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7/22/2019 Micro-Albuminuria in diabetes mellitus
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Microalbuminuria: today
epidemiology data and
current pathogenetic viewsBy D.T. Karamitsos
Giancarlo Viberti
Professor of Diabetes and Metabolic MedicineA great investigator in microalbuminuria
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Microalbuminuria today
epidemiology data and currentpathogenetic views
D. Karamitsos
in
New trends in diabetic nephropathy
9th October 2009
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Proteins in urine
[beta]-2 microglobulin
immunoglobulin light chains
small amounts of albumin Tamm--Horsfall glucoprotein (from tubules)
Most of the protein in normal urineis the TammHorsfall glucoprotein
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ProteinuriaandMicroalbuminuria (MAU)
Upper normal Urinary protein excretion
300mg/24h
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Methods for MAU
RIA
ELIZA
Radial immunodiffusion
Solid phage fluoroimmunoassay
immunoturbitometry
Screening with Micral test(dip strips) Sensitivity 86-100%,
Specificity 91-97%
Pou lsen et al. Diab Metab 1992;18:395-400.
Marshal et al. Clin Chem 1992;38:588-591.
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MAUassessment
24h urine collection
Random(better early morning speciment)
Albumin to creatinine ratio (mg/g)
Good correlation to 24h urine collection
For Alb/Creat ratio:
No vigorous exercise the last 24hLimitations in muscular man or cachectic patient
-underestimated in muscular
-overestimated in cachectic
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Factors that increase the albumin in
urine
Heavy exercise
Fever
High protein diet
Urinary infection
Heart failure rterial hypertension
Erect position for long
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Natural history ofMAU
CreatinineC
learance
Microalbuminuria Frank proteinuria
24 hour
Urinaryprotein
16 g
-300mg
- 30mg
Years of diabetes Microalbuminuria
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Significance of MAU
Generalized endothelial dysfunction
Marker for diabetic vascular disease
Marker for nephropathy
Means early mortality in type 1 or 2 DM Regression to normoalbuminuria is possible but rare
without intensive treatment
But no good relation to structural glomerular changes
Jarr et et al. Diabet Med 1984;1:17-19
Mogensen J Intern Med 2003;254:45-66.
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MAU
predictive of nephropathy
Type 1 DM pts with MAU
X 20greater risk for proteinuriaand decline of GFR
over the next 10-14 years
Factors: Poor metabolic control and hypertension
The decl ine of GFR starts when the AER exceeds 105mg /24h
Parving et al. Ac ta Endoc rino l (Copenh) 1982;100:550-555
Mathiesen et al. Diabeto logia 1984;26:406-410.
Vibert i et al. Lancet 1982;I:1430-1432.
Mog ensen et al. N Eng J Med 1984;311:89-93.Rud berg et al. Kidney Int 1992;41:822-828.
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Pathogenesis of microalbuminuria
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Podocytes
Podocytes normally prevents proteinleakage out in the urinary space
PodocytesEpithelium
of glomerulus
Messangial cells
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70000 podocytes
diameter
mw
diameter
mw
Capillary
wall
Proximal
tubule
Fenestrated
Capillaries
Basement
membrane
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Altered biochemistry
of basement membrane
-Increased glucoseReactive oxygen species-diminished angrin
-local increase of Ang IIdiminished nephrin-Podocytes apoptosis and detachement
-Increase permeability of albumin
Gaddameedi et al. Cur Op Nephr Hypertens 2008;17 : 32-36
-Diminished proteoglycans (heparane sulfate)
-Loss of negative anions
Older theory
New theory
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Proteins of slit diaphragm
nephrin, podocin,
P-cadherin,
mFAT 1, the nephrin homologue neph 1, and associated
intracellular proteins such as CD2AP.
The structu ral and fun ct ion al integr i ty of the GF barr ier is dependent on
interact ions amongs t th is pro teins.
Hyperg lycemiaaffect these pro teins w ith f inal result pod ocytes in jury.
Reddy et al. Curren t Opin ion in Neph rol and Hypert. 2008;17: 32-36
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Hyperglycemia the responsible
factor
Hyperglycemia Diminished Angrin
Increased Ang II
ROS
Diminished Nephrin
Podocytes
apoptosis, Injury
and dysfunction
Increased secretion of
VEGF
Capillary dilatation
Intraglomerular hypertension
Detachement of podocytes
Injuriy to the
glomerulus
endotheliun
AlbuminuriaProteinuria
Chronic inchemic
Injury to the
tubulointerstitium
Mechanical stress
TGF-1 Fibrosis
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Lysosomes and MAU
The proximal kidney tubules contain lysosomesthat
beakdown the reabsorbed proteins
Hyperglycemia causes dysfunction of degradation
pathwaythat may lead to albuminuria
Hyperglycemia is harmfull to this tubular function
because leads to increased Ang IIand TGF-1that
cause hypertrophy and fibrosis
Com per et al. Curr Diab Rep. 2008;8:477-485.
Piwow ar et al. Med. Sc i. Mon it. 2006;12:CR210-214.
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Heparan sulphate expression
In experimental and early human diabetic
nephropathy urinary albumin excretion is not caused
by loss of glomerular HS expression or sulfation and
suggest other mechanisms to explain increased
glomerular albumin permeability.
(method of antibodies for glomerular Heparan sulfate
expression)
Van den Born et al. J B iocem . 2006;281:29606-29613.
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Epidemiology of MAU
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Natural history of diabetic
nephropathy
Renal disease affects 30-40% of diabetic people
Microalbuminuria usually presents during
second decade of diabetes Proteinuria usually develops after a further 10
years
Once proteinuria is present starts renal decline
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Epidemiology of MAU
DM type 1=prevalence 21%
DM Children=prevalence 9,7%
DM type 2=prevalence 39%MacroAlb 10%
NormoAlb 51%
Hypertension= 8-23%
K lein et al. Arch Intern Med 1992;152:153-158
Moo re et al. Arch Dis Chi ld 2000;83:239-243
Parvin g et al. K idney Int 2006;69:2057-2063
Futr aku l et al. Renal Failur e 2009;31:140-143
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Normoalbuminuria MAU
in Type 2 DM ~2,0%till 2,5%per year
25%by 10 yearsof diagnosis DM
Adler et al. Kid ney Int 2003;63:225-232.
Rug genenti et al. N Eng J Med 2004;331; 1941-1951.
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NormoalbuminuriaMAUType 1 DM: in 10 years
30% microalbuminuria40% proteinuria
30%
normoalbuminuria
Parving et al. Acta Endoc rino l 1982;100:550-555
Vibert i et al. Lancet 1982;I:1430-1432.
Mog ensen et al. N Eng Med 1984;311:89-93
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Normoalbuminuria MAU Type 1 DM: After 18 years of follow up
Microalbuminuria (persistent) 34 %
Hov ind et al. BMJ 2004;328:1105-1109.
Spontaneous permanent regression from microalbuminuria to
normoalbuminuria is rare, suggesting that, in most cases,
microalbuminuria represents relentless progressive nephropathy
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MAU Proteinuria
Type 2 DMRate of 2,8per year
Adler et al. Kid ney Int 2003;63:225-232.
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MAU Proteinuria
With new treatment strategies possibly
reduced the rate of progression
BP treatment ?
Better diabetes management ?
Over 5-10 years proteinuria ~30%
Caram or i et al. Diabetes 2000;49:1399-1408.
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Natural history of MAUin type 1 DM
64% of the patients that developed
microalbuminuria reverted to
normoalbuminuria without treatment
From other six papers the regression was
35%, 39%, 40%, 51%, 58%, 59%
The earlier the age of diabetes appearance the
higher the regression of microalbuminuria
Stein ke et al. Diabetes 2005;54:2164-2171
Gio rg ino et al.(Eurodiab) Diabeto log ia 2004;47:1020-1028And others
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Natural history of MAUin adolescents with type 1 DM
Those with bordeline microalbuminuria have double
risk for persistent microalbuminuria
Incidence of persistent microalbuminuria 4,6% per
1000 patient-years
Regression of microalbuminuria in 58% of patients
Stone et al. Diabetes 2006;29:2072-2077.
Perkin s et al. N Eng J Med 2003;348:2285-2293
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MAU prevalence
in obesity
BMI30 27,2%
RR for u rine album in> 20mg/l is 8,0
if BMI is above 80thpercenti le
Kawar et al. Nephron Clin Prac 2009;112:c205-212
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MAU and CV mortality 1
in type 2 DM
-Microalbuminuria predics mortality RRX5
-Microalbuminuria predicts incident clinical CHD
-Jarret RJ, Vibert i GC, Arg yropou los A , et al
Diab Medic ine 1984;1:17-19.
-Mutto ck et al. Diabetes 1998;47:1786-1792
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MAU and CV mortality 2
Relative risk 2,94 - 3,72
Strong relationship between
Microalbuminuria and severity of CAD
Deveci et al. Ang iolo gy 2009;EHP
Lju ngman et al. Am J Hypertens 1996;9:770-778
Borc h-Joh nsen et al. A rterios sc ler Thromb Vasc B iol 1999;19:1992-1997.
Haffner SM et all. A rterio sc leros is 1990;10:727-731.
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MAU anemia
From 502 pts Anemia 23%
Normal alb/creat ratio 19%
Microalbuminuria 29%
Proteinuria 41%
Anemia GFR
Normal
Normal
Abnormal
Adetu nj i et al. Diab Res Cli n Prac t 2009;85:179-182
MAU d i l
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MAUand survivalof type 2 DM patiets
0
10
20
30
40
50
60
140
Urine albumin concentration (g/ml
%s
urvivalafter
9,5years
Series1
57%
43%
22%
29%
Mogensen CE. N Eng J Med 1984;310:356-360.
Viberti G
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Viberti G.
Regression of albuminuria: latest evidence for a
new approach.
J Hypertens suppl 2003;21:s24-s8.
Blockade of the renin-angiotensin system with ACE
inhibitors or AR-blockers is a most effective means of
treating MAU and preventing its progression to overt
nephropathy and, perhaps, the associated CV disease.
The combination of these agents with diuretics, even
when used in low doses, may further reduce AER in thesepatients.
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Summary of MAU (1)
MAU is the earliest detectable clinical abnormality in
diabetic glomerulopathy
Pathogenetic implication of proteoglycans loss has
been recently questioned
Injury of podocytes is propably the most important
factor
Hyperglycemia Increases the local Ang II
Ang II Increases VEGF and decreases nephrin which
are the mediators of albuminuria.
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Summary of MAU (2)
MAU may regress
MAU predics the development of Renal disease in
type 1 DM (x20 proteinuria over 10 years)
MAU predics the development of Renal disease in
type 2 DM (x5 proteinuria over 10 years)
MAU means increased CV morbidity and mortality
MAU is suggestive for better treatment of diabetesand hypertension