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  • What is Microalbuminuria (MA)? MA defined: 30-300mg albumin in urine over 24 hrs or (20-200 µg/min). Not detected on ‘protein’ dipstick. Most accurate assessment is 24hr collection, however most convenient and sufficient screening test is an Albumin : Creatinine ratio on spot urine (usually first morning) Why is Microalbuminuria important? MA is a marker of early stage renal damage. The degree of microalbuminuria is proportional to the degree of vascular damage. Regression decreases risk. MA is a signal from the kidney that CV risk is increased. American Diabetes Association (ADA). Diabetic Nephropathy. Diabetes Care . 2004; 27: (Suppl 1): S79-83 Garg JP, Bakris GL. Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med 2002;7:35-43
  • CV Risk increases with Degree of Proteinuria – so microalbuminuria is as important as proteinuria. Proteinuria is a window into blood vessel integrity and its presence predicts poor survival. The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients with type 2 diabetes who were followed for 5 years. Over 6 years 8% of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria died - predominantly from cardiovascular disease; P < 0.01 [normoalbuminuria versus micro- and macroalbuminuria] and P < 0.05 [microalbuminuria versus macroalbuminuria]. 1. Gall MA, Borch-Johnsen K, et al. Diabetes 1995; 44(11):1303-1309.

Microalbuminuria Microalbuminuria Presentation Transcript

  • Dr A. Alfi Consultant Nephrologist Transplant physician Head of Department of Nephrology KAAH& OC, Jeddah A Valid Risk Predictor in Diabetic Patients Microalbuminuria Dr M. Al-Ameen Nephrology Specialist Transplant physician KAAH& OC- Jeddah
  • Case
    • 50 year-old female.
    • Known type 2 diabetes 5 years earlier.
    • presented to OPD for routine visit.
    • No history of hypertension.
    • Not known to have had a previous CV event.
    • She visits the ophthalmologist annually with no retionopathy reported.
    • Her medications include:
      • an over-the-counter multivitamin.
      • an oral hypoglycemic agent.
      • a statin for known hypercholesterolemia.
    • She is otherwise well.
    • Findings on physical examination are unremarkable.
    • Except that her BP that previously was less than 130/80, became 135/85.
  • Case: Questions
    • Should the woman be screened for microalbuminuria on this visit ?
    • What is the best way to screen for it ?
    • If the test result is positive, what does this mean in terms of the patient's risk for cardiovascular and renal disease ?
    • Is there anything that can be done medically for microalbuminuria ?
    • What follow-up is required, including management of other risk factors ?
    • Sheldon et al; 2002CMAJ • September 3, 2002; 167 (5)
  • Definition of Microalbuminuria (MA)
    • Normally only a small amount of albumin is filtered at the glomerulus, and most of that albumin is degraded and reabsorbed by the proximal tubule.
    • Usually only <1 mg/dl of albumin appears in the urine.
    • However, a number of conditions can temporarily or permanently cause an increase in urinary protein excretion by either altering glomerular membrane permeability, inducing glomerular capillary hypertension, or reducing tubular reabsorption.
    • Tobe et al; Can Med Assoc J 2002;167:499–503.
  • Definition of Microalbuminuria (MA)
    • Microalbuminuria (MA) is defined as the range in between: urinary excretion of albumin of 20 to 200 ug/minute or 30 to 300 mg/24 hours.
  • Definition of MA
    • There is difference between proteinuria and albuminuria.
    • Normal protein in urine should not exceed 150 mg/day.
    • This 150 mg protein includes Tamm Horsfall protein (~70mg), protein of blood group (~35mg), other proteins (enzymes, hormones, Ig etc..) and Albumin (0-30mg) .
    • So, Albumin in urine should not exceed 30mg/day.
    • The standard urinalysis dipstick, however, can detect albumin only at levels greater than 300 mg/24 hours, but MA can be accurately measured by several widely available sensitive methods (ELISA, RIA, nephelometry).
    Definition of MA
    • Normalbuminuria = < 20 ug/minute or
    • < 30 mg/24 hours.
    • Microalbuminuria = the range in between: urinary excretion of albumin of 20 to 200 ug/minute or 30 to 300 mg/24 hours.
    • Macroalbuminuria = more than 200 ug/min, or 300 mg/24 hours.
    Definition of MA
  • Definition of MA Condition Urine Dipstick Daily urine mg /d Timed Urine Collection mcg/min Normoalbuminuria Negative < 30 <20 Microalbuminuria Negative 30-299 20-199 Macroalbuminuria Positive >300 >200
    • Race/ethnicity
    • Male gender
    • Older age
    • Low birth weight
    • Diabetes
    • Hypertension
    • Obesity
    • Smoking
    Causes of MA Non-modifiable Modifiable well proven likely
    • High salt diet
    • High protein diet
    • Hyperlipidemia
    • Fever
    • Exercise
    • CHF
    • UTI
    • Vaginal discharge
  • Causes of MA
    • Langston C in 2004 classified MA as:
        • Prerenal : strenuous exercise, fever, hypothermia, seizures, and venous congestion.
        • Renal MA: the goal of this lecture
        • Postrenal : UTI and hematuria if there is sufficient blood to cause the urine to be grossly pink or red.
        • Langston C;journal of A A H A 40:251-254 (2004)
    • So, before dignosis of renal MA, prerenal and postrenal causes shold be excluded
  • Urine Tests for MA
    • Albumin-to-Creatinine Ratio in a random spot collection
    • 24-h Urine Collection with creatinine, allowing the simultaneous measurement of creatinine clearance
    • Timed (e.g., 4-h or overnight) collection.
    • Albumin-to-Creatinine Ratio is preferred (easy and accurate):
      • First-void or other morning collections are best because of the known diurnal variation in albumin excretion
      • If this timing cannot be used, uniformity of timing for different collections in the same individual should be employed.
    Urine Tests for MA
  • Measurement of MA
    • Specific assays :
        • Radioimmunoassay
        • Enzyme-linked immunosorbent assay
        • Nephelometry
    • Reagent tablets or dipsticks for microalbumin may be carried out, since they show acceptable sensitivity (95%) and specificity (93%) when carried out by trained personnel.
        • All positive tests by reagent strips or tablets should be confirmed by more specific methods.
  • MA: Susceptible diabetics
    • If the urine albumin excretion is in the upper range of normal (20–30 mg/d).
    • If the systolic blood pressure is greater than 130 mm Hg.
    • If the glycosylated hemoglobin level is greater than 8. or
    • If the total cholesterol level is greater than 5.24 mmol/L.
    • Sheldon et al; 2002CMAJ • September 3, 2002; 167 (5)
  • MA: PREVALENCES in the General Population normal 0-10mg/l macroproteinuria >200 mg/l microalbuminuria 20-200 mg/l (~7%) high-normal albuminuria 10-20 mg/l Hillege HL et al. J Int Med 2001;249:519-26 Microalbuminuria was present in 7.2% of the subjects and independently associated with age, gender, hypertension, diabetes, smoking, previous myocardial infarction and stroke.
  • Incidence of MA
    • Microalbuminuria is likely to be found in one-third or more of diabetic patients.
    • Sheldon et al; 2002 CMAJ • September 3, 2002; 167 (5)
  • MA: Pathogenesis Metabolic Changes Structural Changes Functional Changes Macroalbuminuria Hyperglycemia CKD CVD Microalbuminuria
  • MA: Pathogenesis
  • MA: Pathogenesis
    • Structural Changes
    • Mesangial Expansion
    • GBM Thickening
    • Renal Hypertrophy
    • Glomerulosclerosis
    • Functional Changes
    • Incresed Renal Plasma Flow
    • Hyperperfusion
    • Afferent Arterioar VD, Efferent Arteriolar VC
    • Increase Intraglomerular Pressure
    • Increased Glomerular Hydrostatic Pressure
    • Hyperfiltration
    • Metabolic Changes
    • Advanced glycosylation end products
    • GF, Cytokines (TGF-B)
    • Protein Kinase C
    • Polyol pathway
    • Reactive Oxygen Species
    • Endothelial Dysfunction
    • Angiotensin II
    • G lucotoxicity
  • Pathogenesis: Role of Endothelial Dysfunction
    • MA is thought to be the consequence of generalized endothelial damage along the vascular tree, including the glomerulus .
    • Enzymes involved in the metabolism of anionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuria and the associated complications.
    • Genetic polymorphism of such enzymes is possibly the main reason for variation in susceptibility.
    • Deckert et al, Dibetologia, 1989
  • Natural History in DM 1
    • Microalbuminuria is not usually a presenting finding at the onset of DM1.
    • After a 5- to 10-yr duration of diabetes, susceptible patients develop intermittent microalbuminuria before having persistent microalbuminuria
  • Natural History in DM 1
  • Natural History in DM 2
    • Because of the insidious onset of DM2, the true duration of the disease is often not known. It has been reported that a duration of >6 yr of diabetes may have existed before diagnosis
    • Subjects often present with microalbuminuria at that point.
    • However, diabetic nephropathy in DM2 is similar to nephropathy in DM1 with similar pathology, response to interventions of glucose control and anti-angiotensin II therapy, and progression to chronic renal failure
  • Significance of MA in Diabetic Patients
    • MA predicts clinical nephropathy.
    • MA predicts an increased incidence of cardiovascular disease and cardiovascular mortality.
    • In other words, MA doubled the risk of having a cardiovascular event in diabetic pts.
    • MA is a marker of early stage renal damage.
    • The degree of microalbuminuria is proportional to the degree of damage.
    • Regression of MA decreases the risk.
    MA Predicts Overt Nephropathy
    • In type 1 Diabetes without specific intervention:
      • Only 80 % of microalbuminuric patients will develop macroalbuminuria.
      • Only 50 % at 10 y and 75% at 20 y of macroalbuminuric patients willdevelop ESRD.
    MA Predicts Overt Nephropathy American Diabetic Association. Diab Care 2004
    • In type 2 Diabetes without specific intervention:
      • Only 20 – 40 % of microalbuminuric patients will develop macroalbuminuria.
      • Only 20% of macroalbuminuric patients over 20 y will develop ESRD.
    MA Predicts Overt Nephropathy American Diabetic Association. Diab Care 2004
  • MA and CV Risks
    • MA is the strongest independent determinant of ischaemic heart disease since confers a two to four-fold increased risk for this illness among diabetic and hypertensive or borderline hypertensive subjects.
    Jensen JS et al. Hypertension.2000; 35 : 898–903.
  • All CV Risks Are Related to MA
    • Microalbuminuria is related to a number of clinical variables such as:
    • Practically, all recognised cardiovascular risk factors are related to microalbuminuria.
    • Age
    • Male gender
    • Race
    • Hyperglycaemia
    • Hyperlipaemia
    • Hyperinsulinaemia
    • Hypertension
    • Obesity
    • LVH
    • Smoking habits
    • Diet
    • Microalbuminuria could simply reflect an augmented susceptibility to atherosclerosis linked to common pathogenetic factors (for instance endothelial dysfunction).
    MA and CV Risks
    • The relationship between microalbuminuria and atherosclerotic processes seems very tight and increased urinary albumin excretion (UAE) has been considered a marker of prevalent subclinical atherosclerosis.
    MA and CV Risks Jensen JS et al. J Hum Hypertens 1997; 11 : 727–732. Agrawal B et al. J Hypertens 1996; 14 : 223– 228.
    • In a large cross-sectional study of 11,343 nondiabetic hypertensive patients, those with microalbuminuria had a significantly higher prevalence ( P < .001) of:
      • Coronary artery disease (31% vs 22%)
      • Left ventricular hypertrophy (24% vs14%)
      • Previous stroke (6% vs 4%)
      • Peripheral vascular disease (7% vs 5%).
    MA and CV Risks Agrawal B et al. J Hyperten 1996; 14:223–228.
    • Factors that cluster with microalbuminuria
    • Insulin resistance
    • Central obesity
    • Low levels of high-density lipoprotein cholesterol
    • High triglyceride levels
    • Systolic hypertension
    • Lack of nocturnal dip in blood pressure on 24-hour monitoring
    • Salt sensitivity
    • Endothelial dysfunction
    • Hypercoagulability
    • Impaired fibrinolysis
    • Renal dysfunction
    MA and CV Risks
  • Is the risk due to later overt nephropathy?
    • HOPE study investigators found that :
      • Microalbuminuria was a strong predictor of risk for cardiovascular disease even after adjustment for renal function.
      • Thirty eight percent of the HOPE study patients had diabetes, mostly type 2.
    • Gerstein et al; Diabetes Care 2000; 23:B35–B39.
    • In type 1 diabetes, in contrast to type 2 diabetes, the relation between microalbuminuria and cardiovascular morbidity and mortality has been mainly attributed to the later development of overt nephropathy.
    • However, in adults with type 1 diabetes, microalbuminuria alone has been associated with excess cardiovascular mortality.
    Is the risk due to later overt nephropathy? Agardh CDet al. Diab Res Clin Pract 1997; 35(suppl):113–121.
  • MA in Essential Hypertension
    • Microalbuminuria can be detected in up to 40% of the population with established hypertension, particularly in those patients not controlled satisfactorily by anti-hypertensive therapy.
    • Even blood pressure levels between 130 and 139/80 and 89 mmHg are significantly associated with microalbuminuria
    Ruilope LM. Nephrol Dial Transplant (2004) 19: 524-528
  • MA and Metabolic Syndrome
    • Hyperinsulinaemia and peripheral resistance to insulin action seem to be features of microalbuminuric patients
    Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14
    • Microalbuminuria is also associated with the metabolic syndrome, which includes insulin resistance, low HDL cholesterol levels, high triglyceride levels, and truncal obesity.
    • Current evidence strongly suggests that hyperinsulinemia is associated with a greater risk for cardiovascular disease.
    • Patients with type 1 and type 2 diabetes mellitus with microalbuminuria are more insulin-resistant than those without microalbuminuria.
    MA and Metabolic Syndrome
  • MA and Metabolic Syndrome
    • Insulin promotes albumin transcapillary excretion, thus determining albuminuria, but preliminary studies do not seem to support this conclusion. OR
    • MA could be the result of insulin action at the renal level.
    • Palaniappan et al. NHANES III. Am J Hypertens 2003;16:952-8.
    MA and Metabolic Syndrome Prevalence of MetS in subjects with microalbuminuria or normoalbuminuria
  • Microalbuminuria CVD Risk Factors CKD Risk Factors Metabolic Syndrome MA and Metabolic Syndrome
  • MA and Salt Sensitivity
    • Salt-sensitive hypertensive patients show higher albumin excretion rates than salt-resistant patients.
    • Furthermore, when salt sensitive patients are given a high-sodium diet they show an increase in fitration fraction, glomerular pressure, and albumin excretion rate.
    Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14
  • MA and Atherogenic Serum Lipid Profile
    • Microalbuminuria is associated with an increased LDL:HDL cholesterol ratio and lower HDL cholesterol, as well as with higher uric acid levels.
    • Furthermore, age, BMI, diastolic blood pressure, LDL cholesterol and uric acid independently and significantly influence the variation of microalbuminuria.
    • The relationship between these classical atherogenic risk factors and microalbuminuria suggest that the latter could be a reflection of atherogenic vascular damage.
  • MA & Endothelial Dysfunction
    • Data support the concept that the presence of MA warning that there is a problem with the vasculature.
    • The presence of MA is a marker of extensive endothelial dysfunction and a predictor of increased cardiovascular risk.
    Chugh A, Bakris GL. J Clin Hypertens (Greenwich). 2007 Mar;9(3):196-200.
  • Recent Report of Stehouwer and Smulders 2006
    • The most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease.
    Stehouwer CD , Smulders YM .J Am Soc Nephrol. 2006 Aug;17(8):2106-11.
  • Albuminuria and CV Risk in Diabetics Pts Normoalbuminuria n = 191 Microalbuminuria n = 86 Macroalbuminuria n = 51 Status at baseline Years p < 0.01 normoalbuminuria vs. micro- and macroalbuminuria p < 0.05 microalbuminuria vs. macroalbuminuria Gall MA. et al. 1995 Survival
  • Hillege HL et al Circulation 2002;106:1777-82 MORTALITY with albuminuria Normo albuminuria High Normal Microalbuminuria Macroalbuminuria
  • RISK FACTORS and ALL CAUSE MORTALITY Diercks J et al. JACC 2002;40:1401 Microalbuminuria Hypertension Hypercholest. Smoking Overweight Diabetes
  • Mortality rate according to urine albumin and proteinuria status
    • Valmadrid et al. Arch Intern Med. 2000; 160:1093-1100.
  • Verhave et al . JASN 2003;14:1330-5 Age (yrs) 20 30 40 50 60 70 80 UAE (mg/24h) 6 7 8 9 10 11 12 13 Male Female MA and Age Urinary Albumin Excretion Increase with Age
  • Verhave J.C. et al. JASN 2003; 14:1330-5 MA and BMI BMI (kg/m 2 ) 20 22 24 26 28 30 32 UAE (mg/24h) 6 7 8 9 10 11 12 13 Male Female Urinary Albumin Excretion Increase with  BMI
  • MA and SMOKING Pinto-Sietsma SJ et al. Ann Int Med 2000;133:585-91
  • MA and Hormonal Therapy Oral contraceptives Second generation Third generation Hormone Replacement Therapy  5 year used >5 year used Premenopausal 1.90 (1.23 - 2.93) 2.04 (1.28 - 3.25) 1.39 (0.63 - 3.06) Postmenopausal 2.05 (1.12 - 3.77) 1.28 (0.37 - 4.50) 2.56 (1.32 - 4.97) MonsterTBM et al. Arch Int Med 2001;161:2000-2005
  • So…
    • Microabuminuria is a sign of early renal damage
    • More importantly , it is an independent sign of significantly increased risk of MI, CVA and vascular death.
    • Microalbuminuria should be looked for in all pts with DM and hypertension.
  • MA: Practical Perspective
    • Screening of all diabetic and hypertensive patients by conventional dipstick for urinary albumin.
    • If +ve means that albumin > 300 mg/ 24h  Renal damage started  evaluate for CKD staging and management
    • If dipstick is –ve  Test for MA (UAE 30-300mg/24h)  Evaluate for underlying risk factors  immediately start management strategy.
  • MA: Practical Perspective
    • Determination of MA is recommended in the
    • initial work-up of subjects with primary hypertension
    Verdecchia P, Reboldi G P. Blood Pressure. Volume 13, Number 4/August 2004
  • MA: Practical Perspective
  • MA: Practical Perspective Diabetes Mellitus
    • Glycemic Control
    • BP Control
    • ACE-I/ARBs
    • nd CCB
    Primary Prevention Microalbuminuria D. Nephropathy ESRD/ Death Secondary Prevention Tertiary Prevention
    • BP Control
    • ACE-I/ARBs
    • Anemia Control
    • Ca/Po4 Control
    • BP Control
    • ACE-I/ARBs
    • nd CCB
    Preventive Strategy
  • Management Strategy Proteinuria MA Later Hypertension Obesity Glycemia Lipids Smooking
  • Management Strategy Protein < 1g/d MA Later BP < 125/75 Weight Strict BG Control Normalise Lipids Stop Smooking
  • Management Strategy ACE-I/ARB ACE-I/ARB Later Control Diet Strict BG Control Normalise Lipids Stop Smooking ACE-I/ARB
  • Management Strategy
    • Among available antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists seem to be superior to other antihypertensive drugs in reducing UAE.
    • The dual blockade of the renin-angiotensin system with an ACE inhibitor and an angiotensin II receptor antagonist is a new and promising approach to control UAE in hypertensive patients
    Management Strategy Verdecchia P, Reboldi G P. Blood Pressure. Volume 13, Number 4/August 2004
  • MA: Primary Prevention
    • Patients with family history of HTN and/ or cardiovascular events in 1st degree relatives.
    • Hypertensive patients or even have small increase in systemic BP, within the normal range or loss of nocturnal dipping.
    • Hovind P et al. (2004). Br Med J 328:1105
    • Daneman D et al (1994) Kidney Int 46:1154–1159
    • Patients with poor glycemic control: Sustained hyperglycemia HbA1c > 8.6.
    • Patients who have retinopathy.
    • Dyslipidemic patients.
    • Smokers.
    Target Diabetic Populations
  • MA: Primary Prevention
    • Patients with protein intakes greater than 20% of energy intake.
    • Marion J et al. Current Diabetes Reports 2003, 3:412-417
    • Patients who have slightly elevated urinary albumin excretion: upper limit of normal.
    • Rossing P et al. (2002). Diabetes Care 25: 859 – 864 .
    • Patients with short stature or History of Low Birth weight. Hovind P et al. (2004). Br Med J 328:1105
    • Women using Oral contraceptive.
    • Ahmed SB et al (2005). Diabetes Care 28:1988 – 1994.
    • Presence of Cardiovascular risk markers.
    Target Diabetic Populations
  • MA: 1ry Preventive Measures
    • Glycaemic control should be optimised, with FBS < 6 mmol/l and/or HbA1c < 7%
    • Mentain Target BP < 130/80
    • ACE-I/ ARBs:
    • Cigarette smoking should be actively discouraged
    • Mentian Lipid Profile :
        • LDL<100 mg/dl (<2.6 mmol/l)    
        • Triglycerides<150 mg/dl (<1.7 mmol/l)    
        • HDL>40 mg/dl (>1.0 mmol/l)
  • MA: 1ry Preventive Measures
  • MA: 1ry Preventive Measures
    • Protein Intake
      • Not to exceed a protein intake of 20% of total energy.
      • Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26.
      • Fish : Diet including a high amount of fish protein lessen the risk of DN. Mollsten AV et al. Diabetes Care 24:805–810, 2001
      • Chicken : A normoproteic diet with chicken as the only source of meat may represent an alternative strategy for treatment of patients with type 2 diabetes and microalbuminuria.
      • Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651.
      • Fish and Chicken : A normoproteic diet with chicken and fish as the only meat protein source decreases the GFR in the hyperfiltering normoalbuminuric IDDM patients. The GFR reduction after this diet is similar to that observed after an LPD.
      • Pecis M et al. Diabetes Care 17:665–672, 1994
  • MA: 1ry Preventive Measures
    • Sodium Intake : High sodium intake should be avoided.
    • Avoidance of Oral Contraceptive.
    • Correction of CV Risk Factors.
    • Life Style Changes :
        • Moderate weight loss (7% body weight)
        • Regular physical activity (150 min/week)
        • Dietary fiber (14 g fiber/1,000 kcal) and foods containing whole grains
        • Reduced intake of fat to reduce calories.
  • Thanks