Microalbuminuria: today epidemiology data and current pathogenetic views By D.T.

Karamitsos

Giancarlo Viberti
Professor of Diabetes and Metabolic Medicine

A great investigator in microalbuminuria

Microalbuminuria today epidemiology data and current pathogenetic views

D. Karamitsos
in

New trends in diabetic nephropathy

9th October 2009

Proteins in urine
[beta]-2 microglobulin immunoglobulin light chains small amounts of albumin

Tamm--Horsfall glucoprotein (from tubules)

Most of the protein in normal urine is the TammHorsfall glucoprotein

Proteinuria and Microalbuminuria (MAU)

Upper normal Urinary protein excretion
<150 mg/24h

Upper normal Urinary albumin excretion

< 30 mg/24h or < 20 g/min

Microalbuminuria= Albumin in urine 30-300 mg/24h Macroalbuminuria= Albumin in urine >300 mg/24h

Methods for MAU

RIA ELIZA Radial immunodiffusion Solid phage fluoroimmunoassay immunoturbitometry

Screening with Micral test (dip strips)

Sensitivity 86-100%, Specificity 91-97%

Poulsen et al. Diab Metab 1992;18:395-400. Marshal et al. Clin Chem 1992;38:588-591.

MAU assessment
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 24h Limitations in muscular man or cachectic patient -underestimated in muscular -overestimated in cachectic

Factors that increase the albumin in urine

Heavy exercise Fever High protein diet Urinary infection Heart failure rterial hypertension Erect position for long

Natural history of MAU

Creatinine Clearance

16 g Microalbuminuria
24 hour Urinary protein

Microalbuminuria

Frank proteinuria

-300mg - 30mg

Years of diabetes

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

Jarret et al. Diabet Med 1984;1:17-19 Mogensen J Intern Med 2003;254:45-66.

MAU

predictive of nephropathy
Type 1 DM pts with MAU X 20 greater risk for proteinuria and decline of GFR over the next 10-14 years Factors: Poor metabolic control and hypertension

The decline of GFR starts when the AER exceeds 105mg/24h

Parving et al. Acta Endocrinol (Copenh) 1982;100:550-555 Mathiesen et al. Diabetologia 1984;26:406-410. Viberti et al. Lancet 1982;I:1430-1432. Mogensen et al. N Eng J Med 1984;311:89-93. Rudberg et al. Kidney Int 1992;41:822-828.

Pathogenesis of microalbuminuria

Podocytes
Podocytes normally prevents protein leakage out in the urinary space
Podocytes Epithelium of glomerulus

Messangial cells

Capillary wall

Proximal tubule

mw <7000 diameter <4nm

mw >70000
diameter >8nm

podocytes

Fenestrated Capillaries Basement membrane

Altered biochemistry of basement membrane

Older theory -Diminished proteoglycans (heparane sulfate) -Loss of negative anions New theory

-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

Proteins of slit diaphragm

nephrin,
podocin, P-cadherin,

mFAT 1,
the nephrin homologue neph 1, and associated intracellular proteins such as CD2AP.
The structural and functional integrity of the GF barrier is dependent on
interactions amongst this proteins. Hyperglycemia affect these proteins with final result podocytes injury.

Reddy et al. Current Opinion in Nephrol and Hypert. 2008;17: 32-36

Hyperglycemia the responsible factor

Mechanical stress Hyperglycemia ROS Diminished Angrin Podocytes apoptosis, Injury and dysfunction Increased Ang II TGF-1 Diminished Nephrin Fibrosis Increased secretion of VEGF

Chronic inchemic Injury to the tubulointerstitium

Capillary dilatation Intraglomerular hypertension Detachement of podocytes

Injuriy to the glomerulus endotheliun

AlbuminuriaProteinuria

Lysosomes and MAU

The proximal kidney tubules contain lysosomes that beakdown the reabsorbed proteins Hyperglycemia causes dysfunction of degradation pathway that may lead to albuminuria Hyperglycemia is harmfull to this tubular function because leads to increased Ang II and TGF-1 that

cause hypertrophy and fibrosis

Comper et al. Curr Diab Rep. 2008;8:477-485. Piwowar et al. Med. Sci. Monit. 2006;12:CR210-214.

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 Biocem. 2006;281:29606-29613.

Epidemiology of MAU

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

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%
Klein et al. Arch Intern Med 1992;152:153-158 Moore et al. Arch Dis Child 2000;83:239-243 Parving et al. Kidney Int 2006;69:2057-2063 Futrakul et al. Renal Failure 2009;31:140-143

Normoalbuminuria MAU
in Type 2 DM ~2,0% till 2,5% per year 25% by 10 years of diagnosis DM

Adler et al. Kidney Int 2003;63:225-232. Ruggenenti et al. N Eng J Med 2004;331; 1941-1951.

Normoalbuminuria MAU

Type 1 DM: in 10 years

30% microalbuminuria 40% proteinuria

30% normoalbuminuria
Parving et al. Acta Endocrinol 1982;100:550-555 Viberti et al. Lancet 1982;I:1430-1432. Mogensen et al. N Eng Med 1984;311:89-93

Normoalbuminuria MAU
Type 1 DM: After 18 years of follow up Microalbuminuria (persistent) 34 %
Spontaneous permanent regression from microalbuminuria to normoalbuminuria is rare, suggesting that, in most cases, microalbuminuria represents relentless progressive nephropathy

Hovind et al. BMJ 2004;328:1105-1109.

MAU Proteinuria
Type 2 DM Rate of 2,8 per year

Adler et al. Kidney Int 2003;63:225-232.

MAU Proteinuria
With new treatment strategies possibly reduced the rate of progression
BP treatment ? Better diabetes management ?

Over 5-10 years proteinuria ~30%

Caramori et al. Diabetes 2000;49:1399-1408.

Natural history of MAU in 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

Steinke et al. Diabetes 2005;54:2164-2171 Giorgino et al.(Eurodiab) Diabetologia 2004;47:1020-1028 And others

Natural history of MAU in 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. Perkins et al. N Eng J Med 2003;348:2285-2293

MAU prevalence in obesity

BMI<25 BMI 25-30 BMI>30 3,1% 12,1% 27,2%

RR for urine albumin> 20mg/l is 8,0 if BMI is above 80th percentile

Kawar et al. Nephron Clin Prac 2009;112:c205-212

MAU and CV mortality 1 in type 2 DM

-Microalbuminuria predics mortality RRX5 -Microalbuminuria predicts incident clinical CHD

-Jarret RJ, Viberti GC, Argyropoulos A, et al

Diab Medicine 1984;1:17-19. -Muttock et al. Diabetes 1998;47:1786-1792

MAU and CV mortality 2

Relative risk 2,94 - 3,72 Strong relationship between Microalbuminuria and severity of CAD

Deveci et al. Angiology 2009;EHP Ljungman et al. Am J Hypertens 1996;9:770-778 Borch-Johnsen et al. Arteriosscler Thromb Vasc Biol 1999;19:1992-1997. Haffner SM et all. Arteriosclerosis 1990;10:727-731.

MAU anemia
From 502 pts Anemia 23%
Anemia
GFR Normal Normal Abnormal

Normal alb/creat ratio Microalbuminuria Proteinuria

19% 29% 41%

Adetunji et al. Diab Res Clin Pract 2009;85:179-182

MAU and survival

of type 2 DM patiets
60

57%
50

% survival after 9,5 years

43%
40

30

29% 22%

Series1

20

10

0
<15 16-29 30-140 >140

Urine albumin concentration (g/ml

Mogensen CE. N Eng J Med 1984;310:356-360.

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 these patients.

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.

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 diabetes and hypertension