COMMENTARY

How a Low-Protein Diet Can Delay Dialysis in Patients With Chronic Kidney Disease

Kam Kalantar-Zadeh, MD, MPH, PhD

Disclosures

November 05, 2021

At any given time, an estimated 15% of the US adult population has chronic kidney disease (CKD). It manifests as reduced kidney function to below 60% of its normal range (estimated glomerular filtration rate < 60 mL/min/1.73 m2) or by spillage of protein into the urine. The many causes of CKD include diabetes, hypertension, glomerulonephritis, and cystic kidney diseases. CKD is an irreversible malady with no known cure, and it invariably worsens over time. CKD is associated with higher mortality risks as it advances. If the patient does not die of cardiovascular or infectious events, end-stage renal disease ensues and the patient requires maintenance dialysis therapy or kidney transplantation to survive.

Each year, 130,000 Americans transition to dialysis, which is not only costly but also associated with poor health-related quality of life and an early mortality of more than 20% in the first year. Hence, slowing CKD progression and preventing or delaying dialysis can have major favorable implications for CKD outcomes.

There has been growing recognition that conservative management, including kidney-preserving strategies without dialysis, is a viable patient-centered treatment option for many people with CKD. The kidney-preserving approach of conservative therapy, which differs from supportive or palliative care, can be achieved by pharmacologic interventions. Medications that alter renal hemodynamics (intraglomerular pressure, for example) can help preserve kidney function longer through mechanisms other than by improving systemic blood pressure or glucose control in patients with hypertension or diabetes. Whereas decade-old angiotensin pathway modulators (ACE inhibitors and ARBs) and emerging SGLT2 inhibitors are increasingly used in CKD management, the role of integrated or multimodal interventions, including the potentially synergistic and additive effect of diet and lifestyle modifications in addition to pharmacotherapy, has not been well examined in this population. This is in sharp contrast to the well-known integrative approaches to heart disease, whereby pharmacotherapy including statins is almost invariably combined with diet and lifestyle adjustments. A plant-dominant, low-protein, low-salt diet may help mitigate glomerular hyperfiltration and preserve kidney function while also leading to other favorable alterations, such as in acid-base homeostasis and bone and mineral disorders.

Simply Put: We Eat Way Too Much Meat

Although the recommended dietary allowance of protein is 0.8 g/kg/d, Americans on average consume much higher amounts — usually 1.2 g/kg/d or more. Evidence suggests that by increasing intraglomerular pressure with resultant glomerular hyperfiltration, high dietary protein intake may adversely affect kidney health over time across populations with or at risk for CKD (Kalanter-Zadeh and colleagues; Ko and colleagues). Amino acid infusion worsens glomerular hyperfiltration, especially in persons with poorly controlled diabetes. Independent of the quantity of dietary protein intake, plant-based protein has salutary renal hemodynamic effects compared with animal protein in persons with and those without diabetes. However, higher dietary protein intake is often recommended to combat obesity (Pasiakos and colleagues; Athinarayanan and colleagues), even though some studies indicate that "high biologic value" proteins from animal sources may be associated with worse renal outcomes.

Evidence has shown that a low-protein diet (< 0.8 g/kg/d) may preserve kidney function longer in persons with CKD. A low-protein diet has consistently been shown to lower intraglomerular pressure; this may preserve long-term kidney function, as corroborated in both animal models and in human studies of CKD, including several meta-analyses (Malhotra and colleagues; Fouque and colleagues; Chewcharat and colleagues; Rhee and colleagues; Jiang and colleagues). Although most research findings support a dietary protein intake of 0.6 to less than 0.8 g/kg/d for CKD management, some data suggest that a dietary protein intake below 0.6 g/kg/d may result in even slower CKD progression; however, a protein intake of 0.6 to less than 0.8 g/kg/d is considered the most pragmatic and safest target when used without amino acid or keto acid supplementation. The scientific premise for these targets was presented in a critical review of 16 low-protein diet trials, and in a parallel review and meta-analysis of these same studies, a low-protein diet was associated with a lower risk for end-stage renal disease, azotemia, acidemia, hyperphosphatemia, and mortality.

Safety of and adherence to a low-protein diet are the same as that of a normal-protein diet, and there is no malnutrition or protein-energy wasting. Although most studies suggest that a low-protein diet ameliorates CKD progression, some have had mixed findings (Kalantar-Zadeh and Moore; Joshi and colleagues); one example is the primary analysis of the Modification of Diet in Renal Disease (MDRD) Study, which excluded diabetic patients. This showed that in those with severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease.

In part because of these somewhat negative findings from the MDRD Study, as well as the impractical aspects of previous, outdated dietary regimens, low-protein diets have not been widely utilized as a renoprotective intervention in most kidney care centers.

Thus, there is an urgent need to move nephrology from a mostly pharmacologic-to-dialysis axis to a multimodal approach that also includes nutritional management of kidney disease.

The PLADO Diet

About 15%-25% of daily calories in the typical US diet come from proteins, with less than one third from plant-based sources. Evidence suggests that animal-based protein is more harmful to kidney health, whereas a plant-dominant (PLADO) low-protein diet is protective and may slow CKD progression. A PLADO diet provides dietary protein intake of 0.6 to less than 0.8 g/kg/d, with more than 50% plant-based sources. The PLADO diet is consistent with the US recommended dietary allowance of protein intake of 0.8 g/kg/d, which has a high safety margin given that the lowest protein requirement to avoid catabolic changes is 0.45-0.5 g/kg/d, on the basis of established metabolic studies.

In addition to reducing glomerular hyperfiltration and intraglomerular pressure, the PLADO diet ameliorates CKD progression via multiple pathways (Table):

Table. Benefits and Challenges of the PLADO Low-Protein Dieta

Benefits of PLADO Diet

Potential Challenges

Lowering intraglomerular pressure Risk for protein-energy wasting
Less interstitial fibrosis from lower trimethylamine N-oxide Inadequate essential amino acids
Synergistic effect with RAAS inhibitors and SGLT2 inhibitors Undermining obesity management
Controlling uremia and delaying dialysis High glycemic index
Preventing cardiovascular harms of meat High potassium load and hyperkalemia
Less absorbable phosphorus Low palatability and adherence
Lowering acid-load with less acidogenicity Inadequate fish intake if vegan
High dietary fiber enhancing GI motility  
Favorable changes in microbiome  
Less inflammation and oxidative stress  
GI = gastrointestinal; PLADO = plant-dominant; RAAS = renin-angiotensin-aldosterone system; SGLT2 = sodium-glucose cotransporter 2
a Involving > 50% plant sources. Adapted from Kalantar-Zadeh and colleagues.

Can diet enforce the effect of pharmacotherapy in CKD? The synergistically additive effect of a low-protein diet on angiotensin pathway modulators in CKD has been relatively consistently reported in the scientific literature (Koppe and Fouque; Kalantar-Zadeh and Fouque). Although a recent secondary analysis of several relatively small SGLT2 inhibitor trials suggested that a high-protein diet did not offset the benefits of SGLT2 inhibition, in some of these trials, dapagliflozin vs placebo reduced the urinary albumin-to-creatinine ratio by 21% in the high-protein group vs 28% in the low-protein group, suggesting 39% more effect of SGLT2 inhibitor if combined with lower protein intake. Hence, it may be true that a low-protein diet could offer additional synergistic benefits to patients undergoing "flozination" with SGLT2 inhibitors.

Finally, the July 2019 US President's executive order seeks to reduce the number of Americans developing kidney failure by 25% by 2030 through improved efforts to prevent, detect, and slow the progression of CKD. This timely effort underscores the importance of preventive CKD measures and reiterates the critical, underappreciated role of dietary interventions in optimizing kidney health. A multimodal integrated approach that includes both medication and nonpharmacologic interventions is based on the scientific premise that feasible dietary interventions should be tested in CKD and prioritized as the cornerstone of nonpharmacologic treatment in slowing CKD progression and avoiding or delaying dialysis.

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