis of the MDRD study a close association between achieved dietary protein intake and the rate of decline in GFR has been demonstrated [91]. A 0.2 g/kg/day lower achieved protein intake was associated with a 1.15 ml/min/year slower mean decline in GFR. However, as demonstrated above, it is difficult to obtain the prescribed level of long-term dietary protein restriction in chronic renal disease [40;61;72;73]. It has proved to be difficult to lower dietary protein intake to less than 0.8 g/kg/day over extended periods of time [90] and patients with advanced non-diabetic renal disease is only able to lower their protein intake by 0.1 to 0.2 g/kg/day despite intensive nutritional counseling [92].

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