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1
Aug. 26, 2017 Semmelweis University
Sadayoshi Ito
Tohoku University, SENDAI
Serum Uric Acid and Urinary
pH as Risk Factors of CKD and CVD
The 24th Budapest Nephrology School
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COI
NON
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Urine of the first grade students of Tohoku University
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Pink Urine syndrome
Student Check-up (n=4940) 216(4.4%) with PUS ・Cloudy orange urine ・Pink sediment after centrifugation (Uric acid precipitation)
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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All subjects (−) (+) p
n 4940 4724 216
Gender (M / F) 3651 / 1289 3478 / 1246 173 / 43
% Male (%) 73.91 73.62 80.09 0.031
Age (years) 18.40 ± 1.14 18.40 ± 1.15 18.36 ± 0.74 0.496
BMI (kg/m2) 21.38 ± 3.00 21.33 ± 2.96 22.48 ± 3.56 <0.001
U-pH 5.97 ± 0.44 5.98 ± 0.44 5.75 ± 0.37 <0.001
SBP (mm Hg) 128.2 ± 15.7 128.0 ± 15.8 132.4 ± 16.6 0.0002
DBP (mm Hg) 73.15 ± 11.05 73.03 ± 11.05 76.00 ± 10.75 0.0001
HR (bpm) 88.97 ± 15.86 88.81 ± 15.78 92.64 ± 17.10 0.0014
Mean ± SD.
PUS is associated with high BMI, low UpH, higher BP and higher Heart rate
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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In the logistic regression analysis, the presence or absence of UPS was used as the dependent variable, and gender, U-pH, BMI, age, SBP, DBP, and HR were used as the independent variables. U-pH (β = -1.392, p<0.0001), BMI (β= 0.085, p<0.0001), and HR (β = 0.011, p = 0.019) were extracted as independent factors.
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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vs. U-pH p
n 300 -
Gender (M/F) 200 / 100 -
BMI (kg/m2) 23.4 ± 5.2 −0.35 0.011
SBP (mm Hg) 129.7 ± 19.3 −0.27 0.024
DBP (mm Hg) 75.7 ± 11.1 −0.20 0.030
WC (cm) 78.0 ± 13.2 −0.40 0.005
HR (bpm) 93.2 ± 17.7 0.01 0.863
CPR (μg/day) 21.5 ± 1.7 −0.26 0.022
AGT (ng/day) 1615.4 (110.9–74597.9) −0.47 <0.001
TBARS (µM/day) 4.3 ± 1.4 −0.70 <0.001
MG (nM/day) 1237.0 ± 498.6 −0.44 <0.001
U-Na (mM/day) 130.5 ± 31.0 −0.44 <0.001
U-pH 6.0 ± 0.6 - -
Mean ± SD, median (range). CPR: urinary C-peptide excretion
Characteristics of the 300 participants and the relationship between various parameters and urinary pH.
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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Amadri 3-deoxyglucosone (DG)
Metabolism of MG
Glucose
Glyceraldehyde
3-Phosphate
pyruvate
TCA
F-1,6-bP Dihydroxyacetone
Phosphate (DHAP)
Methylglyoxal
(MG)
G-3P dehydrogenase;
S-D-lactoyl
glutathione
Gly-I
D-lactate
GSH
Gly-II
Hemithioacetyl
Glyoxylase system
AngII, RAGE
ROS
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(a)
(b)
ESR spectrum
H2O2 (10mM)
MGO (3.9 mM)
Hydroxyl radical
(Nakayama M, et al. Redox Rep 12; 125-133, 2007)
(c)
MnO MnO
H2O2 + MGO (3.9 mM)
undetermined Carbon-centered radical
Methyl radical CH3・
Hydroxyl radical
C
3 H C
O O
H
C
Very reactive aldehyde
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In the multiple-regression analysis, U-pH was used as the dependent variable, and gender, BMI, age, SBP, DBP, HR, WC, as well as excretion of urinary CPR, angiotensinogen, methylglyoxal, TBARS, and Na were used as the independent variables. Only TBARS (β = -0.421, p<0.0001) and angiotensinogen (β= 0.000, p<0.0001) were extracted as independent variables.
Low urinary pH may be associated with activation of RAAS and ROS
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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Intracellular pH
Acid overload Sulfate, FFA
Urine citrate
Pathogenesis of Pink Urine Syndrome
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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Fatty acid
β-oxidation
Ammonium
production
Fatty acids Glutamine
Fatty acyl CoA
Glutamate
Propionyl-Co-A
(for odd chain
fatty acids)
Acetyl-Co-A
Isocitrate
Citrate α-Ketoglutarate
Krebs
cycle Oxaloacetate
Malate
Fumarate
Succinyl-Co-A
Succinate
NH4+
NH4+
Metabolic syndrome
(Bobulescu IA: Curr Opin Nephrol
Hypertens 19; 393-402, 2010)
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Urine pH and metabolic derangements
Low urinary pH: Obesity, type 2 DM, uric acid stone
The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers.
(Cameron M, et al: Kidney Int 81:1123-30, 2012)
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Acid – base balance
Acid load – Buffer = UNAE
UNAE=urinary net acid excretion
Food (protein) Reabsorption Metabolism
HCO Others
3 -
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H+ NH3
NH4 +
MCD
(Kamel KS, et al: Q J Med 98; 57-68, 2005)
Urine pH is determined by H+ and NH3 secretion
H + A - ・
(TA)
TA+ UNAE= NH4 +
TA: Titratable Acid (amount of NaOH to bring urine pH to 7.4)
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Thin
descending
limb
Glutamine HCO3 - Renal vein
Na+ NH4 +
NH4 +
Cortex
Medulla
Competes
with K+
NH4 +
Na+ , Cl-
1
2 3
(Kamel KS, et al: Q J Med 98; 57-68, 2005)
NH4+ NH3 + H+
Ammonium production and recycling in the kidney
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Healthy volunteers (HVs) Uric acid stone formers (UASFs)
Gender: M/F 6/3 9/1
Age (years) 52.8±13.1 57.0±8.2
Weight (kg) 85±19 109±19*
Height (cm) 171±10 172±6
Body mass index (kg/m2) 28.5±4.3 36.9±6.8*
SUA (mg/dl) 6.0±1.6 8.0±1.5*
Bicarbonate (mEq/l) 27.0±1.3 26.1±3.3
Venous pH 7.41±0.02 7.40±2.02
Abbreviations: F, female; M, male.
Demographic
*P<0.05, t-test (Cameron M, et al: Kidney Int 81; 1123-1130, 2012)
Controlled diet
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(Cameron M, et al: Kidney Int 81; 1123-1130, 2012)
Urine pH: controlled diet
7.5
7.0
6.5
6.0
5.5
5.0
4.5
08 12 16 20 00 04 08
HV UASF
Uri
nar
y p
H
Time Meals are indicated by black boxes.
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(Cameron M, et al: Kidney Int 81; 1123-1130, 2012)
60
50
40
30
20
10
0
Tota
l uri
c ac
id, m
g/h
08 12 16 20 00 04 08
Time
HV UASF
08 12 16 20 00 04 08
Time
HV UASF
25
20
15
10
5
0 Un
dis
soci
ated
uri
c ac
id, m
g/h
Urate excretion
a b
(a)Total (urate+undissociated uric acid), (b)Undissociated uric acid excretion in urine. Black boxes represent meals.
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(Cameron M, et al: Kidney Int 81; 1123-1130, 2012)
Urinary Net Acid Excretion
10
8
6
4
2
0
-2 08 12 16 20 00 04 08
Time
Uri
nar
y n
et a
cid
ex
cret
ion
, mEq
/h
HV UASF
Black boxes represent meals.
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Acid load despite identical meal
• Increased endogenous acid production: lactate, keto-acids, et
• Increased alkali loss in the intestine • Increased absorption of exogenous
organic acid from intestinal bacterial sources
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(Maalouf NM, CJASN 5; 1277-1281, 2010)
Proportion of NAE excreted as ammonium (NH4+/NAE) in nine volunteers with type 2 diabetes (T2DM;●) and 16 age- and BMI-matched
volunteers without type 2 diabetes (Controls; ♦) evaluated while consuming a fixed metabolic diet. Horizontal bars indicate means for each
group. NH4+/NAE was significantly lower in patients with type 2 diabetes than in control subjects (0.70 ± 0.12 versus 0.94 ± 0.36; P < 0.01).
Results represent the mean of two 24-hour urine collections for each participant
P<0.01 1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Controls
(N=16)
T2DM
(N=9)
U N
H4
+/N
AE
7.0
6.5
6.0
5.5
5.0
4.5
24-h
r U
pH
P<0.01
Controls
(N=16)
T2DM
(N=9)
Low Urine pH and Ammonia Excretion type 2 DM
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Urine pH and renal-vascular damages in real world
• Significance of urine pH in DM has not been elucidated
• Ogawa followed up 400 DM patients from 2003 to 2013.
• Fifty patients were lost mostly due to Great East Japan Earthquake
• Specialist’s cares: best possible treatments
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The study subjects’ demographic and clinical data at the baseline and endpoint.
Baseline (2003-4) Endpoint (2012-13) p
Age (years) 53.7 ± 13.6 - -
Gender (M/F) 157 / 193 - -
Duration (years) 11.8 ± 7.8 - -
BMI (kg/m2) 25.5 ± 5.0 25.5 ± 5.0 0.802
WC (cm) 91.9 ± 13.9 91.9 ± 13.6 0.983
UpH 6.0 ± 0.8 6.2 ± 2.6 0.201
PG (mg/dL) 129.0 ± 48.0 119.4 ± 19.2 0.734
HbA1c (%) 6.9 ± 1.1 6.5 ± 0.5 0.0042
SBP (mmHg) 134.5 ± 18.6 128.0 ± 10.9 < 0.0001
DBP (mmHg) 80.1 ± 10.3 76.4 ± 7.2 < 0.0001
HR (bpm) 73.0 ± 14.1 70.4 ± 8.5 < 0.0001
TC (mg/dL) 188.3 ± 34.5 192.8 ± 25.7 0.257
TG (mg/dl) 120.6 ± 70.2 114.8 ± 52.1 0.583
HDL-C (mg/dL) 55.7 ± 15.8 57.5 ± 15.3 0.019
BUN (mg/dL) 19.6 ± 9.9 25.5 ± 16.7 < 0.0001
eGFR (ml/min/1.73 m2) 72.7 ± 19.8 55.5 ± 16.2 < 0.0001
ACR (mg/g Cre) 24.8 (0.0-4735.6) 55.1 (3.8-4999.5) < 0.0001
UA (mg/dL) 6.2 ± 1.7 6.5 ± 1.4 0.046
ALT (U/L) 23.6 ± 22.6 26.9 ± 15.2 < 0.0001
AST (U/L) 25.2 ± 16.0 25.7 ± 9.6 < 0.0001
K+ (mEq/L) 4.4 ± 0.5 4.5 ± 0.5 0.676
Na+ (mEq/L) 140.8 ± 2.3 139.9 ± 2.6 0.0142
Cl- (mEq/L) 103.6 ± 3.2 105.4 ± 4.6 0.0002
TP (g/dL) 7.2 ± 0.5 7.1 ± 0.3 0.0018
Hb (g/dL) 12.8 ± 1.7 13.1 ± 1.3 0.0030
Plt (104/μL) 22.5 ± 6.6 18.0 ± 10.7 0.0003
WBC (103/μL) 6.2 ± 1.8 6.1 ± 1.5 0.241
PWV (cm/s) 1573.5 ± 718.7 1612.3 ± 423.2 0.283
ABI 1.1 ± 0.1 1.1 ± 0.2 0.211
IMT (mm) 0.7 ± 0.3 1.3 ± 1.1 < 0.0001
8-OHdG (ng/mg Cre) 9.7 ± 4.5 -
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The study subjects’ demographic and clinical data at the baseline and endpoint.
Baseline (2003-4) Endpoint (2012-13) p
Age (years) 53.7 ± 13.6 - -
Gender (M/F) 157 / 193 - -
BMI (kg/m2) 25.5 ± 5.0 25.5 ± 5.0 0.802
UpH 6.0 ± 0.8 6.2 ± 2.6 0.201
HbA1c (%) 6.9 ± 1.1 6.5 ± 0.5 0.0042
SBP (mmHg) 134.5 ± 18.6 128.0 ± 10.9 < 0.0001
HR (bpm) 73.0 ± 14.1 70.4 ± 8.5 < 0.0001
eGFR (ml/min/1.73 m2) 72.7 ± 19.8 55.5 ± 16.2 < 0.0001
ACR (mg/g Cre) 24.8 (0.0-4735.6) 55.1 (3.8-4999.5) < 0.0001
UA (mg/dL) 6.2 ± 1.7 6.5 ± 1.4 0.046
PWV (cm/s) 1573 ± 718 1612. ± 423 0.283
ABI 1.1 ± 0.1 1.1 ± 0.2 0.211
IMT (mm) 0.7 ± 0.3 1.3 ± 1.1 < 0.0001
8-OHdG (ng/mg Cre) 9.7 ± 4.5 -
DM 10-year follow-up study (n=350)
Despite of good glycemic and BP control, obesity, renal and vascular damages were not halted. ΔGFR 17/10 years
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Correlations between %IMT, %PWV, %eGFR, Δ log ACR and baseline parameter.
IMT PWV eGFR ACR
% IMT % PWV % eGFR ΔL ACR
r p r p r p r p
UpH -0.37 < 0.01 -0.12 0.01 0.23 < 0.01 -0.16 0.04
BMI 0.16 0.02 0.09 0.35 -0.17 0.05 0.13 0.05
UA 0.11 0.04 -0.06 0.57 -0.29 < 0.01 -0.10 0.08
HbA1c 0.01 0.95 -0.02 0.78 -0.12 0.08 -0.05 0.71
eGFR -0.17 0.01 -0.10 0.04 -0.01 0.80 -0.15 0.04
ACR 0.02 0.59 0.31 < 0.01 -0.26 < 0.01 -0.28 < 0.01
SBP 0.06 0.38 0.06 0.42 -0.07 0.12 0.16 0.04
HR 0.09 0.26 -0.01 0.83 -0.02 0.58 0.04 0.74
Acidic urine and uric acid were associated with renal-vascular damages
Ogawa S et al :BMJ Open Diabetes Res Care. 2015 Jun 30;3(1):
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%IMT Coefficient Std. Err p 95% Conf. Interval
UpH -55.332 10.712 0.000 -76.403 -34.260
BMI 1.228 2.410 0.611 -3.513 5.970
UA -4.982 4.477 0.267 -13.788 3.824
eGFR -0.160 0.369 0.664 -0.887 0.566
A multiple regression analysis that used the %IMT as the dependent variable and factors that individually correlated with %IMT as independent variables.
UpH is the only parameter
Ogawa S et al :BMJ Open Diabetes Res Care. 2015 Jun 30;3(1):
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New-onset CKD
• Logistic regression analysis for new-onset CKD (eGFR < 60 ml/min/1.73 m2) : acidic urine was an independent risk factor (p = 0.001), with an odds ratio of 0.522777 (Ref UpH < 6: 95% CI: 0.3526216 - 0.77504).
• In those who developed CKD, low UpH was also an independent risk factor in multiple regression analysis that used % change in eGFR as a dependent variable (β = 2.365226, p = 0.036).
Ogawa S et al :BMJ Open Diabetes Res Care. 2015 Jun 30;3(1):
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UpH Coefficient Std. Err p 95% Conf. Interval
8-OHdG -0.083 0.009 < 0.001 -0.101 -0.064
BMI 0.005 0.013 0.707 -0.020 0.030
UA -0.053 0.229 0.021 -0.098 -0.008
eGFR 0.006 0.002 0.001 0.003 0.010
ACR 0.000 0.000 0.002 0.000 0.000
HR -0.005 0.002 0.034 -0.009 0.000
A multiple regression analysis using UpH as the dependent variable and factors that correlated with UpH at baseline as independent variables.
Low UpH is associated with high ROS and serum UA Ogawa S et al :BMJ Open Diabetes Res Care. 2015 Jun 30;3(1):
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Intracellular pH
Acid overload Sulfate, FFA
Urine citrate
Pathogenesis of Pink Urine Syndrome
Ogawa S, et al: Clin Exp Nephrol 2015:19:822-9
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H++HCO3-←H2O+CO2 (3)
CO2
Glucose gluconeogenesis glycolysis
Phosphoenolpyruvate
PEPCK (2)
starvation, insulin resistance diabetes mellitus
Serine, Cysteine, Threonine, Glycine, Alanine Tryptophan
Pyruvate
Pyruvate carboxylase CO2
Oxaloacetate
Pyruvate dehydrogenase
Acetly-CoA
Citrate
α-ketoglutarate
Fumarate
Succinyl-CoA
Tyrosine, Phenylalanine
Isoleucine, Methionine, Valine, Threonine
Glutamata Glutamine
H+
NH4+
NH3
Histidine, Proline, Hydroxyproline, Arginine
TCA cycle
(4)
(4)
(4)
(5) NH3
mitochondrion
PEPCK: Phosphoenolpyruvate carboxykinase
Glycogenic amino acids
TCA cycle: tricarboxylic acid cycle
(1)
(Ogawa S, et al: Tohoku J Exp Med 239; 103-110, 2016)
The relationship, under acidotic conditions, between glucose metabolism and amino acids use in the renal proximal tubules.
malate shuttle
Oxaloacetate
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• Studied the relationship between
urine pH and urinary amino acids.
• Multiple regression analysis shows
that low urinary pH can be
explained by only low urinary
glutamate excretion (β = 0.0387, p<
0.0001)
• Glutamate is reabsorbed, but not
utilized for ammonia production.
• Where did it go?
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Nrf2 (Nuclear factor-erythroid related factor-2 )
ROS
Kobayashi A. et al. (2004) Mol. Cell Biol. 24:7130-7139.
NQO1
keap 1
Glutathione
Keap 1 and Nrf2 as defense mechanism for Stress
Low Urine pH Oxidative stress marker
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近位尿細管にNrf2は発現・活性化しているのか? Nrf2 Nrf2 Nrf2
NQO1 NQO1 NQO1
Diabetic N IgA Miminal Change
S Ogawa et al JSN 2014
Oxidative Stress and renal amino acid metabolism
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Glucose
Phosphoenolpyruvate
Pyruvate
Oxaloacetate
Fumarate
Succinyl-CoA
α-ketoglutarate
Glutamate
Glutamine
H+ NH3
H+ NH3
CO2 Lactate
Pentose phosphate pathway (PPP) Nucleotide
Uric acid
Glu
tam
ino
lysi
s
Glutathione
A
B
C
Cysteine
Nrf2 OS Glycogenic amino acids
Relations between synthesis of ammonia and Nrf2 and glucogenic amino acids.
(Ogawa S, et al: Tohoku J Exp Med 239; 103-110, 2016)
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Clin Exp Nephrol. 2017 Mar 22. The relationship between the renal reabsorption of cysteine and the lowered urinary pH in diabetics Ogawa S et al ・100 non-diabetic obese individuals and 100 diabetics ・blood amino acids, urinary amino-acid excretion, and their relationship with the UpH
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Urine pH: unrecognized risk factor or marker of metabolic insults
Excessive acid loads
Subclinical acidosis
Inflammation, RO, RAAS
Organ damages
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(Goraya N, et al: Kidney Int 86; 1031-1038, 2014)
Error bars (mean±s.e.) of plasma creatinine-calculated estimated GFR (crGFR) (left) and plasma cystatin C–calculated estimated GFR (cysGFR) (right) across four time points including baseline and 3 years’ follow-up.
*P<0.05 vs. Usual Care at 2 year;+P<0.05 vs. Usual Care at 3-year follow-up.
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Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative
Damage in Proximal Tubular Cells
Tomokazu Souma,*† Michiaki Abe,*‡ Takashi Moriguchi,† Jun
Takai,† Noriko Yanagisawa-Miyazawa,* Eisuke Shibata,* Yasutoshi
Akiyama,* Takafumi Toyohara,*
Takehiro Suzuki,* Masayuki Tanemoto,* Takaaki Abe,* Hiroshi
Sato,* Masayuki Yamamoto,† and Sadayoshi Ito*
JASN 22:635-48, 2011
Low urinary pH may not only be a marker (or insult) of renal damages but also be a contributor to renal damages
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HK-2 Cell
Proximal tubular cells)
Chamber pH:7.0, 6.6, 6.4, 6.0
±OA-Alb15g/L
Am J Physiol Renal Physiol. (2002) 283:F20-8.
O2・- DHE
Ethidium
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Influence of pH on OA-Alb-induced ROS generation
HK-2 cells; florescence microscopy
second
Ethidium
(U)
pH6.0
pH6.4
(Souma T, Abe M, et al: JASN 22:635-48, 2011)
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Pyk2 connects pH and protein overload
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Urine pH: unrecognized risk factor or marker of metabolic insults
Excessive acid loads
Subclinical acidosis
Inflammation, RO, RAAS
Cardio-Renal damages
Low urine pH
Reduced NH 3
Mets