• 
• 

Three Part Question

In [patients with diabetic nephropathy] does [dietary protein restriction] slow [progression of renal dysfunction]?

Clinical Scenario

A 47 y/o Caucasian woman was diagnosed with DM at age 28. After an unplanned weight loss of 80 pounds in 5 months, she consulted a physician. Upon initial visit her fasting blood glucose was 250 mg/dL and her 2 hour postprandial blood glucose was 400 mg/dL. Her HgA1C was 9.1%; further workup revealed micro-albuminuria with a 24-hour urine albumin excretion of 260 µg and a serum creatinine of 1 mg/dL.

She was managed with exercise, metformin and glyburide and soon after was well-controlled with a HgA1c between 6.7 to 7.2%. Two years later her creatinine level was found to be 1.3 mg/dL. She is started on an ACE inhibitor. Still two years later her incidental creatinine is 1.7 mg/dL. You wonder if the addition of dietary protein restriction would be of utility in such a patient.

Search Strategy

PubMed all dates; Limits: Core clinical journals.
Search phrase: "protein restriction diabetic nephropathy"
(("proteins"[MeSH Terms] OR "proteins"[All Fields] OR "protein"[All Fields]) AND restriction[All Fields] AND ("diabetic nephropathies"[MeSH Terms] OR ("diabetic"[All Fields] AND "nephropathies"[All Fields]) OR "diabetic nephropathies"[All Fields] OR ("diabetic"[All Fields] AND "nephropathy"[All Fields]) OR "diabetic nephropathy"[All Fields])) AND jsubsetaim[text]

Search Outcome

27 papers found, 7 of which are review articles.
Of 27, 18 papers were determined to be relevant.
Of the 18, 5 are review articles.

Journals with papers include Diabetes, Annals of Internal Medicine, Am J Clin Nutr, Archives of Internal Medicine, New England Journal of Medicine, Lancet and others.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. 1996 Apr 1 United States	Patients with both diabetic and nondiabetic chronic renal disease.	The purpose of this study was to use meta-analysis to assess the efficacy of dietary protein restriction in previously published studies of diabetic and nondiabetic renal diseases, including the Modification of Diet in Renal Disease Study.	Decline in GFR	In five studies of insulin-dependent diabetes mellitus, a low-protein diet significantly slowed the increase in urinary albumin level or the decline in glomerular filtration rate or creatinine clearance (relative risk, 0.56 [CI, 0.40 to 0.77])	Heterogeneous patient group: Only 108 patients in five studies of type I diabetes mellitus were included in the meta-analysis compared to 1413 patients in five studies of nondiabetic renal disease.
			Progression of renal disease	Dietary protein restriction effectively slows the progression of both diabetic and nondiabetic renal diseases.
Raal FJ, Kalk WJ, Lawson M, Esser JD, Buys R, Fourie L, Panz VR. 1994 Oct South Africa	32 insulin-dependent diabetes mellitus (IDDM) (≥10 years) patients with documented proteinuria who were attending a renal diabetic clinic in Johannesburg.	To assess whether moderate dietary protein restriction can delay the progression of overt diabetic nephropathy, 22 subjects with insulin-dependent diabetes mellitus were randomly assigned to an unrestricted protein diet (> 1.6 g.kg body wt-1.d-1) or a moderately protein-restricted diet (0.8 g.kg body wt-1.d-1) and followed prospectively for six months.	Glomerular Filtration Rate	Patients consuming the unrestricted protein diet showed a progressive decline in GFR of 1.3 mL/min/month. Patients consuming the moderately protein-restricted diet demonstrated stabilization of the GFR.	26/32 patients agreed to participate. More patients in moderately protein-restricted diet were taking ACE inhibitors (7/11 compared with 6/11 in the unrestricted group).
			Proteinuria	Unrestricted diet: no change. Restricted diet: marked decreased in the degree of proteinuria (2.15-1.15 g/d, P=0.036).
			Progression of diabetic nephropathy	Moderate dietary protein restriction can ameliorate progression of overt diabetic nephropathy.
Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. 1991 Jan 10 United States	35 patients with insulin-dependent (Type I) diabetes mellitus and clinically evident nephropathy	This group studied the effect of reduced intake of protein and phosphorus on the progression of renal disease. he low-protein, low-phosphorus diet contained 0.6 g of protein per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of sodium. The control diet consisted of the patient's prestudy diet with the stipulation that it contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of phosphorus.	Progression of diabetic renal failure	ietary restriction of protein and phosphorus can retard the progression of renal failure in patients with Type I diabetes mellitus who have nephropathy.	Small n = 35 patients
Brouhard BH, LaGrone L. 1990 Oct United States	Group 1: 8 patients with insulin-dependent diabetes mellitus with nephropathy (micro-albuminuria [greater than or equal to 30 micrograms/minute]) Group 2: 7 controls; group of similar patients.	12-month study of 8 patients (and 7 controls), both with IDDM. Group 1: chronically decreased their dietary protein intake to a mean of 0.6 g/kg/day Group 2: maintained their unusual dietary protein intake of 1.0 g/kg/day	GFR	Increased in Group 1 (dietary intake regulated); Decreased in control group.	Small n = 15 patients (8 dietary intake regulated, 7 control).
			Urine urea and microalbuminuria	Both urine urea and microalbuminuria decreased significantly (p less than 0.05) in the low protein group.
			Progression of loss of renal function	This study indicates that sustained dietary protein restriction can help to preserve renal function, decrease albuminuria, and lower the baseline GFR while maintaining functional renal reserve in patients with insulin-dependent diabetes mellitus.

Comment(s)

Most of the studies-to-date have used small patient populations and have not all explicitly controlled for confounding factors (e.g. the use of an ACE inhibitor by some patients and not by others, both within the same study and the same group). A British study (Bending et al, Diabetes. 1988 Dec;37(12):1641-6) has elucidated the renal response to protein restriction: short-term dietary protein restriction reduces diabetic proteinuria independently of blood glucose or systemic blood pressure changes by improving glomerular permselectivity. All studies analyzed in this Best Bet have found some benefit for protein restriction with respect to renal integrity, most often with a slowed progression of renal dysfunction in diabetic nephropathy.

Clinical Bottom Line

A protein restriction (e.g. 0.6 g/kg/day) diet should be considered for patients with diabetic nephropathy as it appears to slow the progression of renal dysfunction.

References

1. Michael T. Pedrini, MD; Andrew S. Levey, MD; Joseph Lau, MD; Thomas C. Chalmers*, MD; and Ping H. Wang, MD The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. 1 April 1996 | Volume 124 Issue 7 | Pages 627-632
2. Frederick J Raal, W John Kalk, Marie Lawson, Jan D Esser, Ria Buys, Louise Fourie, and Vanessa R Panz. Effect of moderate dietary protein restriction on the progression of overt diabetic nephropathy: a 6-mo prospective study. Am J Clin Nutr 1994;60:579-85.
3. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR. Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 1991 Jan 10;324(2):78-84.
4. Brouhard BH, LaGrone L. Effect of dietary protein restriction on functional renal reserve in diabetic nephropathy. Am J Med. 1990 Oct;89(4):427-31