Data Support Low-Protein Diet for Conservative Management of CKD

Nutritional intervention strategies provide an alternative, conservative approach to management of chronic kidney disease (CKD)—allowing patients at least the possibility of delaying or avoiding dialysis, according to a comprehensive review published this month in The New England Journal of Medicine.

While questions remain, an analysis of the best available research evidence supports the concept of using a low-protein diet for conservative management of CKD—including a significantly lower risk of progression to end stage renal disease. “A low-protein diet appears to enhance the conservative management of non-dialysis dependent CKD and may be considered as a potential option for CKD patients who wish to avoid or defer dialysis initiation and to slow down the progression of CKD,” said Kamyar Kalantar-Zadeh, MD, MPH, PhD, of the University of California Irvine.

Major new review of nutritional management in CKD

Of course, the notion of a low-protein, low-salt diet for patients with kidney disease is by no means a new one. “However, reinvigoration of this idea is considered to have important clinical and public health implications because it may help with conservative and alternative management of CKD,” Kalantar-Zadeh said. “If there is the opportunity to continue to manage CKD without dialysis therapy, if successful, then that will be the preferred option for many patients.”

Along with Denis Fouque, MD, PhD, of Université Claude Bernard Lyon, France, Kalantar-Zadeh co-authored the review of current evidence on nutritional management of CKD, published in the November NEJM. In addition to other constituents, the review highlights new and emerging knowledge on the role of dietary protein in CKD progression.

As kidney disease progresses, protein-energy wasting is common, requiring dietary adjustments. The authors summarize animal studies suggesting that a low-protein diet has a “preglomerular effect”—enhancing the postglomerular effect of angiotensin-pathway modulators and thus lowering intraglomerular pressure. Experimental evidence also suggests that the protective effects of a low-protein diet interact synergistically with the direct effects of a low-sodium diet.

What does that mean for low-protein diets in humans? So far, the data have been inconsistent. Most controlled trials have supported the beneficial effects of restricted protein intake on CKD. However, the largest such trial, the Modification of Diet in Renal Disease (MDRD) study, concluded that a low-protein diet had only a minimal effect on progression of CKD, whereas Kalantar-Zadeh’s review of secondary analyses suggests that the MDRD study was more effective than originally thought.

More recently, analysis of data from the Atherosclerosis Risk in Communities (ARIC) Study suggested that the source of protein matters. Risk of CKD was higher in individuals reporting a high intake of red and processed meats, but lower in those with a higher intake of nuts, legumes, and low-fat dairy products. “Altogether, the current evidence suggests that a low-protein diet mitigates proteinuria in both experimental models and human kidney disease,” Kalantar-Zadeh and Fouque write.

That preliminary conclusion is supported by a meta-analysis of clinical trial data, published last month in the Journal of Cachexia, Sarcopenia and Muscle. The lead authors were Connie M. Rhee, MD, MSc, and Seyed-Foad Ahmad, MD, MPH, of the University of California Irvine. Csaba P. Kovesdy, MD, of the University of Tennessee, Memphis, is a coauthor of the new review, along with Kalantar-Zadeh, as the corresponding author.

In a systematic review, the authors identified 16 controlled trials of low-protein diet—with a protein intake of less than 0.8 g/kg/d—including comparison of clinical outcomes. To ensure meaningful sample size, the analysis was limited to randomized trials including at least 30 patients.

Analysis of pooled data showed that the risk of progression to end stage renal disease was 4% lower for patients receiving a low-protein diet, compared to those receiving higher-protein diets (overall risk difference 0.04, 95% confidence interval 0.07 to 0.02). There was a trend toward a lower risk of death from any cause, although the difference was not significant.

Low-protein diets were also associated with a significant 1.46 mEq/L increase in serum bicarbonate (95% confidence interval 1.04 to 1.87). There was no significant difference in serum phosphorus.

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An additional meta-analysis compared outcomes for patients receiving very low-protein diets of less than 0.4 mg/kg/d with low-protein diets of 0.4 to 0.6 mg/kg/d. The results showed a significant 13% reduction in the risk of progression to ESRD with very low-protein diets. The estimated glomerular filtration rate was lower by 3.95 mL/min/1.73 m2 in patients receiving very low-protein diets, along with a trend toward lower serum urea.

“An effective means to delay or defer dialysis therapy”

Thus the best available evidence points toward the possibility of dietary interventions for conservative management of CKD. For decades, dialysis has been considered a lifesaving treatment for patients with advanced kidney disease. Efforts to improve patient outcomes have generally focused on providing more dialysis and initiating dialysis earlier.

However, recent studies have questioned that assumption. “Discoveries in the past five or six years have encouraged us to rediscover conservative management as an option in addition to renal replacement therapy,” Kalantar-Zadeh said. He points to a 2009 NEJM study showing a “substantial and sustained” decline in functional status after initiation of dialysis in nursing home residents with ESRD.

The focus on nutritional management is by no means intended to address resource constraints or challenges in access, nor to address the high costs of dialysis, according to Kalantar-Zadeh. “On the contrary, this is a decision for people who prefer an alternative to dialysis therapy,” he said. “Nutritional therapy provides us with yet another option to help millions of CKD patients worldwide.”

Just as nephrologists try to delay progression of CKD and ESRD with medications such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, “nutritional management gives us yet another angle for us to delay CKD progression, as well as to manage uremia,” said Kalantar-Zadeh. “It allows us to be able to control symptoms and allow patients to add a few months to years if not longer without dialysis therapy—if that’s their preferred choice. It’s not necessarily 100% successful, but it may work in many patients, and should be tried.”

Nutritional therapy may also play an important role in mitigating the increased risk of CKD and ESRD after nephrectomy—including living-donor and cancer nephrectomy. “A moderately low-protein diet—less than 1 g/kg/d—may help with the longevity of the solitary kidney,” Kalantar-Zadeh said.

Further research is needed to provide a “more robust, evidence-based approach” to nutritional strategies for patients with kidney disease. Kalantar-Zadeh highlighted the importance of conducting studies under current clinical conditions—including the recent trend toward a diet higher in protein and lower in carbohydrates and fat. Such high-protein diets have become a popular weight-reduction strategy, but their effects on long-term kidney function remain unclear.

The NEJM review addresses many aspects of nutritional management for patients with CKD—not only protein but also sodium and fluids, potassium, phosphorus, calcium and vitamin D, and carbohydrates, fats, and dietary energy, and the microbiome, among other topics. It also includes tables and supplementary materials summarizing the low-protein diet and the evidence supporting its use in patients with CKD.

Kalantar-Zadeh acknowledged the significance of the publication of this major review of nutritional therapy for CKD, timed to correspond with Kidney Week—the largest and most important annual meeting of the world nephrology community. “For the ASN this is symbolically and strategically very important,” he said.

December 2017 (Vol. 9, Number 12)

References

1. Kalantar-Zadeh K, Fouque D. Nutritional management of chronic kidney disease. N Engl J Med 2017; 377:1765−1776.

2. Klahr S, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994; 330:877−884. [MDRD Study].

3. Levey AS, et al. Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J Am Soc Nephrol 1999; 10:2426–2439.

4. Haring B, et al. Dietary protein sources and risk for incident chronic kidney disease: results from the Atherosclerosis Risk in Communities (ARIC) Study. J Ren Nutr 2017; 27:233−242.

5. Rhee CM, et al. Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. J Cachexia Sarcopenia Muscle 2017 Nov 2. doi: 10.1002/jcsm.12264.

6. Kurella TM, et al. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med 2009; 361:1539–1547.