TIME TO RETIRE MICROALBUMIN“the affirmative case”

Richard J MacIsaacPhD FRACP

Department of Endocrinology & Diabetes,St Vincent's Hospital & University of Melbourne

AACB 53rd Annual Scientific ConferenceSeptember 2015

TIME TO RETIRE MICROALBUMIN“the affirmative case”

Vs

It is time for micoalbuminuria to step down!

Microalbuminuria X• Microalbuminuria = A2• High Variability• Low Specificity• Spontaneous Regression• Δ AER ≠ Δ GFR

Microalbuminuria å Good prognostic marker

NM

µ

A paradigm of Diabetic Kidney Disease based solely onmicroalbuminuria needs to be questioned!

What is microalbuminuria?

Microalbuminuria refers to a range ofurinary albumin excretion

excretion

Microalbuminuria DOES NOT refer to fragments of urinary albumin

Immunochemically unreactive albumin in urine: fiction or reality? Speeckaert MM et al.Critical Reviews in Clinical Laboratory Sciences, 2011; 48(2): 87–96

Microalbuminuria as aprognostic marker

Higher levels of urinary albumin excretion within thenormal range predict faster decline in glomerular

filtration rate in diabetic patients

Babazono T et al. Diabetes Care 2009;32:1518-1520

WomenMen

Measurable Urinary Albumin Predicts Cardiovascular Risk evenamong Normoalbuminuric Patients with Type 2 Diabetes

Ruggenenti P et al. J Am Soc Nephrol 2012,23:1717

Why has microalbuminuria reigned solong as the preeminent marker of

diabetic kidney disease?

An Immunoassay method for urinary albumin at low concentrationsH.Keen & C. Chlouverakis

THE LANCET1963, 2(7314): 913-914

Summary of early studies demonstrating that microalbuminuriapredicts diabetic nephropathy* (DN) in type 1 diabetes

Viberti Parving Mogensen Mathiesen(1982) (1982) (1984) (1984)

No of patients 63 23 43 71

Age (years) 40 32 25 30

Follow-up (years) 14 6 10 6

Proposed discrimination 30 30 15 70rate (µg/min)

Development of DN below 2/55 2/15 0/29 3/64discrimination value

Development of DN above 7/8 6/8 12/14 7/7discrimination value (88%) (75%) (86%) (100%)

*Definition of DN included: protein excretion > 500 mg/24 h, AER > 150 µg/min, AER > 200 µg/min oralbustix positive depending on the study

MacIsaac RJ and Jermus G, Curr Opin Nephrol Hypertens 2011,20:246–257

UREMIA INVESTIGATION, 9(2), 85-95 (1985-86)Microalbuminuria: An Early MarkerOf Renal Invilvement in Diabetes

C. E. Mogensen, M.D.A.Chachati, M.D.C.K. Christensen, M.D.C.F. Close, M.D.T. Deckert, M.D.E. Hommel, M.D.J. Kastrup, M.D.P. Lefebvre, M.D.E.R. Mathiesen, M.D.B. Feldt-Rasmussen, M.D.A. Schmitz, M.D.G.C. Viberti, M.D.

“According to evaluations anddiscussions among the presentauthors, the following criteriamay be used for the classificationand renal involvement in theinsulin-dependent patient only,both in clinical work and inresearch projects.

Microalbuminuria is presentwhen urinary albumin excretionrate is greater that 20 µg/minless than or equal to 200µg/min.”

Log AER

Normoalbuminuria(AER < 20 g/min)

Microalbuminuria(AER 20-200 g/min)

Macroalbuminuria(AER > 200 g/min)

GFR100

(ml/min)

Evolution of Diabetic CKD

IncipientNephropathy

OvertNephropathy

GFR10 15 20 yrs

Microalbuminuria-variability

201612

840

ALBUMINEXCRETIONRATE(μg/min)

VARIANCEOF ALBUMINEXCRETIONRATE(μg/min)

NIGHT URINEDAY URINE

p< 0.0005

p< 0.05

CONTROLS DIABETICS

Mogensen CE et al Uremia Investigation 1985-86,9(2):85-95

400

300

200

100

0

High intra-individual day-to-day variation (CV) ofurinary albumin excretion (40-50%)

Seasonal variations of urinary albumin creatinineratio in Japanese subjects with type 2 diabetes

and early nephropathy?

Wada et al. Diabetic Medicine 2012,29:506-508

Microalbuminuria-specificity

The disease spectrum of microalbuminuriaand its role as an indicator of inflammation

Microalbuminuria as a Risk Predictor in Diabetes: The Continuing SagaBakris GL & Molitch M Diabetes Care 2014,37:867-875

The disease spectrum of albuminuria and itsassociated CV risk and kidney disease presence

Microalbuminuria as a Risk Predictor in Diabetes: The Continuing SagaBakris GL & Molitch M Diabetes Care 2014,37:867-875

Does microalbuminuria representan irreversible stage of

Diabetic Kidney Disease?

Type 1 diabetes Type 2 diabetesPerkins et al. NEJM (2003) 348: 2285 Aracki et al. Diabetes (2005) 54:2983

Factors associated with regression:Microalbuminuria of short duration,RAS blockers, low A1c/SBP

Factors associated with regression:Microalbuminuria of short duration,low A1c/SBP & lipid levels

Microalbuminuria: Rates ofremission/regression vs progression

216 patients with micro

113 patients studied

23/113 66/113 21/113(20%) (58%) (19%)

Normo Micro Macro

6 years 6 years

386 patients with micro

220 patients studied

88/220 99/220 33/220(40%) (45%) (15%)

Normo Micro Macro

Does kidney structure andfunction correlate with

microalbuminuria?

Prevalence of low glomerular filtration rate(GFR < 60 ml/min/1.73m2) and normoalbuminuria

'Progressive diabetic nephropathy. How useful is microalbuminuria?: contra‘MacIsaac et al RJ Kidney Int 2014, 86:50

GFR < 60 ml/min/1.73m2)

Biopsy findings in microalbuminuric patients with type2 diabetes and preserved renal function

I III

II

Fioretto et al., Diabetologia 1996, 39, 1569-1576

Interstitialchanges

Fioretto P, Mauer M, Brocco E et al. Patterns of renal injury in NIDDM patients withmicroalbuminuria. Diabetologia 1996; 39: 1569

Is microalbuminuria a validsurrogate end point in

clinical trials?

‘Progressive diabetic nephropathy. How useful is microalbuminuria?: contra’MacIsaac RJ et al Kidney Int 2014, 86:50

Microalbuminuria

Macroalbuminuria

Summary

IS IT TIME TO RETIRE MICROALBUMINURIA?

Vote: YES

Microalbuminuria = A2

High Variability

Low Specificity

Spontaneous Regression

Δ AER ≠ Δ GFR

Problems with urinary albumin within the microalbuminuric range

IS IT TIME TO RETIREMICROALBUMINURIA?

Retire the name- VOTE YES

Retire micro-albuminuriafrom its preeminentrole in CKD in diabetes VOTE YES

IS IT TIME TO RETIREMICROALBUMINURIA?

IS IT TIME TO RETIREMICROALBUMINURIA?

YES

Progression versus remission/regressionof microalbuminuria

‘Progressive diabetic nephropathy. How useful is microalbuminuria?: contra’MacIsaac RJ et al. Kidney Int 2014, 86:50

*regression