Dietary Acid Reduction With Fruits and Vegetables or Bicarbonate Attenuates Kidney Injury in Patients With a Moderately Reduced Glomerular Filtration Rate Due to Hypertensive Nephropathy

Nimrit Goraya; Jan Simoni; Chanhee Jo; Donald E Wesson

Disclosures

Kidney Int. 2012;81(1):86-93. 

In This Article

Discussion

Dietary acid reduction with oral NaHCO3 for 5 years ameliorated kidney injury and slowed GFR decline in CKD subjects with moderately reduced eGFR due to hypertensive nephropathy.[4] The present studies extend these observations by showing that (1) 30 days of HCO3 or F+V comparably decreased kidney injury in subjects with CKD 2 but not with CKD 1 due to hypertensive nephropathy; and (2) kidney injury reduction was more evident in CKD 2 than in CKD 1. The data support the fact that both F+V and NaHCO3 are kidney-protective adjuncts to reduced Sys BP and angiotensin-converting enzyme inhibition in hypertensive and possibly other nephropathies.

Kidney injury did not change significantly after 30 days of HCO3 or F+V in CKD 1. By contrast, F+V and NaHCO3 each significantly and comparably decreased kidney injury in CKD 2. Animals with 2/3 nephrectomy have reduced GFR without metabolic acidosis, similar to CKD 2, and reduced dietary acid with base-inducing protein, or with NaHCO3 each decreased kidney injury and slowed GFR decline.[6,7] The 2/3 nephrectomy animals had acid retention by microdialysis, which mediated kidney injury and progressive GFR decline despite the absence of metabolic acidosis.[6,7] Amelioration of acid retention associated with reduced GFR with either dietary intervention decreased kidney injury and slowed GFR decline.[6,7] Because CKD 2 subjects without metabolic acidosis appear to have acid retention[14] similar to 2/3 nephrectomy animals, we hypothesize that amelioration of acid retention with each strategy decreases kidney injury in CKD 2. Because dietary acid intake and the initial and follow-up 8 h NAE after 30 days of HCO3 or F+V were not significantly different, each intervention appears to have reduced acid retention similarly. Together, the data support the fact that decreased kidney injury induced by dietary acid reduction was mediated by amelioration of acid retention in CKD 2.

Dietary acid reduction with F+V, but not NaHCO3, in CKD 2 (Table 2) was accompanied by a significant decrease in Sys BP, which might add cardiovascular protection to F+V as a potentially kidney-protective intervention. Reduced Sys BP with F+V was evident in both CKD 1 and CKD 2 in subjects starting a vegetarian diet.[15] Sys BP reduction decreases Ualb in primary hypertension[16] and the statistically greater reduction in Ualb in CKD 2 subjects given F+V compared with NaHCO3 might have been mediated by Sys BP reduction in CKD 2 subjects given F+V but not NaHCO3. In addition, lower UNaV in F+V compared with NaHCO3 and Time Control CKD 2 subjects, consistent with reduced Na+ intake, might also have contributed to lower Ualb in CKD 2 subjects given F+V.[17] Reduced UNaV and increased UKV in F+V (Table 3), consistent with reduced and increased intake of each, respectively, likely mediates this BP reduction.[18,19] In addition, reduced body weight (Table 3) with F+V might also have contributed.[20] Furthermore, the greater Ualb decrease in CKD 2 than in CKD 1 group given F+V was associated with greater Sys BP reduction in CKD 2 than in CKD 1 group given F+V. Consequently, greater Sys BP reduction might have mediated the greater Ualb decrease in CKD 2 than in CKD 1 group given F+V. Dietary Na+ reduction decreases Sys BP more in those patients with reduced than normal GFR,[21] and possibly explains greater Sys BP reduction in CKD 2 than in CKD 1.

Because K+ depletion increases BP,[19] changes in K+ balance might also have contributed to differences in Sys BP among CKD 2 groups. The increased UK in F+V is consistent with an increase in K+-containing foods as determined from follow-up 3-day diaries in these CKD 2 subjects, and this dietary change would be expected to promote a decrease in BP.[19] By contrast, 3-day diaries showed no increase in K+-containing foods in CKD 2 subjects given NaHCO3, yet they had increased UK in response to NaHCO3 as observed by others.[22] Greater UK in CKD 2 patients given NaHCO3 combined with a slight but significant decrease in plasma K+ (Table 3) might indicate reduced K+ stores. Consequently, mild K+ depletion in CKD 2 given NaHCO3 might have limited or precluded Sys BP reduction in these CKD 2 subjects, potentially making this strategy for dietary acid reduction less cardiovascular protective than F+V. Although no CKD 2 group given F+V experienced an increase in plasma K+, caution is warranted in prescribing F+V to CKD subjects with lower GFRs.

Urine NAG excretion assessed tubulo-interstitial injury,[11] a component of kidney injury that was induced by dietary acid and ameliorated by dietary alkali and by diets containing base-inducing protein in animals with moderately[6,7] and severely[23] reduced GFR. Similarly, dietary alkali ameliorated UNAG in subjects with CKD due to hypertensive nephropathy with moderately[4] and severely[24] reduced eGFR. The UNAG data support that neither F+V nor NaHCO3 decreased tubulo-interstitial injury in CKD 1. By contrast, UNAG data in CKD 2 support that tubulo-interstitial injury worsened after 30 days of no intervention, but that F+V and NaHCO3 each decreased tubulo-interstitial injury after 30 days. Unlike Ualb, net UNAG decrease was not significantly different between CKD 2 given NaHCO3 and F+V. These latter data support that dietary acid reduction was the greater contributor to decreased tubulo-interstitial injury in CKD 2 than Sys BP reduction, and further support the greater role of acid retention in mediating tubulo-interstitial injury.

UTGF, a possible mediator of hypertensive nephropathy,[12] decreased significantly among all three CKD 1 groups and the net decrease was not significantly different among groups. These data suggest that dietary acid reduction had no measurable UTGF effect in CKD 1, and that lower Sys BP in F+V compared with the remaining CKD 1 groups also did not additionally affect UTGF. Because all groups underwent 6 months of aggressive BP reduction before entering the protocol,[25] sustained effects of this BP reduction might have reduced UTGF similarly in all three CKD 1 groups.[26] Similar to UNAG, UTGF increased in CKD 2 without intervention but UTGF decreased significantly in CKD 2 patients given NaHCO3 and F+V, and the net UTGF decrease between the two interventions to reduce dietary acid was not different. These latter data support the fact that reduced dietary acid decreased UTGF and, similar to the data described for UNAG, the lower Sys BP in CKD 2 given F+V compared with NaHCO3 appears not to have been additive after 30 days. Dietary acid reduction decreased Ualdo in humans with moderately reduced eGFR in this and previous studies,[14] and did so in animals with moderately reduced GFR.[7] Because aldosterone increases UTGF in animals,[27] reduced kidney aldosterone might mediate decreased UTGF in response to dietary acid reduction. Furthermore, because there was no significant difference in net UTGF decrease among CKD 1, because UTGF increased without intervention in CKD 2 but not in CKD 1, and because the net decrease in UTGF was not significantly different after dietary acid reduction with F+V and HCO3 in CKD 2, despite Sys BP reduction in F+V but not HCO3, the data support that acid retention present in CKD 2, and not in CKD 1,[14] more importantly mediates increased UTGF in CKD 2 than Sys BP.

Both dietary acid reduction interventions decreased UET and Ualdo in CKD 2 but not in CKD 1. Because UET and Ualdo are respective surrogates of their kidney levels in animals with and without reduced GFR,[7,22] these data support the fact that dietary acid reduction decreased kidney ET-1 and aldosterone levels in CKD 2 but not in CKD 1. Because the increased kidney ET-1 and aldosterone levels in animals with reduced GFR are mediated by retained acid due to decreased GFR[7,13] and CKD 2 subjects appear to have retained acid,[14] these data support the fact that decreased retained acid mediated the decrease in UET and Ualdo induced by dietary acid reduction. Given that endothelins and aldosterone mediate kidney injury in animals with reduced GFR and that decreasing their levels ameliorates kidney injury,[7,22] decreased kidney ET-1 and aldosterone levels likely contributed to the reduction in kidney injury associated with reduced dietary acid.

Table 3 shows that although the net UET decrease was similar between CKD 2 subjects given NaHCO3 and F+V, Ualdo decrease was statistically significantly greater in CKD 2 patients given NaHCO3 than in those given F+V. Although each intervention reduced dietary acid as evidenced by reduced urine NAE, the NaHCO3 intervention was accompanied by increased Na+ intake without additional K+ intake. On the other hand, the F+V intervention was accompanied by reduced Na+ intake and increased K+ intake. These two factors would be expected to promote greater Ualdo reduction in NaHCO3 than in F+V. The greater Ualdo reduction in NaHCO3 versus F+V subjects might be expected to lead to greater reduction in kidney injury in NaHCO3 versus F+V CKD 2 subjects, given animal studies that support a role for aldosterone, in addition to ET-1, in mediating kidney injury and GFR decline in animals with partial nephrectomy.[7] Nevertheless, and as indicated earlier, changes in the three parameters of kidney injury support comparable reduction of kidney injury in CKD 2 subjects given NaHCO3 and F+V. The observation that greater Ualdo reduction induced by NaHCO3 than F+V was not accompanied by a greater reduction of kidney injury parameters in CKD 2 subjects given NaHCO3 might be explained, at least in part, by stable Sys BP during the 1-month follow-up in the NaHCO3 subjects as compared with a significant reduction in Sys BP in the F+V subjects. Consequently, CKD2 subjects given NaHCO3 might have had a greater decrease in kidney injury parameters if their Sys BP was similarly reduced. On the other hand, greater kidney injury reduction might become evident in the CKD 2 subjects given NaHCO3 with a longer follow-up. Additional and longer-term studies will be needed to address this issue.

In summary, these studies support the fact that kidney injury increased without dietary acid reduction and show that 30 days of dietary acid reduction with NaHCO3 or F+V reduced kidney injury in subjects with CKD stage 2 eGFR due to hypertensive nephropathy. The present studies also show that F+V, but not NaHCO3, reduced Sys BP, suggesting a possible advantage of F+V as a strategy to reduce dietary acid for kidney protection. These studies encourage longer-term studies to determine whether F+V, similar to NaHCO3, is an effective adjunct to Sys BP reduction and angiotensin-converting enzyme inhibition in slowing GFR decline in hypertensive and possibly other nephropathies.

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