Rosemary Dodds

Restriction of dietary protein and progression of renal failure in diabetic nephropathy

In a study of the effect of a low-protein diet on the progression of renal disease 19 insulin-dependent diabetic patients with persistent clinical proteinuria were observed for 12-39 (mean 29) months while they were on a normal-protein diet (1.13 [0.06] g/kg per day), then for 12-49 (mean 33) months on a low-protein diet (0.67 [0.03] g/kg per day). The low-protein diet had no adverse effect on nutrition or glycosylated haemoglobin concentration. Mean supine blood pressure (BP) fell slightly on the low-protein diet and was probably due to the start or modification of antihypertensive medication in 9 patients. The mean rate of decline in glomerular filtration rate fell from 0.61 (SEM 0.14) ml/min per month with the normal-protein diet to 0.14 (0.08) with the low-protein diet, and this effect remained highly significant after adjustment for blood pressure, energy intake, and glycosylated haemoglobin. The rise in the fractional clearance of albumin during a normal-protein diet stopped with the low-protein diet, and there was a significant fall in albumin excretion from 467 (95% CI 234-895) micrograms/24 h on the normal-protein to 340 (138-719) on the low-protein diet. Thus, a low-protein diet, with its reduction in protein and possibly other dietary components such as phosphate or fat, seems to retard the rate of decline of glomerular filtration rate in diabetic nephropathy independently of blood pressure changes and glycaemic control.

Effect of protein restriction in insulin dependent diabetics at risk of nephropathy.

Persistent proteinuria is strongly associated with increased mortality in insulin dependent diabetes, and risk of this condition can be predicted many years in advance by subclinical increases in albumin excretion rate (microalbuminuria). Eight normotensive insulin dependent diabetics with microalbuminuria who had overnight albumin excretion rates of between 15 and 200 micrograms/min underwent a three week randomised crossover study of their normal protein diet (median 92 (range 55-117) g/day) and a low protein diet (47 (38-57) g/day). Both diets were isoenergetic, and the low protein diet was supplemented with calcium and phosphate. Median overnight albumin excretion rate fell from 23.0 (15.0-170.1) micrograms/min during the normal diet to 15.4 (4.1-97.8) micrograms/min during the low protein diet. No consistent change was found in urinary excretion of beta 2 microglobulin during the two diets. The reduction in albumin excretion rate was accompanied by a significant fall in median glomerular filtration rate and fractional renal clearance of albumin. Kidney volume remained unchanged. There were no significant changes in glycaemic control or arterial blood pressure. In these few patients restriction of dietary protein had a beneficial effect on microalbuminuria, independent of changes in glucose concentrations and arterial blood pressure.

Renal response to restricted protein intake in diabetic nephropathy

Proteinuria in diabetes is associated with progressive glomerular damage. We studied the effects of 3-wk dietary protein restriction on proteinuria and renal function in 10 insulin-dependent diabetic men with diabetic nephropathy. Patients were randomly assigned by a crossover design to 40-g low-protein diet (LPD) or usual-protein diet (UPD). Glomerular filtration rate and renal plasma flow were measured by inulin and p-aminohippurate clearance at the end of each period under conditions of sustained euglycemia. Total calorie intake, body weight, serum albumin and total protein concentrations, hematocrit, blood pressure, and glucose control were similar during the two diets. Achieved protein intake was 46 ± 3 g/day during LPD and 81 ± 4 g/day during UPD (P < .001). Urinary urea appearance and plasma urea were significantly lower on LPD. Median total urinary protein was reduced from 3.9 g/day (range 0.5–12.3) on UPD to 2.4 (range 0.2–9.0) on LPD (P < .006), and there was a significant fall in the median fractional clearance of albumin from 2.0 × 10−4 (range 0.1–90.9) on UPD to 1.0 × 10−4 (range 0.1–51.4) on LPD and IgG from 2.1 × 10−5 (range 0.2–238) to 1.5 × 10−5 (range 0.1–77) (P < .006 and P < .02, respectively). The reabsorption rate of β2-microglobulin was similar on the two diets and glomerular filtration rate, renal plasma flow, and filtration fraction remained unchanged. Thus, short-term dietary protein restriction reduces diabetic proteinuria independently of blood glucose or systemic blood pressure changes by improving glomerular permselectivity.

Renal Functional Response to Protein Loading in Type 1 (Insulin-Dependent) Diabetic Patients on Normal or High Salt Intake

Insulin-dependent diabetes mellitus (IDDM) patients may have an increased intrarenal angiotensin II activity. In diabetic patients, captopril increases the renal hemodynamic response to an amino acid infusion. We investigated the effects of two salt diets on arterial pressure and renal response to a protein load in 10 normotensive (blood pressure < 140/90 mm Hg) IDDM patients (aged 30 +/- 3 years) who had diabetes for 7 +/- 4 years and normoalbuminuria levels [albumin excretion rate 4.8 (2.5-19.1) microg/min]. After 1 week of normal (approximately 100 mmol/day; approximately 100 mEq/l) and 1 week of high (approximately 300 mmol/day; approximately 300 mEq/l) salt intake, renal hemodynamic studies were performed at baseline and after a protein load (meat meal) of 100 g/1.73 m2. The mean 24-hour urinary sodium excretion levels were 99 +/- 27 and 293 +/- 80 mmol (mEq) with normal and high salt intake, respectively. No significant changes were seen in plasma sodium and glucose control with the normal and high salt diets, respectively: plasma sodium 135 +/- 3 vs. 137 +/- 1 mmol/l (mEq/l), (p = 0.08) and glycated hemoglobin 9.1 +/- 1.9 vs. 9.4 +/- 2.1% (p = 0.36). The body weight (70.9 +/- 12 vs. 71.8 +/- 13 kg; p = 0.015) was significantly higher with a high salt diet. The mean arterial pressure was similar with both diets (normal vs. high salt diet 91 +/- 9 vs. 89 +/- 6 mm Hg, p = 0.25). The plasma renin concentration [28 +/- 15 vs. 16 +/- 6 microU/ml(168 +/- 90 vs. 96 +/- 36 pmol/l), p = 0.013] and angiotensin II [8.8 +/- 4.4 vs. 6.4 +/- 3.5 pg/ml (0.052 +/- 0.025 vs. 0.038 +/- 0.021 nmol/l), p = 0.016] were significantly lower with the high salt diet. Following protein loading, the glomerular filtration rate increased with both diets: normal salt diet 114 +/- 26 vs. 128 +/- 30 ml/min/1.73 m2(1.9 +/- 0.43 vs. 2.13 +/- 0.50 ml/s/1.73 m2), p = 0.04; high salt diet 118 +/- 23 vs. 127 +/- 29 ml/min/1.73 m2 (1.97 +/- 0.38 vs. 2.12 +/- 0.48 ml/s/1.73 m2), p = 0.13. The change in renal plasma flow was similar to that of the glomerular filtration rate with normal and high salt intake, respectively: 566 +/- 94 vs. 617 +/- 142 ml/min/1.73 m2 (9.44 +/- 1.57 vs. 10.29 +/- 2.37 ml/s/173 m2), p = 0.0017; 572 +/- 125 vs. 600 +/- 110 ml/min/1.73 m2 (9.54 +/- 2.08 vs. 10.00 +/- 1.83 ml/s/1.73 m2), p = 0.057. In this subset of normotensive normoalbuminuric IDDM patients, a high salt intake did not promote an exaggerated renal response to the protein load despite inhibition of the renin-angiotensin system.

Effect of low protein diet on the renal response to meat ingestion in diabetic nephropathy

Abstract. We measured the renal haemodynamic and proteinuric response to a meat meal (MM) in ten persistently proteinuric insulin‐dependent diabetic patients in a randomized cross‐over study of 3 weeks on low protein diet (LPD) or normal protein intake (NPD). On LPD, protein intake (0.64±0.05 vs 1.15±0.09 g kg‐1 body weight (BW) per day, P<0.001), plasma urea (6.6±1.3 vs 11.0±2.0 mmol 1‐1, P<0.01) and urea appearance (0.06±0.01 vs 0.16±0.03 gN kg‐1 body weight per day, P<0.001) were lower. Baseline glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR) were similar on the two diets and there were no significant average changes in these variables after the meat meal on either diet (NPD, before vs after MM: GFR: 67±11 vs 71±13 ml min‐1 1±73 m‐2; RPF: 479±70 vs 512±81 ml min‐1 1±73 m‐2; RVR: 181±45 vs 179±52 mmHg min‐1 1‐1); (LPD, before vs after MM: GFR: 64±10 vs 67±11 ml min‐1 1±73 m‐2; RPF: 506±60 vs 533±52 ml min‐1 1±73 m‐2; RVR: 151±28 vs 146±32 mmHg min‐1 1‐1). However, all patients with baseline GFR above 60 ml min‐1 1.73 m‐2 showed a GFR rise in response to the meat meal on both diets, while patients with lower baseline values tended to reduce their GRF. Baseline fractional albumin clearance was lower on LPD (geometric mean [range]: 1.15 [0.10–50.53].10‐4) than on NPD (l.74[0.17–56.99]×10‐4). MM produced a significant increase in the fractional clearance of albumin of ±69% on NPD to 2±94(0±37–113±42)×10‐4 (P<0.02), and of ±62% on LPD to 1.86(0.13–82.90)×10‐4(P<0.01). The magnitude of these changes was not statistically different. In proteinuric insulin‐dependent diabetic patients on NPD the renal vasodilatory response to a meat meal is blunted particularly when basal GFR is depressed. LPD does not restore physiological renal response and, while reducing baseline proteinura, fails to prevent proteinuric effect of meat ingestion.

Protein Restriction, Blood Pressure and the Progression of Diabetic Nephropathy

Diabetic nephropathy is the long-term complication of diabetes responsible for the greatest increased mortality. Clinical nephropathy is characterised by a triad consisting of persistent proteinuria (total urinary protein greater than 0.5 g/24 h), rising arterial pressure and declining renal function. The role of treatment of raised blood pressure and the influence of dietary protein restriction on the established progressive phase of the disease are discussed. Subclinical elevations of urinary albumin excretion rates (greater than 30 micrograms/min; microalbuminuria), glomerular hyperfiltration and marginal elevations of arterial pressure are early markers of later clinical nephropathy which appear to respond to strict blood glucose control, blood pressure treatment and lowered dietary protein intake. Recent evidence to suggest that an inherited predisposition to raised arterial pressure may confer the susceptibility to diabetic nephropathy is presented.