First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease
Abstract
:1. Introduction
2. Historical Background of Low-Protein Diet Recommendations
3. Effectiveness and Safety of Low-Protein Diets
3.1. Effectiveness of Low-Protein Diets in 18 Studies Cited by Kalantar-Zadeh et al.
3.2. Effectiveness of Low-Protein Diets in Nine Studies Cited in the KDIGO 2020
3.3. Reviewing Randomized Clinical Trial Meta-Analyses
3.4. Considering the Safety of Low-Protein Diets
4. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Appendix A
References
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CKD Stage | Normal Kidney Function with Increased CKD Risk | Mild-to-Moderate CKD | Advanced CKD | Transition to Dialysis | Ongoing Dialysis | Any Stage with PEW |
CKD stage (mL/min/1.73 m2) | eGFR ≥ 60 with CKD risk | 60 > eGFR ≥ 30 | 30 > eGFR or proteinuria > 0.3 g/day | |||
Daily protein intake (g/kg) | <1.0 | <1.0 | 0.6–0.8 including 50% HBV, or <0.6 with EAA or KA | 0.6–0.8 on non-dialysis days and > 1.0 on dialysis days | 1.2–1.4 | >1.5 |
Other considerations | Increased proportion of plant-based protein | Consider 0.6–0.8 if eGFR < 45 |
First Author | Reference Numbers | Patients | Intervention (Daily Protein Intake) | Comparison | Outcome | Results |
---|---|---|---|---|---|---|
Rosman | [20] | Ccr 10–60 mL/min n = 228 non-DM | 0.6 g (CKD3), 0.4 g (CKD4–5) | Usual Protein | SCr10% elevation at 2 years | ○ 40% vs. 75% (CKD 3) ○ 50% vs. 97% (CKD 4–5) |
Rosman | [21] | Ccr 10–60 mL/min n = 248 non-DM | 0.6 g (CKD3), 0.4 g (CKD4–5) | Usual Protein | Ccr decline | ▲ −0.28 vs. −0.31 (CKD 3) ○ −0.16 vs. −0.20 (CKD 4–5) |
Ihle | [22] | Cr 4–11 mL/min CKD, n = 64 non-DM | 0.4 g | Usual Protein | ESRD | ○ 2/31 vs. 9/33 |
Lindenau | [23] | Ccr < 15 mL/min, n = 40 no description of primary renal disease | 0.4 g + keto acids | 0.6 g | Bone biopsy | ○ keto acids reduce bone fibrotic change |
Williams | [24] | SCr > 1.70 (Male), > 1.47 (Female) mg/dL, n = 95 12/95 (12.6%) were DKD | 0.6 g | 0.8 g | Ccr decline | ▲ −0.56 vs. −0.69 |
Locatelli | [14] | CKD 3–5, n = 456 non-DM | 0.6 g | 1.0 g | SCr doubling or HD | ▲ 27/226 vs. 42/230 |
Klahr | [13] | GFR 25–55 mL/min/1.73 m2, n = 585 GFR 13–24 mL/min/1.73 m2, n = 255 3% was DKD | 0.58 g in study 1 0.28 g + keto acid in study 2 | 1.3 g study 1 0.58 g study 2 | GFR decline | −3.6 vs. −4.0 −4.4 vs. −3.6 |
Montes-Delgado | [25] | CRF, n = 33 9/33 (27.3%) were DKD | 0.6 g + high energy | 0.6 g | Ccr decline | ○ 11 → 10.7 vs. 18.3 → 13.8 |
Malvy | [26] | GFR < 20 mL/min/1.73 m2, n = 50 non-DM | 0.3 g + keto acid | 0.65 g | GFR < 5 mL/min/1.73 m2 | ▲ 100% vs. 100% |
Teplan | [27] | Ccr 22–36 mL/min, n = 105 non-DM | 0.6 g + EPO + keto acid 0.6 g + EPO | 0.6 g | Ccr decline | ○−0.672 (EPO + keto acid) vs. −2.124 (control) ▲ −1.512 (EPO) vs. −2.124 (control) |
Prakash | [28] | Ccr 20–50, n = 34 20/34 (58.8%) were DKD | 0.3 g + keto acids | 0.6 g + placebo | eGFR decline | n.a. 28.1 → 27.6 vs. 28.6 → 22.5 |
Brunori | [29] | CKD 5, n = 56 non-DM | 0.3 g + keto acids | 1.2 g + HD start | Mortality | ▲ 12.7% vs. 16.3% |
Mircescu | [30] | CKD 4–5, n = 53 non-DM | 0.3 g + keto acids | 0.6 g | Urea | ▲ Urea nitrogen 73.3 → 56.5 vs. 63.0 → 67.2 |
Cianciaruso | [31] * | CKD 4–5, n = 423 12% was DKD | 0.55 g | 0.80 g | PEM, HD, GFR decline | ▲ PEM2 vs. 1, HD41 vs.42, GFR −0.19 vs. −0.18 |
Di Lorio | [32] | CKD moderate-advanced, n = 32 20/32 (62.5%) were DKD | 0.3 g + keto acids | Low protein | Proteinuria | ○ 58% reduce |
Jiang | [33] * | PD, n = 34 2/34 (5.9%) were DKD | 0.6–0.8 g/kg IBW With or without Keto acids | 1.0−1.2 | GFR decline | Without keto acids 4.0 → 2.3 vs. 4.3 → 2.6 With keto acids 3.8 → 3.4 vs. 4.3 → 2.6 |
Jiang | [34] | PD, n = 60 3/60 (5.0%) were DKD | 0.6–0.8 g/kg IBW With or without Keto acids | 1.0−1.2 | Peritoneal function | ▲ without keto acids ○ with keto acids |
Garneata | [35] | CKD 4–5, n = 207 non-DM | 0.3–0.4 g + keto acids + vegetarian | 0.6 g | HD start or GFR 50% loss | ○ 13% vs. 42% |
First Author (Year Published) | Reference Numbers | Patients | Intervention (I) (Daily Protein Intake) | Comparison (C) | GFR (mL/min/1.73 m2) or Ccr (mL/min) Decline per Year in I | GFR (mL/min/1.73 m2) or Ccr (mL/min) Decline per Year in C | Statistical Significance between Groups |
---|---|---|---|---|---|---|---|
Rosman (1989) | [21] | Ccr 10–60 mL/min n = 248 non-DM | 0.6 g (CKD 3), 0.4 g (CKD 4–5) | Usual Protein | Ccr−3.36(CKD 3) Ccr−1.92 (CKD 4–5) | Ccr−3.72 (CKD 3) Ccr−2.40 (CKD 4–5) | n.s. (CKD 3) ○ (CKD 4) |
Ihle (1989) | [22] | SCr 4–11 mg/dL, n = 64 non-DM | 0.4 g | Usual Protein | Ccr−1.8 mL/min | Ccr−6.0 mL/min | ○ |
Williams (1991) | [24] | SCr > 1.70 (Male), > 1.47 (Female) mg/dL, n = 95 12/95 (12.6%) were DKD | 0.6 g | 0.8 g | Ccr−6.72 | Ccr−8.28 | n.s. |
Locatelli (1991) | [14] | CKD 3–5, n = 456 non-DM | 0.6 g | 1.0 g | Ccr−1.8 | Ccr−1.0 | n.s. |
Klahr (1994) | [13] | GFR 25–55 mL/min/1.73 m2, n = 585 GFR 13–24 mL/min/1.73 m2, n = 255 3% was DKD | 0.58 g study 1 0.28 g + keto acid study 2 | 1.3 g study 1 0.58 g study 2 | −3.6 −3.6 | −4.0 −4.4 | n.s. n.s. |
Malvy (1999) | [26] | GFR < 20, n = 50 non-DM | 0.3 g + keto acid | 0.65 g | −3.26 | −2.89 | n.s. |
Prakash (2004) | [28] | Ccr 20–50 mL/min, n = 34 20/34 (58.8%) were DKD | 0.3 g + keto acid | 0.6 g + placebo | −2.0 | −8.1 | ○ |
Mircescu (2007) | [30] | CKD 4–5, n = 53 non-DM | 0.3 g + keto acids | 0.6 g | −3.1 | −4.9 | n.a. |
Cianciaruso (2009) | [31] | CKD 4–5, n = 423 12% was DKD | 0.55 g | 0.80 g | −2.28 | −2.16 | n.s. |
Garneata (2016) | [35] | CKD 4–5, n = 207 non-DM | 0.3–0.4 g + keto acids + vegetarian | 0.6 g | −2.9 | −7.1 | ○ |
First Author (Year Published) | Reference Number | Patients | Intervention | Comparison | Mortality | Cause of Death |
---|---|---|---|---|---|---|
Hansen (2002) | [39] | T1DM, AER > 300 mg/day, eGFR 68 ± 31 mL/min/1.73 m2, n = 82 | 0.6 g/kg | Usual protein | ○ 2/41 vs. 7/41 | Heart failure, 4; myocardial infarction, 5 |
Koya (2009) | [40] | T2DM, proteinuria > 1 g/day, eGFR 62.3 ± 25.3 mL/min/1.73 m2, n = 112 | 0.8 g/kg | 1.2 g/kg | n.s. 1/56 vs. 1/56 | Sepsis, 1; myocardial infarction, 1 |
First Author (Year Published) | Reference Number | Patients | Intervention | Comparison | GFR Decline per Year in I | GFR Decline per Year in C | Statistical Significance between Groups |
---|---|---|---|---|---|---|---|
Zeller (1991) | [41] | T1DM, proteinuria > 500 mg/day, eGFR 47.4 ± 5.8 mL/min/1.73 m2, n = 35 | 0.6 g/kg | Usual protein | −3.0 | −12.7 | ○ |
Brouhard (1990) | [42] | T1DM, albuminuria >4 3.2 mg/day, eGFR 81.1 ± 31.5 mL/min/1.73 m2, n = 15 | 0.6 g/kg | Usual protein | −18 | −25 | ○ |
Ciavarella (1987) | [43] | T1DM, Proteinuria > 500 mg/day, CCr 100.6 ± 29.6 mL/min, n = 16 | 0.71 ± 0.12 g/kg | Normal protein (1.44 ± 0.12 g/kg) | 39.6 | −10.8 | n.s. |
Dullaart (1993) | [44] | T1DM without DKD, proteinuria < 500 mg/day, GFR > 90 mL/min/1.73 m2, n = 30 | 0.79 ± 0.16 g/kg | Usual protein | −9 | −5 | n.s. (both groups showed significant reduction within group) |
Dussol (2005) | [45] | T1DM and T2DM, Micro- or macroalbuminuria, GFR 80 ± 20 mL/min/1.73 m2, n = 47 (T1DM, 10; T2DM, 37) | 0.8 g/kg | Usual protein | −3.5 | −2.5 | n.s. |
Hansen (2002) | [39] | T1DM, Albuminuria > 300 mg/day, eGFR 68 ± 31 mL/min/1.73 m2, n = 82 | 0.6 g/kg | Usual protein | −3.8 | −3.9 | n.s. |
Meloni (2002) | [46] | T1DM and T2DM, Nephropathy and HT, GFR 44.8 ± 5.7 mL/min/1.73 m2, n = 69 (T1DM, 32; T2DM, 37) | 0.6 g/kg | Usual protein | −6.15 | −6.26 | n.s. |
Raal (1994) | [47] | T1DM, proteinuria dipstick positive, GFR 58 ± 23 mL/min/1.73 m2, n = 22 | 0.8 g/kg | >1.6 g/kg | 6 | −16 | n.a. |
First Author (Year Published) | Reference Number | Trial Number | Type of Diabetes | eGFR Decline | Proteinuria or the Albumin Excretion Rate | Conclusion of the Paper | ||
---|---|---|---|---|---|---|---|---|
Results | Heterogeneity | Results | Heterogeneity | |||||
Pedrini (1996) | [49] | 5 (including 2 non-randomized study) | T1DM, n = 3 T2DM, n = 0 Mix, n = 0 Total n = 3 | Significant reduction, RR = 0.56 | n.a. | Significant reduction, RR = 0.56 | n.a. | Protein restriction is effective for slowing the progression of DKD |
Robertson (2007) | [52] | 12 (including 3 non-randomized study) | T1DM n = 7, T2DM n = 2, Mix n = 0, Total n = 9 | n.s. n.s. n.s. n.s. | not applicable | Not reported | Not reoprted | Protein restriction appears to slightly slow the progression of DKD |
Pan (2008) | [53] | 8 | T1DM n = 4, T2DM n = 2, Mix n = 2, Total n = 8 | n.s. n.s. n.s. n.s. | not applicable | n.a. n.a. n.a. significant reduction (SMD −0.69) | n.a. | Protein restriction is not associated with improvement of renal function |
Nezu (2013) | [54] | 13 | T1DM n = 6, T2DM n = 5, Mix n = 2 Total n = 13 | n.s. n.s. n.s. significant improvement 5.82 mL/min/1.73m2 | I2 = 92% | n.s. | not applicable | Protein restriction is significantly associated with improvement of diabetic nephropathy |
Zhu (2018) | [55] | 11 | T1DM n = 5, T2DM n = 4, Mix n = 2, Total n = 11 | n.s. n.s. n.s. n.s. | not applicable | n.s. | not applicable | Protein restriction is not significantly associated with improvement of renal function |
Li (2019) | [56] | 20 (including 11 for eGFR evaluation) | T1DM n = 5, T2DM n = 5, Mix n = 1, Total n = 11 | n.a. n.a. n.a. n.s. | not applicable | n.a. n.a. n.a. significant reduction (SMD −0.62) | I2 = 87.0% | No statistical difference was found in GFR between the two groups. |
Li (2020) | [57] | 9 | T1DM n = 5, T2DM n = 2, Mix n = 2, Total n = 9 | n.a. n.a. n.a. significant improvement 3.86 mL/min/1.73 m2 | I2 = 89% | n.a. n.a. n.a. significant reduction (SMD −0.88) | I2 = 90.0% | Dietary protein intake of < 0.8 g/kg was strongly associated with a slow decline in eGFR. |
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Yamada, S. First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease. Diabetology 2021, 2, 51-64. https://doi.org/10.3390/diabetology2020005
Yamada S. First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease. Diabetology. 2021; 2(2):51-64. https://doi.org/10.3390/diabetology2020005
Chicago/Turabian StyleYamada, Satoru. 2021. "First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease" Diabetology 2, no. 2: 51-64. https://doi.org/10.3390/diabetology2020005
APA StyleYamada, S. (2021). First, Do No Harm: Critical Appraisal of Protein Restriction for Diabetic Kidney Disease. Diabetology, 2(2), 51-64. https://doi.org/10.3390/diabetology2020005