Current issues of ACP Journal Club are published in Annals of Internal Medicine


Letter

Dietary protein and blood pressure intervention failed to slow renal disease progression

ACP J Club. 1994 Nov-Dec;121:84. doi:10.7326/ACPJC-1994-121-3-084



To the Editor

At variance with the Modification of Diet in Renal Disease (MDRD) study findings (1, 2), the results of our recent meta-analysis (3) indicated a 40% reduction in “renal death” (i.e., starting dialysis or death) from reduced protein intake among patients with renal impairment. Some caveats to the MDRD findings have already been discussed (4) and we would like to expand on them.

Assessment of the efficacy of a treatment in renal failure should be based on clinical criteria such as death, transplantation, or the need for dialysis. An intermediate criterion, such as the rate of decline in glomerular filtration rate (GFR), is interesting as a secondary outcome but has limitations (5) that raise difficulties in interpreting the MDRD study. First, the choice of the same parameter (GFR decline) as a success criterion and as a withdrawal criterion could alter the comparability of the 2 groups, as shown in Figure 2 of the MDRD paper (1), and bias the comparison.

Second, what is the benefit to the patients if the GFR was decreased less but more renal deaths occurred in the same group? It would be informative to know how many renal deaths occurred in the treated and control groups at 2.2 years, the average follow-up in the MDRD study. Despite analyzing heterogeneous trials in our meta-analysis (3), we observed 156 renal deaths among 890 patients (17.5%) compared with 136 among 840 patients (16.2%) in the MDRD study. This consistency gives strength to the “renal death” criterion and we suggest that renal death be reported in future studies involving the natural progression of renal disease, as has been done recently (6).

The results of the MDRD study do not warrant the conclusion that a low-protein diet fails to delay end-stage renal disease. Additional trials are needed.

Denis Fouque, MD
Maurice Laville, MD
Jean-Pierre Boissel, MD
University Claude Bernard
Lyon, France

In response

The MDRD Study hypothesis is that patients with diverse renal diseases would respond uniformly to blood pressure (BP) and dietary interventions. We now know that pursuing a lower-than-usual BP goal benefits patients with urinary protein excretion > 1 g/d (1, 2), but no evidence exists that patients without proteinuria benefit. Thus, we agree with Dr. Harvey (3) that physicians should consider a BP goal lower than that recommended by the Joint National Committee in patients with urine protein excretion > 1 g/d.

The response to diet interventions was more uniform among patients with various renal diseases. Study 1 was inconclusive because of the faster decline in GFR during the first 4 months in patients assigned to the low-protein diet. Despite a slower decline thereafter, no beneficial effect was shown, but a longer follow-up might reveal a benefit.

In study 2, a marginal (P = 0.07) benefit existed for the very-low-protein diet supplemented with a mixture of ketoacids and aminoacids when compared with the low-protein diet. No comparison was done, however, with a usual-protein diet. In correlation analysis (4), a higher follow-up protein intake was associated with faster progression. Although not definitive, this and other studies (5) suggest that compliance with a low-protein diet may slow the progression of renal disease in patients with a GFR < 25 mL/min per 1.732. This conclusion is consistent with the findings of the meta-analysis by Fouque and colleagues (6), which mainly included studies of patients with a baseline GFR in the range of values in study 2.

The methods for estimating GFR slope in both studies 1 and 2 took into account patients who died, developed renal failure, or reached “GFR stop points” (study 1 only). Thus, our results are not biased by the occurrence of these events. In study 1, 103 of 255 patients (40%) died or developed renal failure. Thus, the occurrence of death or renal failure could have been used as the primary outcome. No significant difference existed, however, between the diet groups or between the BP groups in the proportion of patients reaching this end point in either study 1 or 2.

Saulo Klahr, MD
Andrew S. Levey, MD
Gerald J. Beck, PhD
Washington University School of Medicine
St. Louis, Missouri


References

1. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-84.

2. Dietary Protein and Blood Pressure Intervention Failed To Slow Renal Disease Progression. ACP J Club. 1994 Sep-Oct:46(Ann Intern Med. vol 121, suppl 2). Abstract of: Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-84.

3. Fouque D, Laville M, Boissel JP, et al. Controlled low protein diets in chronic renal insufficiency: meta-analysis. BMJ. 1992;304:216-20.

4. Narins RG, Cortes P.The role of dietary protein restriction in progressive azotemia.N Engl J Med. 1994;330:929-30.

5. Boissel JP, Collet JP, Moleur P, Haugh M. Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol. 1992;43:235-44.

6. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456-62.

1. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-84.

2. MDRD Study Group. [Abstract]. J Am Soc Nephrol. 1993;4:254.

3. Harvey J. Commentary on “Dietary protein and blood pressure intervention failed to slow renal disease progression.” ACP J Club. 1994 Sep-Oct:46(Ann Intern Med. vol 121, suppl 2). Comment on: Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-84.

4. MDRD Study Group. Abstracts of the Second Spring Clinical Nephrology Meetings, National Kidney Foundation, April 7-10, 1994.

5. Ihle BE, Becker GH, Whitworth JA, Charlwood RA, Kincaid-Smith PS. The effect of protein restriction on the progression of renal insufficiency. N Engl J Med. 1989;321:1773-7.