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Dietary Potassium in Chronic Kidney Disease: Do Not Restrict the Evidence

Published:March 12, 2021DOI:https://doi.org/10.1053/j.jrn.2020.12.012
      Dear Editors,
      With interest we read the systematic review and meta-analysis by Morris et al.
      • Morris A.
      • Krishnan N.
      • Kimani P.K.
      • Lycett D.
      Effect of dietary potassium restriction on serum potassium, disease progression, and mortality in chronic kidney disease: a systematic review and meta-analysis.
      which concluded that dietary potassium (K+) restriction in patients with chronic kidney disease (CKD) is associated with a 0.22 mEq/L decrease in serum K+ and 40% lower mortality hazard, but not with progression of CKD. However, we would like to raise 2 points of concern, including (1) a discrepancy between the results of the meta-analyses and the original studies and (2) an overestimation of the effect of dietary K+ restriction on serum K+.
      The meta-analysis in which Morris et al. analyzed the association between urinary K+ excretion (UK, as proxy for dietary K+ intake) and mortality included 4 studies. The hazard ratios calculated from the studies by He et al.,
      • He J.
      • Mills K.T.
      • Appel L.J.
      • et al.
      Urinary sodium and potassium excretion and CKD progression.
      Leonberg-Yoo et al.,
      • Leonberg-Yoo A.K.
      • Tighiouart H.
      • Levey A.S.
      • Beck G.J.
      • Sarnak M.J.
      Urine potassium excretion, kidney failure, and mortality in CKD.
      and Eisenga et al.
      • Eisenga M.F.
      • Kieneker L.M.
      • Soedamah-Muthu S.S.
      • et al.
      Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients.
      were all <1 and therefore favored dietary K+ restriction. All 3 original studies, however, reported the opposite association. Leonberg-Yoo et al. and Eisenga et al. showed that UK < reference was significantly associated with a greater risk of all-cause mortality (hazard ratios of 1.5-1.7 and >2, respectively).
      • Leonberg-Yoo A.K.
      • Tighiouart H.
      • Levey A.S.
      • Beck G.J.
      • Sarnak M.J.
      Urine potassium excretion, kidney failure, and mortality in CKD.
      ,
      • Eisenga M.F.
      • Kieneker L.M.
      • Soedamah-Muthu S.S.
      • et al.
      Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients.
      He et al. used the lowest UK quartile as reference and showed in the fully adjusted model that all-cause mortality was lower in all higher quartiles, although this was not statistically significant.
      • He J.
      • Mills K.T.
      • Appel L.J.
      • et al.
      Urinary sodium and potassium excretion and CKD progression.
      The meta-analysis by Morris et al. on urinary K+ and CKD progression showed a hazard ratio >1 for He et al. (favors no restriction) and <1 for Eisenga et al. (favors restriction). Again, the original studies showed the opposite association: He et al. showed that UK > reference increased the risk of CKD progression (hazard ratios 1.0-1.6),
      • He J.
      • Mills K.T.
      • Appel L.J.
      • et al.
      Urinary sodium and potassium excretion and CKD progression.
      whereas Eisenga et al. showed that UK < reference increased the risk of CKD progression (hazard ratios >3.4).
      • Eisenga M.F.
      • Kieneker L.M.
      • Soedamah-Muthu S.S.
      • et al.
      Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients.
      It is also unclear why some studies were excluded from this meta-analysis. The inclusion criteria reported “any stage CKD,” but the analysis of the ONTARGET and TRANSCEND trials was not included, while this study also included a subgroup with eGFR <60 mL/min/1.73m2.
      • Smyth A.
      • Dunkler D.
      • Gao P.
      • et al.
      The relationship between estimated sodium and potassium excretion and subsequent renal outcomes.
      Participants with CKD were also present in other cohorts with baseline eGFR 60-90 mL/min/1.73m2 and albuminuria,
      • Araki S.
      • Haneda M.
      • Koya D.
      • et al.
      Urinary potassium excretion and renal and cardiovascular complications in patients with type 2 diabetes and normal renal function.
      which would classify as CKD Stage G2 A1-A3. Another question is why studies using a spot urine K+ to creatinine ratio or food frequency questionnaires to assess dietary K+ intake were excluded. These considerations are relevant, because at present the majority of available studies shows that higher dietary K+ is associated with better kidney outcomes.
      • Gritter M.
      • Rotmans J.I.
      • Hoorn E.J.
      Role of dietary K+ in natriuresis, blood pressure reduction, cardiovascular protection, and renoprotection.
      A placebo-controlled, double-blind randomized clinical trial is currently investigating whether K+ supplementation slows CKD progression.
      • Gritter M.
      • Vogt L.
      • Yeung S.M.H.
      • et al.
      Rationale and design of a randomized placebo-controlled clinical trial assessing the renoprotective effects of potassium supplementation in chronic kidney disease.
      Our second concern is the time points that were selected to analyze the association between dietary K+ and serum K+. Morris et al. included 2 randomized controlled trials and found that restricted dietary K+ intake (33 mEq/day) reduced serum K+ by 0.22 mEq/L in comparison to “liberal” dietary K+ intake (40 mEq/day). In both studies serum K+ was measured at multiple time points, but only the time points with the greatest differences in serum K+ were included in the meta-analysis. In the study by Arnold et al.,
      • Arnold R.
      • Pianta T.J.
      • Pussell B.A.
      • et al.
      Randomized, controlled trial of the effect of dietary potassium restriction on nerve function in CKD.
      the difference at 6 months was used (0.5 mEq/L), whereas at 24 months this difference was less prominent (0.2 mEq/L). In the study by Cockram et al.,
      • Cockram D.B.
      • Hensley M.K.
      • Rodriguez M.
      • et al.
      Safety and tolerance of medical nutritional products as sole sources of nutrition in people on hemodialysis.
      the difference in serum K+ at day 22 was selected (−0.3 vs. −0.5 mEq/L), whereas no differences at days 8 and 15 were observed (0 vs. 0.1 and −0.4 vs. −0.3 mEq/L). A related question is how representative the 2 studies are for dietary K+ intake, because one study used extremely low K+ liquid diets,
      • Cockram D.B.
      • Hensley M.K.
      • Rodriguez M.
      • et al.
      Safety and tolerance of medical nutritional products as sole sources of nutrition in people on hemodialysis.
      whereas in the other study ∼50% of subjects combined a low K+ diet with K+ binders, which also lower serum K+.
      • Arnold R.
      • Pianta T.J.
      • Pussell B.A.
      • et al.
      Randomized, controlled trial of the effect of dietary potassium restriction on nerve function in CKD.
      Finally, the K+ content of the diet that was classified as liberal intake was still 2-3 times lower than current recommendations. According to a cross-sectional analysis of 3,893 patients with CKD Stage G3b or G4, lowering dietary K+ intake from 40 to 33 mEq/day would lower serum K+ by only 0.02 mEq/L.
      • Gritter M.
      • Vogt L.
      • Yeung S.M.H.
      • et al.
      Rationale and design of a randomized placebo-controlled clinical trial assessing the renoprotective effects of potassium supplementation in chronic kidney disease.
      Similarly, Noori et al.
      • Noori N.
      • Kalantar-Zadeh K.
      • Kovesdy C.P.
      • et al.
      Dietary potassium intake and mortality in long-term hemodialysis patients.
      showed that in 224 hemodialysis patients, predialysis serum K+ was only 0.1 mEq/L higher when comparing the lowest to the highest quartile of K+ intake (23 vs. 88 mEq/day).
      In conclusion, we challenge the conclusion by Morris et al. that dietary K+ restriction is associated with a reduced risk of death in patients with CKD and conclude that the relationship between dietary K+ and serum K+ was overestimated.

      References

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        • Mills K.T.
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        • Kieneker L.M.
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        Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients.
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        • Haneda M.
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        Urinary potassium excretion and renal and cardiovascular complications in patients with type 2 diabetes and normal renal function.
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        • Cockram D.B.
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      Linked Article

      • Dietary Potassium in Chronic Kidney Disease: High Quality Evidence Is Still Needed
        Journal of Renal NutritionVol. 31Issue 6
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          We published a meta-analysis which considered the strength of the current evidence for restricting dietary potassium in chronic kidney disease (CKD).1 We thank Visser et al.2 for their comments and for taking the time to pay such close attention to our results. We have reviewed our analysis in light of these and have found 2 errors. The labeling of the forest plots (Figs. 3 and 4) is incorrect, “Favors no restriction” should be “Favors restriction” and vice versa. In our meta-analysis, we inserted a negative figure, when it should have been positive in Noori et al.
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