Soy-based renoprotection

Table 2 Chronic controlled intervention studies of soy protein and kidney function

Ref.	Study design	Kidney function	Subjects/group	Amount of soy protein used	Control/comparator protein	Duration of intervention	Outcomes	Notes
Liu et al[128]	RC	Pre-hypertensive PM women	90 subjects/group (85, 87 and 81 completed study in the soy, daidzein and placebo groups, respectively)	40 g soy flour/d, 12.8 g soy protein/d	40 g lowfat milk powder (placebo) or 40 g lowfat milk powder with 63 mg/d daidzein	6 mo	No significant changes in most renal parameters were observed between groups	All subjects were equol producers
							Soy flour intake resulted in less decrease in eGFRCockcroft (P = 0.044) and % change in eGFR (P = 0.031) after 6 mo compared to the milk placebo group (P = 0.044)
							Effect of soy flour consumption to increase eGFR was greater in women with higher initial plasma cystatin C concentrations (Cys-C > 1.14 mg/L) (P = 0.001 for eGFRCockcroft) compared to milk placebo
Ahmed et al[131]	RC	Glomerulo-pathy with proteinuria (non-diabetic)	9 subjects/group,	0.8 g/kg per day soy protein	0.8 g/kg per day an animal protein or 0.8 g/kg per day a soy protein + fiber	8 wk	No significant changes in anthropometric measures, serum lipids or proteinuria between diet groups	Significant decreases from baseline in overall energy and protein intake in all groups confounds end of study comparisons
			total 27 subjects (4M, 23F)
Soroka et al[129]	RC	Non-diabetic, non-nephrotic CRF patients (urinary protein excretion < 3 g/d)	9 completed study (5M, 4F)	0.71 g/kg BW protein, mostly soy protein with egg (VPD)	0.85 g/kg per day APD (1:1, animal sources:grains)	6 mo	No difference in renal function between groups seen; both groups saw reduction in rate of GFR decline	High dropout and small number of subjects
							BUN, Urinary N excretion, PCR, 24 h urinary creatinine and phosphate were lower in VPD group	Differences in total energy and protein intake in VPD and APD
D’Amico et al[102], Gentile et al[103]	RC	Non-diabetic, nephrotic patients with proteinuria > 2.5 g/24 h for a mean of 24 mo and HC	20 subjects (9M, 11F)	Protein intake at end of study was calculated from urinary urea excretion to be 1.16 ± 0.04 g/kg per day (98% of this estimated to be soy protein)	Soy protein used in both experimental arms of study; baseline diet was comparator	8 wk for each arm (baseline diet, soy ± 5 g/d fish oil in random order) followed by WO for 3 mo on baseline diet)	Soy diet significantly reduced TC, LDL-C, HDL-C, apoB (P < 0.0001) and apoAI (P < 0.01) compared to baseline; TGs were unaffected; lipids tended towards baseline values after WO	Both diet interventions resulted in modest decrease in BW and BMI (-4%) which was significantly different from baseline; both values tended towards baseline during WO
							Addition of 5 g/d fish oil to soy diet resulted in significant elevation of TC and apoB compared to soy diet alone (P < 0.01)
							Urinary protein, urea, P, Na and creatinine excretion was significantly decreased by both diet interventions (P < 0.01); measures tended towards baseline after WO
							Blood glucose was significantly reduced by both diet interventions (P < 0.01) however soy diet alone reduced blood glucose more than soy diet and fish oil (P < 0.01)
Anderson et al[97]	RC	T2D with proteinuria, obese, and HTN	8 M	1.0 g/kg per day protein, 50% soy protein in soy test diet	1.0 g/kg per day protein, 50% ground beef in animal test diet	8 wk, 4 wk WO	TC and TG decreased by soy diet (P < 0.05) vs animal protein diet	Low number of subjects
							SUN sig decreased by soy protein (P < 0.05)
							Change in GFR similar with both diets
							Urine protein excretion increased by soy vs animal protein diet (P = 0.028)
Azadbakht et al[98]	RP	T2D subjects with nephropathy, proteinuria, HTN	41 subjects: 18 M, 23 F	0.8 g/kg per day protein, 35% soy protein (textured soy protein), 35% animal protein, 30% vegetable protein	0.8 g/kg per day protein, 70% animal and 30% vegetable protein	4 yr	Decreased FPG in soy group (P = 0.03
							Soy protein group decreased TC (P < 0.01), LDL-C (P = 0.01) and TG (P = 0.01
							Serum CRP decreased (P = 0.02) on soy protein diet
							Soy protein diet reduced proteinuria (P = 0.001) and urinary creatinine (P = 0.01)
Miraghajani et al[108,113]	RC	T2D subjects with nephropathy	25 subjects completed the study (10 M, 15 F)	2.5 g soy protein (240 mL soymilk/d)	3.3 g cow milk protein (240 mL milk/d)	4 wk interventions with 2 wk WO	Soy protein consumption resulted in a significant difference in % change of fibrin D-dimer concentrations compared to milk protein (P = 0.04); there were no differences in % changes in TNFα, IL-6, CRP, MDA or fibrinogen concentrations between groups	Amount of soy protein used in diet intervention was low
							Soy protein consumption resulted in significant decrease in systolic BP compared to cow milk protein (-4.50% vs + 5.89%, P = 0.02)
Teixeira et al[106]	RC	T2D subjects with nephropathy	14 male subjects	0.5 g/kg per day soy protein (Approximately equal 50% of total daily intake)	0.5 g/kg per day casein	8 wk interventions with 4 wk WO	Urinary albumin-creatinine ratio was significantly reduced by ISP (P < 0.0001) and increased by casein (P = 0.002)
							Change in urinary albumin-creatinine ratio correlated inversely with plasma isoflavone levels (P = 0.012)
							CrCl did not change (GFR) with either diet
							HDL-C was increased after ISP (P = 0.0041) while it tended to be lower after casein (P = 0.0847)
							TC and LDL-C not changed by either diet
							Total and glycated hemoglobin did not change in either group
							No differences in BP between groups; however soy diet resulted in higher plasma arg/lys ratios (P = 0.0097) which persisted after fasting
Stephens et al[104]	RC	T1D subjects with hyper-filtration GFR > 120 mL/min/1.73 m2	12 subjects completed study (6 M, 6 F 0)	45-55 g/d soy protein to substitute for animal protein in control diet	45-55 g/d animal protein	8 wk interventions; no WO	GFR sig lower in soy group vs control group (P = 0.02)	No washout between interventions
							Excretion of urinary creatinine, urea and Na not diff between groups
							Microalbuminuria within normal ranges and unaffected by diet
							TC and LDL-C significantly reduced in soy group (P < 0.02, 0.05, respectively) whereas TG and HDL-C not diff between groups
							Serum glucose was not affected by soy protein diet but was significantly increased on the control diet (P < 0.05) compared to baseline
							Serum albumin did not change but total serum protein decreased in soy group (P < 0.05)
Chen et al[101]	RP	Nondiabetic hemodialysis patients	Soy group: 10 HL (7 F, 3 M) and 8 NL (6 F, 2 M)	30 g/d soy protein	30 g/d milk protein	12 wk	No significant differences between groups in serum nutritional parameters or hemodialysis adequacy	Test proteins consumed on top of usual hemodialysis diet
							TC and TG decreased in HL subjects consuming soy vs milk protein over time (P < 0.05 at 12 wk)
			Control group: 9 HL (7 F, 2 M) and 10 NL (7 F, 3 M)				Non-HDL-C, apoB, TC/HDL-C ratio and insulin decreased in HL subjects consuming soy vs milk protein at 12 wk (P < 0.05)
							Non-significant differences between protein groups in NL subjects
							Soy protein resulted in significant decrease in fasting insulin in NL group at 12 wk compared to values at baseline (P < 0.05)
Chen et al[100]	RP	Non-diabetic hemodialysis patients with HC	Soy group: 13 (9 M, 4 F)	30 g/d soy protein	30 g/d milk protein	12 wk	No significant differences between groups in serum nutritional parameters or hemodialysis adequacy	Not clear if some of the subject are the same as reported in Chen et al[101] as study protocols are the same
			Milk group: 13 (10 M, 3 F)				TC, non-HDL-C, apoB, TC/HDL-C and LDL-C/HDL-C ratios decreased in subjects consuming soy vs milk protein at 12 wk (P < 0.05)
							No differences in TG between soy and milk groups
							Soy protein resulted in significant decrease in fasting insulin at 12 wk compared to milk protein group (P < 0.05)
Imani et al[110]	RP	PD patients	18 subjects	14 g soy protein at dinner each day	Meat instead of soy protein at dinner	8 wk	Soy protein diet resulted in significant 17% reduction in plasma coagulation factor IX activity compared to control group (P < 0.05)	Study was not blinded
			Soy group (9 M, 9 F),				No significant changes in oxLDL, P, fibrinogen or activities of coagulation factors VII and X between groups	Mean energy and protein intakes were less than recommended amounts (30 kcal/kg per day and 1.2 g/kg per day, respectively) which is common among PD patients
			Control group (9 M, 9 F)
Fanti et al[112]	RP	ESRD patients on chronic HD with elevated CRP (> 10 mg/L)	Soy group = 15; control milk group = 10	25 g/d	25 g/d milk protein	8 wk	5 to 10-fold increase in mean serum IF concentration in soy group at end of study (P < 0.001)	Small number of subjects
							No significant change in CRP between groups, however, significant inverse correlation of CRP with IF concentration	Test proteins provided as beverages, a cereal-type product and as snack bar
							Significant positive correlation of serum IF concentration and serum albumin and IGF-1
Siefker et al[109]	RP	HD patients	17 subjects	25 g soy protein (4 times per week)	Whey protein (exact amount not specified); provided 4 times per week	4 wk	No difference between groups on serum markers of renal function except creatinine; whey protein showed a significant decrease in creatinine from baseline (P < 0.05) whereas there was no change in the soy protein group from baseline	Small number of subjects
			8 subjects on soy protein diet; 9 on whey protein				oxLDL was significantly decreased after soy protein consumption (P < 0.05) compared to baseline; the % change in oxLDL compared to the whey group was significantly different (P < 0.05)
							No differences in plasma concentrations of 8-iso-PGF2α, TNFα, or CRP between diet groups
Tomayko et al[114]	RP	MHD patients	Soy group = 12	27 g/d soy protein	27 g whey protein or noncaloric placebo powder (2 g Crystal Light)	6 mo	A significant time x treatment effect for IL-6 levels (P = 0.036) with both whey and soy protein groups decreasing compared to control group	First study to observe improvements in inflammation and physical function after intradialytic nutritional support in MHD patients with serum albumin ≥ 3.9 g/dL (i.e., not malnourished)
			Whey group = 11				Soy diet resulted in a significant decrease in neutrophil-lymphocyte ratio (systemic inflammation marker) compared to control or whey diet (P = 0.02)
			Placebo control = 15				Alkaline phosphatase, a marker of bone turnover, was increased in the control diet compared with both protein diet groups (P = 0.04)
							A significant time by treatment interaction was seen for gait speed when all 3 groups analyzed (P = 0.048); both soy and whey groups indicated improved gait speed while control diet had a decline
							Shuttle walk test time was significantly improved in the whey group (P < 0.05) and when protein groups were combined (P < 0.05) versus the control group; shuttle walk test time was increased in the soy group but was not significant compared to the control group (which had decreased test times)

8-iso-PGF2: 8-iso-prostaglandin F2; APD: Animal protein diet; BP: Blood pressure; BW: Body weight; CrCl: Creatinine clearance; CRF: Chronic renal failure; CRP: C-reactive protein; eGFR: Estimated glomerular filtration rate; FPG: Fasting plasma glucose; F: Female; GFR: Glomerular filtration rate; GS: Glomerulosclerosis; HC: Hypercholesterolemia; HD: Hemodialysis; HL: Hyperlipidemic; HTN: Hypertension; HDL-C: High density lipoprotein cholesterol; IF: Isoflavones; IL-6: Interleukin-6; LDL-C: Low density lipoprotein cholesterol; M: Male; MDA: Malondialdehyde; MHD: Maintenance hemodialysis; Na: Sodium; NL: Normolipidemic; oxLDL: Oxidized LDL; P: Phosphorus; PD: Peritoneal dialysis; PM: Postmenopausal; RC: Randomized crossover trial; RP: Randomized parallel trial; SUN: Serum urea nitrogen; T1D: Type 1 diabetes; T2D: Type 2 diabetes; WO: Washout; TC: Total cholesterol; TG: Triglycerides; TNF: Tumor necrosis factor; VPD: Vegetable protein diet; ISP: Isolated soy protein; ESRD: End-stage renal disease.