micro-albuminuria in diabetes mellitus

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

micro-albuminuria in diabetes mellitus

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