Article

Dietary Protein and Potassium, Diet–Dependent Net

LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

Acid Load, and Risk of Incident Kidney Stones

Pietro Manuel Ferraro,* Ernest I. Mandel,† Gary C. Curhan,†‡ Giovanni Gambaro,* and Eric N. Taylor‡§

Abstract
Background and objectives Protein and potassium intake and the resulting diet–dependent net acid load may
affect kidney stone formation. It is not known whether protein type or net acid load is associated with risk of
*Division of
kidney stones. Nephrology,
Fondazione
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024

Design, setting, participants, & measurements We prospectively examined intakes of protein (dairy, nondairy Policlinico
animal, and vegetable), potassium, and animal protein-to-potassium ratio (an estimate of net acid load) and risk Universitario
“A. Gemelli”, Catholic
of incident kidney stones in the Health Professionals Follow-Up Study (n=42,919), the Nurses’ Health Study I University of the
(n=60,128), and the Nurses’ Health Study II (n=90,629). Multivariable models were adjusted for age, body mass Sacred Heart, Rome,
index, diet, and other factors. We also analyzed cross-sectional associations with 24-hour urine (n=6129). Italy; †Renal Division,
Department of
Results During 3,108,264 person-years of follow-up, there were 6308 incident kidney stones. Dairy protein was Medicine and
‡
Channing Division of
associated with lower risk in the Nurses’ Health Study II (hazard ratio for highest versus lowest quintile, 0.84; 95% Network Medicine,
confidence interval, 0.73 to 0.96; P value for trend ,0.01). The hazard ratios for nondairy animal protein were Department of
1.15 (95% confidence interval, 0.97 to 1.36; P value for trend =0.04) in the Health Professionals Follow-Up Study and Medicine, Brigham
1.20 (95% confidence interval, 0.99 to 1.46; P value for trend =0.06) in the Nurses’ Health Study I. Potassium intake and Women’s
Hospital, Harvard
was associated with lower risk in all three cohorts (hazard ratios from 0.44 [95% confidence interval, 0.36 to 0.53] Medical School,
to 0.67 [95% confidence interval, 0.57 to 0.78]; P values for trend ,0.001). Animal protein-to-potassium ratio was Boston,
associated with higher risk (P value for trend =0.004), even after adjustment for animal protein and potassium. Massachusetts; and
§
Higher dietary potassium was associated with higher urine citrate, pH, and volume (P values for trend ,0.002). Division of
Nephrology and
Transplantation,
Conclusions Kidney stone risk may vary by protein type. Diets high in potassium or with a relative abundance of Maine Medical
potassium compared with animal protein could represent a means of stone prevention. Center, Portland,
Clin J Am Soc Nephrol 11: 1834–1844, 2016. doi: 10.2215/CJN.01520216 Maine

Correspondence:
Dr. Pietro Manuel
Introduction available on the risk of stones associated with intakes Ferraro, Division of
Although protein intake is thought to be an important of different types of animal protein (i.e., dairy versus Nephrology,
risk factor for kidney stone formation, evidence is nondairy) or vegetable protein. Fondazione
Policlinico A.
limited. Higher animal protein intake may result in Data on the association between intake of potassium, a Gemelli, Catholic
increased urinary excretion of calcium and uric acid marker of dietary intake of organic anion, and risk of University of the
and reduced citrate and urine pH, thus potentially stones also are inconclusive. Higher dietary potassium Sacred Heart, 00168
favoring formation of calcium oxalate and uric acid intake would decrease urinary excretion of calcium, thus Rome, Italy. Email:
stones (1,2). However, relatively few studies have ex- pietromanuel.
potentially protecting against stone formation (7). To
[email protected]
amined associations between animal protein intake date, no trial has examined the effect of a diet rich in
and risk of actual kidney stones. In one randomized fruits and vegetables (a major dietary source of potas-
trial, the risk of recurrence in calcium oxalate stone sium) on the risk of stones; however, potassium citrate
formers with lower animal protein intake was not has been shown to be effective in reducing recurrence in
significantly different from the control group with stone formers (8). Higher potassium intake has been
higher animal protein intake (3), but the study was associated with lower risk of kidney stones in the
limited by the high dropout rate (46%). Observational NHS I and the HPFS but not in the NHS II (4–6).
studies also have reported conflicting results; in par- The balance between protein and potassium intake
ticular, previous analyses of the association between from diet also might be important with regard to risk
animal protein and risk of stones in the Nurses’ of forming kidney stones. These two factors are major
Health Study I (NHS I) and the Nurses’ Health Study determinants of net endogenous acid production
II (NHS II) cohorts showed no association (4,5), and (NEAP), with acid production from sulfur–containing
a positive association in the Health Professionals amino acids from protein counterbalanced by bicar-
Follow-Up Study (HPFS) was only in men with a body bonate generation from alkali–containing potassium
mass index (BMI) ,25 kg/m2 (6). To date, no data are salts (9). Higher estimated NEAP values have been

1834 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 October, 2016
 Clin J Am Soc Nephrol 11: 1834–1844, October, 2016 Protein, Potassium, Acid Load, and Stones, Ferraro et al. 1835

associated with higher urinary calcium and lower citrate the work by Frassetto et al. (9), which is also highly corre-
excretion (10,11), and cross-sectional studies have de- lated with renal net acid excretion (r=0.84).
scribed higher dietary acid load among stone formers
(12); however, the association between dietary net acid
Assessment of Kidney Stones
load and incident kidney stones has not been analyzed Participants who reported the occurrence of a kidney
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq

in longitudinal prospective studies. stone on the biennial questionnaire were asked to com-
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

We analyzed prospective associations between intake of plete a supplementary questionnaire to establish the date
different types of protein (vegetable, dairy, and nondairy of occurrence and accompanying symptoms. For this anal-
animal), intake of potassium, and the interaction between ysis, only kidney stones accompanied by pain and/or
animal protein and potassium intake and risk of incident hematuria were considered; those participants reporting a
kidney stones in three large cohort studies. new stone event without accompanying pain or hematuria
were censored. Evaluation of medical records among 582
participants from the HPFS, 194 participants from the NHS I,
Materials and Methods and 858 participants from the NHS II who reported a kidney
Study Populations
stone confirmed the diagnosis in 95%, 96%, and 98% of
The HPFS was established in 1986 with the enrollment
patients, respectively.
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024

of 51,529 men who were health professionals (dentists,

optometrists, osteopaths, pharmacists, podiatrists, and
veterinarians) between the ages of 40 and 75 years old. Assessment of Other Covariates
The NHS I was established in 1976 with the enrollment of Information on age, BMI, history of diabetes, history of
121,700 women who were registered nurses between the hypertension, use of thiazides, and amount of calcium
ages of 30 and 55 years old, and the NHS II was established supplements was obtained from the biennial questionnaire.
in 1989 with the enrollment of 116,430 women who were Self-reported weight, used to calculate BMI, was validated
registered nurses between the ages of 25 and 42 years old. in the HPFS and the NHS I cohorts (17).
At enrollment, participants from each cohort completed a
questionnaire with detailed information on diet, medical Assessment of Urinary Composition
history, and medications. Participants subsequently were Twenty-four–hour urine samples were collected in three
followed with biennial questionnaires including updated cycles. In the first cycle, participants were eligible if they
information and newly diagnosed diseases. were #70 years of age in the HPFS or #65 years of age in
For this analysis, follow-up was started in 1986 for the the NHS I and had no history of cancer or cardiovascular
HPFS and the NHS I and 1991 for the NHS II (the dates of disease. In the second cycle, participants were eligible if
the first detailed food frequency questionnaire [FFQ]) and they were #75 years of age and had no history of cancer
went until the latest available information on confirmed (other than nonmelanoma skin cancer). The third cycle
incident stones: January of 2012 for the HPFS, May of 2006 was performed only by the participants in the NHS II,
for the NHS I, and May of 2011 for the NHS II. We only with the following criteria: age #55 years old, white
included participants without a history of kidney stones at race, and no history of high BP, coronary heart disease,
baseline; furthermore, participants with a history of ma- or cancer. Urine samples collected in the first two cycles
lignancy (except for nonmelanoma skin cancer) at baseline were analyzed with the system provided by Mission Phar-
were excluded, and those who developed malignancies macal (San Antonio, TX), whereas the samples collected in
during follow-up were censored. For the NHS I, only partic- the third cycle were analyzed by the Litholink Corporation
ipants who answered questionnaires in 1992 (the year of the (Chicago, IL). Participants with a history of kidney stones
first lifetime kidney stone history inquiry) or later were were oversampled in the first two cycles.
included. Participants with possible over- or undercollections (de-
fined as urinary creatinine excretion in the top or bottom
Assessment of Diet 1% of the nonstone-formers distribution) were removed
In 1986 (the HPFS and the NHS I) and 1991 (the NHS II), from the analysis. For participants who provided more
participants completed an FFQ asking about the average than one collection, the first sample was analyzed.
annual intake of .130 foods and 22 beverages; subse-
quently, the information was updated through FFQs every Statistical Analyses
4 years. Frequencies of consumption of each unit of food The analysis of kidney stone risk was prospective;
were used to compute intakes of nutrients using data from dietary intakes were assessed before the incident kidney
the US Department of Agriculture, except for oxalate con- stone. For each cohort, participants were divided into
tent, which was measured by capillary electrophoresis in quintiles of intakes, and time at risk was calculated as time
the majority of foods from the FFQ (13,14). All nutrients from start of follow-up to an incident kidney stone, loss to
were energy adjusted to account for total amount of food follow-up, death, or censoring (whichever happened first).
eaten. FFQs were previously found to be reproducible and Cox proportional hazards regression models generated
valid in the HPFS and the NHS I (15,16). hazard ratios (HRs) and 95% confidence intervals (95% CIs)
Dietary–dependent net acid load was estimated as the adjusted for age (continuous), BMI (13 categories), history
animal protein-to-potassium ratio (APKR), which previ- of diabetes (yes versus no), history of hypertension (yes
ously was shown to be highly correlated with renal net versus no), use of thiazides (yes versus no), supplemental
acid excretion (r=0.90) (9). We also estimated NEAP from calcium intake (four categories), and dietary intakes of fluid,
total protein and potassium intake using the equation in calcium, sodium, fructose, oxalate, phytate (all quintiles), and
 1836 Clinical Journal of the American Society of Nephrology

alcohol (four categories). Vegetable, nondairy animal, and Results

dairy protein models were simultaneously adjusted for In total, 193,676 participants were included in the anal-
the other types of protein and potassium intake (all ysis of incident kidney stones (42,919 from the HPFS, 60,128
quintiles) but not for dietary calcium (because of high from the NHS I, and 90,629 from the NHS II). Baseline
correlation between dietary calcium and dairy protein); characteristics of the study participants are shown in Table
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq

APKR and NEAP models were further adjusted for their 1 and Supplemental Table 1.
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

components: animal protein intake (APKR), all types of

protein (NEAP), and potassium intake (APKR and Association between Type of Protein and Risk of Stones
NEAP). With the components included in the models, Over 3,108,264 person-years of follow-up, 6308 incident
estimates for APKR and NEAP are interpreted as in- kidney stones were confirmed. The association between the
teraction terms. Information on exposures and covariates type of protein and risk of kidney stones is presented in
was updated every 4 years. Tests for linear trends were Tables 2 and 3 and Supplemental Table 2.
constructed by analyzing the median value for each quin- There was a significant inverse association between
tile as a continuous variable. Effect modification by age dairy protein intake and risk of stones in the NHS II (the
(#50 versus .50 years old), BMI (#25 versus .25 kg/m2), multivariate-adjusted HR for the highest quintile compared
and use of thiazides was investigated through interaction with the lowest was 0.84; 95% CI, 0.73 to 0.96; P value for
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024

terms for each type of protein, dietary potassium intake, trend ,0.01) but not in the HPFS (HR, 0.93; 95% CI, 0.78 to
and APKR. 1.10; P value for trend =0.59) or the NHS I (HR, 0.95; 95%
Differences in urinary components across quintiles of CI, 0.76 to 1.17; P value for trend =0.89). The pooled anal-
exposure were analyzed with linear regression models using ysis showed that the HR was 0.89 (95% CI, 0.81 to 0.98;
each urinary component as the dependent variable; adjusted P value for trend =0.06).
for age, BMI, history of kidney stones, history of diabetes, The HRs for nondairy animal protein intake were 1.15 in
history of hypertension, use of thiazides, supplemental the HPFS (95% CI, 0.97 to 1.36; P value for trend =0.04), 1.20
calcium, study cohort, intake of fluid, urine creatinine, in the NHS I (95% CI, 0.99 to 1.46; P value for trend =0.06),
and sodium, and expressed as adjusted means, differences, and 1.02 in the NHS II (95% CI, 0.90 to 1.17; P value for
and 95% CIs. When dietary potassium was used as the trend =0.64). The pooled analysis showed an HR of 1.10
exposure, models were further adjusted for all types of (95% CI, 1.00 to 1.21; P value for trend =0.20). Because the
protein; when protein intake and APKR were used as the higher risk was manifest predominantly in the highest
exposure, models were also further adjusted for dietary quintile of nondairy animal protein, we also analyzed par-
potassium. For these analyses, we used information from ticipants with intakes higher than those in the top quintile
the most recent questionnaire before the urine collection. median. In this subanalysis, the HRs were 1.20 (95% CI,
For each analysis, we evaluated between-cohort hetero- 0.99 to 1.46; P value for trend =0.03) for the HPFS, 1.28
geneity; pooled estimates obtained by random effects (95% CI, 1.02 to 1.61; P value for trend =0.02) for the NHS I,
meta–analysis are presented whenever the P value for het- and 0.97 (95% CI, 0.83 to 1.14; P value for trend =0.66) for
erogeneity was .0.05. the NHS II.

Table 1. Baseline characteristics of the study cohorts

Variable HPFS, n=42,919 NHS I, n=60,128 NHS II, n=90,629

Age, yr 54.3 (9.8) 52.9 (7.1) 36.6 (4.6)

BMI, kg/m2 25.5 (3.4) 25.2 (4.7) 24.6 (5.3)
History of diabetes, % 3 3 1
History of hypertension, % 21 24 6
Thiazide use, % 9 14 2
Calcium supplements use, % 23 57 34
Dietary calcium, mg/d 802 (306) 720 (253) 886 (305)
Supplemental calcium, mg/d 98 (262) 357 (429) 129 (273)
Magnesium, mg/d 355 (83) 300 (69) 316 (75)
Fructose, g/d 25.3 (11.4) 21.6 (9.0) 22.9 (11.0)
Oxalate, mg/d 144 (136) 119 (92) 135 (115)
Phytate, mg/d 943 (392) 708 (269) 783 (240)
Alcohol intake, g/d 11.5 (15.6) 6.2 (10.7) 3.1 (6.1)
Fluid intake, L/d 1.9 (0.8) 2.0 (0.7) 2.1 (0.8)
Dairy protein, g/d 15.9 (9.2) 15.0 (7.8) 18.6 (9.1)
Nondairy animal protein, g/d 51.5 (18.2) 47.1 (14.5) 49.1 (16.2)
Vegetable protein, g/d 24.8 (6.2) 20.2 (4.2) 22.5 (5.0)
Dietary potassium, mg/d 3389 (659) 3002 (562) 2933 (540)

Data are reported as means (SD) for continuous variables. HPFS, Health Professionals Follow-Up Study; NHS I, Nurses’ Health Study I;
NHS II, Nurses’ Health Study II; BMI, body mass index.
 6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

Table 2. Quintiles of dairy protein intake and risk of kidney stones

Cohort Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value for Trend

HPFS
Median, g/d 6.1 10.2 13.8 18.5 28.0 ,0.001
Range ,8.4 8.4–12.0 12.1–15.9 16.0–22.2 .22.2 0.59
Patients 426 427 361 419 330
Person-time 129,932 132,983 134,714 135,399 136,458
Clin J Am Soc Nephrol 11: 1834–1844, October, 2016

Age-adjusted HR (95% CI) 1.00 (reference) 0.97 (0.85 to 1.11) 0.81 (0.71 to 0.94) 0.94 (0.82 to 1.08) 0.76 (0.66 to 0.88)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.97 (0.84 to 1.11) 0.83 (0.71 to 0.96) 1.00 (0.87 to 1.16) 0.93 (0.78 to 1.10)
NHS I
Median, g/d 6.5 10.3 13.6 17.8 25.4 0.003
Range ,8.5 8.5–11.9 12.0–15.5 15.6–20.9 .20.9 0.89
Patients 282 281 275 275 218
Person-time 195,814 202,303 203,431 205,077 203,817
Age-adjusted HR (95% CI) 1.00 (reference) 0.96 (0.81 to 1.13) 0.93 (0.79 to 1.10) 0.93 (0.78 to 1.09) 0.76 (0.63 to 0.90)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.99 (0.84 to 1.17) 1.01 (0.85 to 1.20) 1.06 (0.89 to 1.27) 0.95 (0.76 to 1.17)
NHS II
Median, g/d 8.4 13.0 17.0 22.2 30.7 ,0.001
Range ,10.9 10.9–15.0 15.1–19.3 19.4–25.7 .25.7 ,0.01
Patients 684 655 597 569 509
Person-time 279,594 284,238 286,507 288,062 289,934
Age-adjusted HR (95% CI) 1.00 (reference) 0.93 (0.83 to 1.03) 0.84 (0.75 to 0.93) 0.79 (0.70 to 0.88) 0.70 (0.62 to 0.78)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.97 (0.87 to 1.08) 0.90 (0.80 to 1.01) 0.88 (0.78 to 0.99) 0.84 (0.73 to 0.96)
Pooled cohorts
Age-adjusted HR (95% CI) 1.00 (reference) 0.95 (0.88 to 1.02) 0.85 (0.78 to 0.92) 0.87 (0.77 to 0.99) 0.73 (0.67 to 0.79) ,0.001
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.97 (0.90 to 1.05) 0.90 (0.82 to 1.00) 0.97 (0.86 to 1.08) 0.89 (0.81 to 0.98) 0.06

Multivariate models were adjusted for age, body mass index, history of diabetes, history of hypertension, use of thiazides, supplemental calcium, and intakes of fluid, sodium, potassium,
fructose, oxalate, phytate, alcohol, and all other sources of protein. Medians refer to the first time period; however, dietary variables were updated over the course of the study. HPFS, Health
Professionals Follow-Up Study; HR, hazard ratio; 95% CI, 95% confidence interval; NHS I, Nurses’ Health Study I; NHS II, Nurses’ Health Study II.
Protein, Potassium, Acid Load, and Stones, Ferraro et al.
1837
 6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub
1838

Table 3. Quintiles of nondairy animal protein intake and risk of kidney stones

Cohort Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value for Trend

HPFS
Median, g/d 31.4 42.6 50.3 58.6 72.5 0.004
Range ,38.9 38.9–47.2 47.3–55.4 55.5–66.2 .66.2 0.04
Patients 351 364 379 424 445
Person-time 133,204 133,448 134,142 134,288 134,406
Age-adjusted HR (95% CI) 1.00 (reference) 1.04 (0.90 to 1.20) 1.05 (0.91 to 1.22) 1.17 (1.01 to 1.35) 1.19 (1.04 to 1.37)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.98 (0.84 to 1.14) 0.99 (0.85 to 1.15) 1.09 (0.93 to 1.28) 1.15 (0.97 to 1.36)
NHS I
Clinical Journal of the American Society of Nephrology

Median, g/d 30.9 39.6 45.9 52.8 64.4 0.001

Range ,36.2 36.2–42.9 43.0–49.5 49.6–58.1 .58.1 0.06
Patients 229 253 259 268 322
Person-time 202,112 203,103 203,627 202,284 199,316
Age-adjusted HR (95% CI) 1.00 (reference) 1.10 (0.92 to 1.31) 1.09 (0.91 to 1.30) 1.12 (0.94 to 1.34) 1.34 (1.13 to 1.59)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 1.04 (0.87 to 1.25) 1.02 (0.84 to 1.22) 1.03 (0.85 to 1.25) 1.20 (0.99 to 1.46)
NHS II
Median, g/d 30.9 41.3 48.3 55.8 68.5 0.01
Range ,37.3 37.3–45.1 45.2–52.7 52.8–62.7 .62.7 0.64
Patients 560 645 566 576 667
Person-time 286,109 286,994 286,767 285,358 282,807
Age-adjusted HR (95% CI) 1.00 (reference) 1.14 (1.02 to 1.28) 1.01 (0.90 to 1.13) 1.03 (0.92 to 1.16) 1.21 (1.09 to 1.36)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 1.07 (0.95 to 1.20) 0.91 (0.80 to 1.03) 0.91 (0.80 to 1.03) 1.02 (0.90 to 1.17)
Pooled cohorts
Age-adjusted HR (95% CI) 1.00 (reference) 1.10 (1.02 to 1.19) 1.04 (0.96 to 1.12) 1.09 (1.00 to 1.18) 1.23 (1.14 to 1.33) ,0.001
Multivariate-adjusted HR (95% CI) 1.00 (reference) 1.04 (0.95 to 1.12) 0.95 (0.88 to 1.04) 1.00 (0.89 to 1.12) 1.10 (1.00 to 1.21) 0.20

Multivariate models were adjusted for age, body mass index, history of diabetes, history of hypertension, use of thiazides, supplemental calcium, and intakes of fluid, sodium, potassium,
fructose, oxalate, phytate, alcohol, and all other types of protein. Medians refer to the first time period; however, dietary variables were updated over the course of the study. HPFS, Health
Professionals Follow-Up Study; HR, hazard ratio; 95% CI, 95% confidence interval; NHS I, Nurses’ Health Study I; NHS II, Nurses’ Health Study II.
 Clin J Am Soc Nephrol 11: 1834–1844, October, 2016 Protein, Potassium, Acid Load, and Stones, Ferraro et al. 1839

There was no significant association between intake of multivariable adjustment including main components of
vegetable protein and risk of stones. There was no signif- APKR, those in the highest quintile had 70 (95% CI, 22 to
icant effect modification by age, BMI, or use of thiazides for 118) mg/d lower urine citrate, 0.16 (95% CI, 0.07 to 0.23)
any source of protein. lower urine pH, and 140 (95% CI, 23 to 256) ml/d lower
urine volume.
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq

Association between Intake of Potassium and Risk of Stones Associations between dietary intakes and urine compo-
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

The association between dietary potassium intake and risk sition were similar among those participants with and
of kidney stones is presented in Table 4. After multivariable without a history of kidney stones.
adjustment, there was a strong inverse association between
potassium intake and risk of stones: the HR was 0.44 (95%
CI, 0.36 to 0.53) for the HPFS, 0.57 (95% CI, 0.45 to 0.72) for Discussion
the NHS I, and 0.67 (95% CI, 0.57 to 0.78) for the NHS II (all We found that associations between vegetable, dairy,
P values for trend ,0.001). There was no significant effect and nondairy animal protein intake and kidney stone risk
modification by age, BMI, or use of thiazides. were either null or modest and of borderline statistical
significance. However, different types of protein may affect
the risk of kidney stones differently: in particular, vegetable
Association between Dietary Net Acid Load and Risk of
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024

protein was not associated with risk of stones, dairy protein

Stones
The association between estimated dietary net acid load was associated with reduced risk in younger women, and
and risk of kidney stones is presented in Table 5 and Sup- nondairy animal protein may have been associated with
plemental Table 3. After multivariable adjustment includ- modestly higher risk in men and older women. In contrast,
ing animal protein and potassium intake, there was a higher dietary potassium was associated with a statistically
significant positive association between APKR and risk significant and large reduction in kidney stone risk in all
of stones: the pooled HR was 1.41 (95% CI, 1.18 to 1.68; cohorts. APKR was associated with higher risk of stones,
P value for trend =0.004). A similar association was seen independent of the components of APKR (animal protein
with NEAP (pooled HR, 1.22; 95% CI, 1.05 to 1.41; P value and potassium intake). The 24-hour urine composition also
for trend ,0.01). There was no significant effect modifica- varied by type of protein. Higher dairy protein intake was
tion by age, BMI, or use of thiazides. associated with higher excretion of calcium and citrate but
lower oxalate and uric acid. Higher nondairy animal
protein, however, was associated with significantly lower
Association between Type of Protein and Urinary citrate, higher uric acid, and a more acidic urine. Taken
Composition together, these findings suggest that dairy protein intake
The association between the type of protein and urinary
might have a mixed effect on urinary lithogenic factors. The
composition is reported in Supplemental Tables 4 and 5.
higher urinary calcium might be because of the effect of
After multivariable adjustment, compared with those in the
casein on intestinal calcium absorption (18) and/or the
lowest quintile, those in the highest quintile of dairy protein
higher content of calcium present in dairy products. The
intake had 24 (95% CI, 16 to 32) mg/d higher urine calcium,
latter possibility may explain the lower excretion of oxa-
1.4 (95% CI, 0.5 to 2.4) mg/d lower urine oxalate, 36 (95% CI,
late with higher dairy protein intake, because higher cal-
11 to 60) mg/d higher urine citrate, and higher relative su-
cium in the gut can bind with oxalate, thus reducing
persaturation for calcium phosphate. Those in the highest
intestinal absorption of oxalate (19). However, nondairy
quintile of nondairy animal protein intake had 54 (95% CI,
animal protein may have a more marked prolithogenic
30 to 78) mg/d lower urine citrate, 24 (95% CI, 13 to 35)
effect on urine composition, likely to favor calcium stone
mg/d higher urine uric acid, 0.13 (95% CI, 0.09 to 0.17) lower
formation (because of lower citrate) and uric acid stone
urine pH, and higher relative supersaturation for uric acid.
formation (because of lower pH and higher uric acid).
Another potential mechanism through which large intakes
Association between Potassium Intake and Urinary of animal protein could affect stone risk is the increased
Composition synthesis of oxalate secondary to metabolism of amino
The association between potassium intake and urinary acids, such as hydroxyproline. However, studies with con-
composition is reported in Table 6. After multivariable trolled dietary intakes of oxalate did not find any associa-
adjustment including total fluid intake, those in the high- tion between intake of animal protein and urinary oxalate
est quintile had 1.6 (95% CI, 0.6 to 2.5) mg/d higher urine excretion (20). Similarly, in our study, urinary oxalate was
oxalate, 39 (95% CI, 13 to 65) mg/d higher urine citrate, 26 not higher among participants with larger intakes of ani-
(95% CI, 14 to 38) mg/d higher urine uric acid, 0.15 (95% mal protein.
CI, 0.10 to 0.19) higher urine pH, 237 (95% CI, 173 to 299) A major finding in our study is the strong inverse
ml/d higher urine volume, and significantly lower relative association between higher dietary potassium intake, a
supersaturations for calcium oxalate and uric acid. There marker of dietary intake of organic anion, and risk of
was no association between potassium intake and urinary stones: there was a 33%–56% lower risk of stones for those
excretion of calcium. participants in the highest quintile of potassium intake.
Previous analyses of these cohorts reported associations
Association between Dietary Net Acid Load and Urinary of smaller magnitude for the HPFS (6) and the NHS I (4)
Composition and no association for the NHS II (5). Our updated find-
The association between APKR and urinary com- ings are likely caused by increased statistical power. Par-
position is reported in Supplemental Table 6. After ticipants in the highest quintile of potassium intake had
 6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub
1840

Table 4. Quintiles of dietary potassium intake and risk of kidney stones

Cohort Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value for Trend

HPFS
Median, g/d 2601 3016 3327 3667 4224 ,0.001
Range ,2835 2835–3175 3176–3488 3489–3888 .3888 ,0.001
Patients 567 459 368 332 237
Person-time 128,870 134,246 135,483 135,420 135,469
Age-adjusted HR (95% CI) 1.00 (reference) 0.78 (0.69 to 0.88) 0.64 (0.56 to 0.73) 0.60 (0.52 to 0.68) 0.44 (0.38 to 0.51)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.78 (0.68 to 0.89) 0.64 (0.55 to 0.74) 0.60 (0.51 to 0.70) 0.44 (0.36 to 0.53)
Clinical Journal of the American Society of Nephrology

NHS I
Median, g/d 2323 2694 2971 3261 3722 ,0.001
Range ,2535 2535–2835 2836–3108 3109–3448 .3448 ,0.001
Patients 393 287 245 211 195
Person-time 196,777 203,677 204,510 204,711 200,767
Age-adjusted HR (95% CI) 1.00 (reference) 0.71 (0.61 to 0.82) 0.61 (0.52 to 0.72) 0.53 (0.45 to 0.63) 0.50 (0.42 to 0.60)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.74 (0.63 to 0.87) 0.66 (0.55 to 0.79) 0.58 (0.48 to 0.72) 0.57 (0.45 to 0.72)
NHS II
Median, g/d 2275 2649 2910 3180 3612 ,0.001
Range ,2491 2491–2784 2785–3038 3039–3354 .3354 ,0.001
Patients 815 662 595 533 409
Person-time 282,413 285,735 287,785 286,885 285,518
Age-adjusted HR (95% CI) 1.00 (reference) 0.81 (0.73 to 0.90) 0.72 (0.65 to 0.80) 0.65 (0.58 to 0.73) 0.50 (0.45 to 0.57)
Multivariate-adjusted HR (95% CI) 1.00 (reference) 0.91 (0.82 to 1.02) 0.87 (0.77 to 0.98) 0.83 (0.73 to 0.94) 0.67 (0.57 to 0.78)

Multivariate models were adjusted for age, body mass index, history of diabetes, history of hypertension, use of thiazides, supplemental calcium, and intakes of fluid, calcium, sodium, fructose,
oxalate, phytate, alcohol, and all other types of protein. Medians refer to the first time period; however, dietary variables were updated over the course of the study. Cohort-specific results were
not pooled because of statistically significant test for heterogeneity. HPFS, Health Professionals Follow-Up Study; HR, hazard ratio; 95% CI, 95% confidence interval; NHS I, Nurses’ Health
Study I; NHS II, Nurses’ Health Study II.
 6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

Table 5. Quintiles of animal protein-to-potassium ratio and risk of kidney stones

Cohort Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P Value for Trend

HPFS
Median, g/mEq 0.46 0.59 0.70 0.81 1.01 ,0.001
Range ,0.53 0.53–0.64 0.65–0.75 0.76–0.88 .0.88 ,0.001
Patients 268 336 378 408 573 0.004
Person-time 131,584 132,719 134,206 135,099 135,879
Age-adjusted HR (95% CI) 1.00 (reference) 1.21 (1.03 to 1.42) 1.30 (1.10 to 1.52) 1.35 (1.16 to 1.59) 1.84 (1.58 to 2.14)
Model 1 multivariate–adjusted 1.00 (reference) 1.25 (1.06 to 1.48) 1.33 (1.13 to 1.57) 1.36 (1.14 to 1.60) 1.72 (1.45 to 2.04)
HR (95% CI)
Model 2 multivariate–adjusted 1.00 (reference) 1.19 (0.99 to 1.44) 1.26 (1.01 to 1.53) 1.28 (0.98 to 1.66) 1.63 (1.18 to 2.25)
HR (95% CI)
NHS I
Median, g/mEq 0.46 0.57 0.67 0.77 0.94 ,0.001
Clin J Am Soc Nephrol 11: 1834–1844, October, 2016

Range ,0.50 0.50–0.60 0.61–0.70 0.71–0.82 .0.82 0.004

Patients 205 213 253 301 359 ,0.01
Person-time 201,541 201,865 202,107 202,490 202,439
Age-adjusted HR (95% CI) 1.00 (reference) 1.01 (0.84 to 1.23) 1.21 (1.01 to 1.47) 1.44 (1.20 to 1.74) 1.72 (1.43 to 2.06)
Model 1 multivariate–adjusted 1.00 (reference) 0.98 (0.80 to 1.19) 1.10 (0.90 to 1.35) 1.23 (1.00 to 1.50) 1.29 (1.04 to 1.61)
HR (95% CI)
Model 2 multivariate–adjusted 1.00 (reference) 1.06 (0.85 to 1.32) 1.26 (0.97 to 1.62) 1.45 (1.08 to 1.95) 1.59 (1.10 to 2.31)
HR (95% CI)
NHS II
Median, g/mEq 0.49 0.64 0.74 0.86 1.07 ,0.001
Range ,0.57 0.57–0.69 0.70–0.79 0.80–0.94 .0.94 0.16
Patients 507 549 616 639 703 0.16
Person-time 283,922 284,365 285,185 286,649 288,214
Age-adjusted HR (95% CI) 1.00 (reference) 1.10 (0.97 to 1.24) 1.25 (1.11 to 1.41) 1.34 (1.19 to 1.51) 1.53 (1.35 to 1.72)
Model 1 multivariate–adjusted 1.00 (reference) 1.04 (0.92 to 1.18) 1.11 (0.98 to 1.26) 1.11 (0.97 to 1.27) 1.12 (0.97 to 1.27)
HR (95% CI)
Model 2 multivariate–adjusted 1.00 (reference) 1.07 (0.93 to 1.24) 1.18 (1.00 to 1.40) 1.20 (0.98 to 1.46) 1.25 (0.97 to 1.60)
HR (95% CI)
Pooled cohorts
Age-adjusted HR (95% CI) 1.00 (reference) 1.11 (1.02 to 1.21) 1.26 (1.15 to 1.37) 1.37 (1.25 to 1.49) 1.67 (1.48 to 1.88) ,0.001
Model 1 multivariate–adjusted 1.00 (reference) 1.08 (0.94 to 1.25) 1.18 (1.04 to 1.33) 1.21 (1.07 to 1.37) 1.35 (1.03 to 1.78) 0.02
HR (95% CI)
Model 2 multivariate–adjusted 1.00 (reference) 1.10 (0.99 to 1.22) 1.21 (1.07 to 1.36) 1.26 (1.14 to 1.40) 1.41 (1.18 to 1.68) 0.004
HR (95% CI)

Multivariate model 1 was adjusted for age, body mass index, history of diabetes, history of hypertension, use of thiazides, supplemental calcium, and intakes of fluid, calcium, sodium, fructose,
oxalate, phytate, and alcohol. Multivariate model 2 was further adjusted for animal protein and potassium intake; in these models, animal protein-to-potassium ratios represent interaction
terms. Medians refer to the first time period; however, dietary variables were updated over the course of the study. HPFS, Health Professionals Follow-Up Study; HR, hazard ratio; 95% CI, 95%
confidence interval; NHS I, Nurses’ Health Study I; NHS II, Nurses’ Health Study II.
Protein, Potassium, Acid Load, and Stones, Ferraro et al.
1841
 6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub
1842

Table 6. Pooled adjusted mean values and 95% confidence intervals of 24-hour urine components by quintile of dietary potassium intake

Variable Quintile 1, n=1227 Quintile 2, n=1226 Quintile 3, n=1224 Quintile 4, n=1226 Quintile 5, n=1226 P Value for Trend

Median, mg/d 2641 3052 3357 3691 4162

Creatinine, g 1.3 (1.3 to 1.3) 1.3 (1.3 to 1.4) 1.3 (1.3 to 1.4) 1.4 (1.3 to 1.4) 1.3 (1.3 to 1.4) 0.12
Potassium, mEq 56.1 (54.7 to 57.5) 61.5 (60.1 to 62.8) 63.7 (62.4 to 65.0) 67.6 (66.2 to 68.9) 71.3 (69.9 to 72.7) ,0.001
Calcium, mg 189 (182 to 196) 194 (188 to 201) 195 (189 to 202) 192 (185 to 198) 189 (182 to 196) 0.84
Oxalate, mg 32.6 (31.8 to 33.4) 33.1 (32.4 to 33.9) 32.9 (32.1 to 33.6) 32.9 (32.3 to 33.7) 34.2 (33.4 to 35.0) ,0.01
Citrate, mg 675 (655 to 696) 681 (661 to 700) 703 (683 to 722) 696 (677 to 716) 714 (693 to 735) 0.002
Uric acid, mg 517 (507 to 526) 522 (513 to 531) 527 (518 to 536) 529 (520 to 538) 543 (533 to 552) ,0.001
Clinical Journal of the American Society of Nephrology

Sodium, mEq 151 (147 to 155) 149 (147 to 152) 148 (144 to 152) 150 (146 to 154) 149 (145 to 153) 0.51
Magnesium, mg 104 (102 to 107) 107 (105 to 110) 109 (106 to 112) 110 (108 to 113) 112 (109 to 115) ,0.001
Phosphate, mg 846 (830 to 862) 866 (851 to 881) 850 (835 to 865) 873 (858 to 888) 867 (851 to 883) 0.03
Sulfate, mmol 18.2 (17.8 to 18.6) 18.6 (18.2 to 19.0) 18.7 (18.3 to 19.0) 19.1 (18.8 to 19.5) 19.4 (19.0 to 19.8) ,0.001
Ammonium, mmol 29.2 (28.2 to 30.3) 30.4 (29.5 to 31.3) 28.4 (27.6 to 29.3) 29.4 (28.5 to 30.3) 29.1 (28.1 to 30.0) 0.39
pH, U 5.95 (5.92 to 5.99) 6.00 (5.97 to 6.03) 6.04 (6.01 to 6.07) 6.05 (6.02 to 6.09) 6.10 (6.06 to 6.13) ,0.001
Volume, ml 1737 (1687 to 1788) 1853 (1805 to 1902) 1830 (1783 to 1877) 1878 (1829 to 1926) 1974 (1923 to 2025) ,0.001
SS CaOx
Pharmacal 1.74 (1.58 to 1.91) 1.60 (1.44 to 1.77) 1.60 (1.43 to 1.76) 1.50 (1.34 to 1.66) 1.48 (1.32 to 1.65) ,0.001
Litholink 5.80 (5.46 to 6.13) 5.56 (5.26 to 5.86) 5.54 (5.24 to 5.83) 5.25 (4.95 to 5.54) 5.07 (4.76 to 5.39) 0.001
SS CaP
Pharmacal 1.33 (1.14 to 1.51) 1.39 (1.21 to 1.57) 1.38 (1.20 to 1.56) 1.44 (1.26 to 1.62) 1.37 (1.19 to 1.56) 0.43
Litholink 1.09 (0.99 to 1.19) 1.07 (0.98 to 1.16) 1.14 (1.05 to 1.22) 1.07 (0.98 to 1.16) 1.06 (0.96 to 1.15) 0.21
SS UA
Pharmacal 2.05 (1.80 to 2.30) 1.78 (1.53 to 2.02) 1.76 (1.51 to 2.00) 1.61 (1.37 to 1.85) 1.55 (1.30 to 1.80) ,0.001
Litholink 0.79 (0.72 to 0.86) 0.68 (0.62 to 0.75) 0.66 (0.60 to 0.73) 0.65 (0.59 to 0.72) 0.62 (0.55 to 0.69) 0.002

Models were adjusted for age, body mass index, history of kidney stones, history of diabetes, history of hypertension, total fluid intake, use of thiazides, supplemental calcium, intake of protein
(dairy, nondairy animal, and vegetable), study cohort, urine creatinine, and sodium. Ammonium data were only available for the Nurses’ Health Study II Litholink collection. Pharmacal results
are reported as relative supersaturations, whereas Litholink results as supersaturations. Medians refer to the first time period; however, dietary variables were updated over the course of the
study. SS CaOx, supersaturation calcium oxalate; SS CaP, supersaturation calcium phosphate (brushite); SS UA, supersaturation uric acid.
 Clin J Am Soc Nephrol 11: 1834–1844, October, 2016 Protein, Potassium, Acid Load, and Stones, Ferraro et al. 1843

higher urinary levels of citrate, larger urine volumes, and Disclosures

higher urine pH, resulting in reduced relative supersatu- P.M.F. discloses consultant’s fees from BioHealth Italia (Rivoli,
rations for calcium oxalate and uric acid, despite higher Turin, Italy) (2014–2015). G.C.C. is a consultant for Allena Pharma-
urinary excretion of oxalate. The larger urine volume, even ceuticals (Newton, MA), AstraZeneca Pharmaceuticals (Wilmington,
after adjustment for fluid intake from beverages, might DE), and Exponent (Los Angeles, CA); receives royalties from UpToDate
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq

be explained by the high water content in fruits and (author and Section Editor); and receives honorarium from the American
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

vegetables. Society of Nephrology (Editor-in-Chief of the Clinical Journal of the

We also found an association between higher levels of American Society of Nephrology). All other authors have nothing to
dietary net acid load, estimated by APKR and NEAP, disclose.
and a higher risk of kidney stones. Such associations
were significant, even after including the respective References
components of the ratios in the model. An imbalance 1. Breslau NA, Brinkley L, Hill KD, Pak CY: Relationship of
between intakes of acid-generating and alkali-generating animal protein-rich diet to kidney stone formation and
foods, reflected in higher APKR and NEAP values, calcium metabolism. J Clin Endocrinol Metab 66: 140–146,
respectively, could lead to a series of metabolic derange- 1988
2. Kok DJ, Iestra JA, Doorenbos CJ, Papapoulos SE: The effects of
ments, including higher urinary excretion of calcium dietary excesses in animal protein and in sodium on the com-
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024

(plausibly through bone buffering because of subclinical position and the crystallization kinetics of calcium oxalate
systemic acidosis [10]), reduced excretion of citrate (11), monohydrate in urines of healthy men. J Clin Endocrinol Metab
and reduced urine pH (which would increase the risk of 71: 861–867, 1990
uric acid stones). Of note, we found significantly lower 3. Dussol B, Iovanna C, Rotily M, Morange S, Leonetti F, Dupuy P,
Vazi A, Saveanu A, Loundou A, Berland Y: A randomized trial of
excretion of citrate and lower urine pH for higher quin- low-animal-protein or high-fiber diets for secondary prevention
tiles of APKR and a higher relative supersaturation for of calcium nephrolithiasis. Nephron Clin Pract 110: c185–c194,
uric acid. The APKR results may partially account for 2008
our previous finding that a dietary approaches to stop 4. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ:
hypertension–style diet, which includes higher intakes Comparison of dietary calcium with supplemental calcium and
other nutrients as factors affecting the risk for kidney stones in
of fruits and vegetables and lower intakes of red and women. Ann Intern Med 126: 497–504, 1997
processed meats, is associated with a lower risk of kid- 5. Curhan GC, Willett WC, Knight EL, Stampfer MJ: Dietary
ney stones in the same cohorts (21). factors and the risk of incident kidney stones in younger
Our study has limitations. We did not have information women: Nurses’ Health Study II. Arch Intern Med 164: 885–
891, 2004
on stone composition for all participants and thus, could
6. Taylor EN, Stampfer MJ, Curhan GC: Dietary factors and the risk
not determine whether type of protein or estimated dietary of incident kidney stones in men: New insights after 14 years of
net acid load was associated with risk of selectively forming follow-up. J Am Soc Nephrol 15: 3225–3232, 2004
specific stone types. Also, our study participants are pre- 7. Lemann J Jr., Pleuss JA, Gray RW, Hoffmann RG: Potassium ad-
dominantly white, and our results may not apply to other ministration reduces and potassium deprivation increases uri-
nary calcium excretion in healthy adults [corrected]. Kidney Int
populations.
39: 973–983, 1991
In conclusion, the risk of kidney stone formation asso- 8. Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks
ciated with protein intake may vary by protein type. IR, Brasure M, Kane RL, Ouellette J, Monga M: Medical man-
In contrast with vegetable and dairy protein, nondairy agement to prevent recurrent nephrolithiasis in adults: A sys-
animal protein may be associated with a slightly higher tematic review for an American College of Physicians Clinical
Guideline. Ann Intern Med 158: 535–543, 2013
risk of kidney stones among men and older women.
9. Frassetto LA, Todd KM, Morris RC Jr., Sebastian A: Estimation of
Higher potassium intake is strongly associated with a net endogenous noncarbonic acid production in humans from
lower risk of stones, and a higher estimated net dietary diet potassium and protein contents. Am J Clin Nutr 68: 576–583,
acid load is associated with higher risk independent of 1998
potassium intake. Our data suggest that diets rich in fruits 10. Lemann J Jr., Gray RW, Maierhofer WJ, Cheung HS: The impor-
tance of renal net acid excretion as a determinant of fasting uri-
and vegetables as well as diets with a relative abundance nary calcium excretion. Kidney Int 29: 743–746, 1986
of fruits and vegetables compared with animal protein 11. Lemann J Jr., Bushinsky DA, Hamm LL: Bone buffering of acid and
may represent effective interventions to prevent kidney base in humans. Am J Physiol Renal Physiol 285: F811–F832,
stone formation. 2003
12. Trinchieri A, Maletta A, Lizzano R, Marchesotti F: Potential renal
acid load and the risk of renal stone formation in a case-control
Acknowledgments study. Eur J Clin Nutr 67: 1077–1080, 2013
Because G.C.C. is the Editor-in-Chief of the Clinical Journal 13. Holmes RP, Kennedy M: Estimation of the oxalate content of
of the American Society of Nephrology, he was not involved in foods and daily oxalate intake. Kidney Int 57: 1662–1667,
the peer review process for this manuscript. Another editor 2000
oversaw the peer review and decision-making process for this 14. Taylor EN, Curhan GC: Oxalate intake and the risk for neph-
rolithiasis. J Am Soc Nephrol 18: 2198–2204, 2007
manuscript.
15. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB,
This work was supported by American Kidney Fund Clinical Willett WC: Reproducibility and validity of an expanded self-
Scientist in Nephrology Program and National Institutes of Health administered semiquantitative food frequency questionnaire
research grants DK094910, DK91417, CA186107, CA176726, and among male health professionals. Am J Epidemiol 135: 1114–
CA167552. 1126, 1992
16. Feskanich D, Rimm EB, Giovannucci EL, Colditz GA, Stampfer
The content of this manuscript was presented in abstract form at MJ, Litin LB, Willett WC: Reproducibility and validity of food
the 2015 American Society of Nephrology Kidney Week Meeting intake measurements from a semiquantitative food frequency
(San Diego, CA; November 3–8, 2015). questionnaire. J Am Diet Assoc 93: 790–796, 1993
 1844 Clinical Journal of the American Society of Nephrology

17. Rimm EB, Stampfer MJ, Colditz GA, Chute CG, Litin LB, Willett 21. Taylor EN, Fung TT, Curhan GC: DASH-style diet associates with
WC: Validity of self-reported waist and hip circumferences in reduced risk for kidney stones. J Am Soc Nephrol 20: 2253–2259,
men and women. Epidemiology 1: 466–473, 1990 2009
18. Ferraretto A, Signorile A, Gravaghi C, Fiorilli A, Tettamanti G:
Casein phosphopeptides influence calcium uptake by cultured
Received: February 10, 2016 Accepted: June 20, 2016
human intestinal HT-29 tumor cells. J Nutr 131: 1655–1661,
LBuAlZ7gMg0m5Tncg8iVNc2QJsjJ+WGkFfV2rNOU/0ps/f2xFk1LlcAs131Jc0r5T2dgHKS02gufvQC9y8rHrDrNxEsz7BrQDlPq

2001
Published online ahead of print. Publication date available at www.
Downloaded from http://journals.lww.com/cjasn by bcs+xGo3lFgqU2CN3kOBD6cD+S7vTYL/opOExxJy7W333qvhGub

19. Massey LK, Roman-Smith H, Sutton RA: Effect of dietary oxalate

and calcium on urinary oxalate and risk of formation of calcium cjasn.org.
oxalate kidney stones. J Am Diet Assoc 93: 901–906, 1993
20. Knight J, Easter LH, Neiberg R, Assimos DG, Holmes RP: This article contains supplemental material online at http://cjasn.
Increased protein intake on controlled oxalate diets does not asnjournals.org/lookup/suppl/doi:10.2215/CJN.01520216/-/
increase urinary oxalate excretion. Urol Res 37: 63–68, 2009 DCSupplemental.
6Jfl3XK4BnoLxT2ZHOy4= on 02/11/2024