In their outstanding report, Oosterwijk et al. (1) show that renal outcome is superior in patients with diabetes fed on a high-protein diet compared with that of patients subjected to normal or low-protein diet. These unforeseen and surprising findings contradict our common practice, as for decades, low-protein diet has been recommended especially for patients with chronic kidney disease (CKD), a strategy aimed at slowing its progression. Protein intake as low as 20 g per day (such as Kempner rice diet) was initially recommended, but presently a better tolerated diet containing 0.7 to 0.8 g of full protein per 1 kg of body weight is widely considered for patients with advanced CKD.
The currently adopted physiologic rationale for this strategy is to prevent an increase in transglomerular pressure in response to high protein intake. Indeed, amino acids invoke afferent arteriolar vasodilation and increase transglomerular pressure and glomerular filtration, a phenomenon used to assess the extent of renal functional reserve (2). Moreover, switching from a low- to high-protein diet was found to increase the glomerular filtration rate (GFR) by over 20 mL/min in normal individuals (3). Glomerular hyperfiltration, characterizing patients with early type 2 diabetes, is considered hazardous and is believed to lead to a wear-and-tear injury culminating in glomerular sclerosis and hyalinosis (4). Furthermore, enhanced transglomerular pressure is expected to increase proteinuria in individuals with diabetes, which may intensify fatty acid–associated tubulointerstitial inflammation and consequent injury (5).
There might be a simple physiologic explanation for the unexpected observations by Oosterwijk et al. (1), namely, the current wide use by individuals with diabetes of agents that exert renin-angiotensin system blockade (inhibitors of angiotensin converting enzyme and angiotensin II receptor blockers) as well as inhibitors of sodium–glucose cotransporter 2. These medications reduce transglomerular pressure and proteinuria, renin-angiotensin system blockers by efferent arteriolar vasodilation, and inhibitors of sodium–glucose cotransporter 2 by the attenuation of diabetes-induced vasodilation of glomerular afferent arterioles. Indeed, these interventions were found to substantially attenuate the progressive decline in kidney function over time in patients with diabetes and among patients without diabetes with renal disease, postponing the development of end-stage kidney failure. The old concept of renal protection achieved by low protein intake in CKD patients was established long before these medications became available. Conceivably, their introduction prevents postprandial rises in transglomerular pressure, related to protein intake, and attenuates the consequent wear-and-tear outcome of accelerated glomerular sclerosis and tubulointerstitial damage. Likely, most patients in the study by Oosterwijk et al. (1) were on such medications. However, with sufficient numbers, our hypothesis might be challenged by subgroup and multivariate analysis that includes their individual or combined use.
Our postulated hypothesis addresses the unexpected absence of renoprotective properties associated with low-protein diet, but it does not explain improved renal outcome with high intake of proteins. This issue deserves further evaluation, as other unidentified factors may be advantageous with high-protein diet and confounders may play a role, such as a better apatite and protein intake in patients with slower progression of CKD.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
