Microalbuminuria

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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

    1. 1. Dr A. AlfiDr A. Alfi Consultant NephrologistConsultant Nephrologist Transplant physicianTransplant physician Head of Department of NephrologyHead of Department of Nephrology KAAH& OC, JeddahKAAH& OC, Jeddah Dr A. AlfiDr A. Alfi Consultant NephrologistConsultant Nephrologist Transplant physicianTransplant physician Head of Department of NephrologyHead of Department of Nephrology KAAH& OC, JeddahKAAH& OC, Jeddah Dr M. Al-AmeenDr M. Al-Ameen Nephrology SpecialistNephrology Specialist Transplant physicianTransplant physician KAAH& OC- JeddahKAAH& OC- Jeddah Dr M. Al-AmeenDr M. Al-Ameen Nephrology SpecialistNephrology Specialist Transplant physicianTransplant physician KAAH& OC- JeddahKAAH& OC- Jeddah
    2. 2. CaseCase  50 year-old female.50 year-old female.  Known type 2 diabetes 5Known type 2 diabetes 5 years earlier.years earlier.  presented to OPD forpresented to OPD for routine visit.routine visit.  No history ofNo history of hypertension.hypertension.  Not known to have had aNot known to have had a previous CV event.previous CV event.  She visits theShe visits the ophthalmologist annuallyophthalmologist annually with no retionopathywith no retionopathy reported.reported.  Her medications include:Her medications include: – an over-the-counteran over-the-counter multivitamin.multivitamin. – an oral hypoglycemican oral hypoglycemic agent.agent. – a statin for knowna statin for known hypercholesterolemia.hypercholesterolemia.  She is otherwise well.She is otherwise well.  Findings on physicalFindings on physical examination areexamination are unremarkable.unremarkable.  Except that her BP thatExcept that her BP that previously was less thanpreviously was less than 130/80, became130/80, became 135/85.135/85.
    3. 3. Case: QuestionsCase: Questions  Should the woman be screened forShould the woman be screened for microalbuminuria on this visit ?microalbuminuria on this visit ?  What is the best way to screen for it ?What is the best way to screen for it ?  If the test result is positive, what does thisIf the test result is positive, what does this mean in terms of the patient's risk formean in terms of the patient's risk for cardiovascular and renal disease ?cardiovascular and renal disease ?  Is there anything that can be done medicallyIs there anything that can be done medically for microalbuminuria ?for microalbuminuria ?  What follow-up is required, includingWhat follow-up is required, including management of other risk factors ?management of other risk factors ? SheldonSheldon et al; 2002CMAJ •et al; 2002CMAJ • September 3, 2002; 167 (5)September 3, 2002; 167 (5)
    4. 4. Definition ofDefinition of Microalbuminuria (MA)Microalbuminuria (MA)  Normally only a small amount of albumin is filteredNormally only a small amount of albumin is filtered at the glomerulus, and most of that albumin isat the glomerulus, and most of that albumin is degraded and reabsorbed by the proximal tubule.degraded and reabsorbed by the proximal tubule.  Usually only <1 mg/dl of albumin appears in theUsually only <1 mg/dl of albumin appears in the urine.urine.  However, a number of conditions can temporarily orHowever, a number of conditions can temporarily or permanently cause an increase in urinary proteinpermanently cause an increase in urinary protein excretion by either altering glomerular membraneexcretion by either altering glomerular membrane permeability, inducing glomerular capillarypermeability, inducing glomerular capillary hypertension, or reducing tubular reabsorption.hypertension, or reducing tubular reabsorption. Tobe et al; Can Med Assoc J 2002;167:499–503.Tobe et al; Can Med Assoc J 2002;167:499–503.
    5. 5. Definition ofDefinition of Microalbuminuria (MA)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.
    6. 6. Definition of MADefinition of MA  There is difference between proteinuria andThere is difference between proteinuria and albuminuria.albuminuria.  Normal protein in urine should not exceedNormal protein in urine should not exceed 150 mg/day.150 mg/day.  This 150 mg protein includes Tamm HorsfallThis 150 mg protein includes Tamm Horsfall protein (~70mg), protein of blood groupprotein (~70mg), protein of blood group (~35mg), other proteins (enzymes,(~35mg), other proteins (enzymes, hormones, Ig etc..) andhormones, Ig etc..) and Albumin (0-30mg)Albumin (0-30mg)..  So, Albumin in urine should not exceedSo, Albumin in urine should not exceed 30mg/day.30mg/day.
    7. 7.  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 MADefinition of MA
    8. 8.  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 MADefinition of MA
    9. 9. 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 Definition of MADefinition of MA
    10. 10.  Race/ethnicity  Male gender  Older age  Low birth weight  Diabetes  Hypertension  Obesity  Smoking Non-modifiableNon-modifiable ModifiableModifiable well provenwell proven likelylikely •High salt diet • High protein diet • Hyperlipidemia • Fever • Exercise • CHF • UTI • Vaginal discharge Causes of MACauses of MA
    11. 11. Causes of MACauses of MA  Langston C in 2004Langston C in 2004 classified MA as:classified MA as: 1.1. PrerenalPrerenal:: strenuous exercise, fever, hypothermia,strenuous exercise, fever, hypothermia, seizures, and venous congestion.seizures, and venous congestion. 2.2. Renal MA:Renal MA: the goal of this lecturethe goal of this lecture 3.3. PostrenalPostrenal:: UTI and hematuriaUTI and hematuria if there is sufficientif there is sufficient blood to cause the urine to be grossly pink or red.blood to cause the urine to be grossly pink or red. Langston C;journal of A A H ALangston C;journal of A A H A 40:251-254 (2004)40:251-254 (2004) So, before dignosis of renal MA, prerenal andSo, before dignosis of renal MA, prerenal and postrenal causes shold be excludedpostrenal causes shold be excluded
    12. 12. Urine Tests for MAUrine Tests for MA 1.1. Albumin-to-Creatinine RatioAlbumin-to-Creatinine Ratio in ain a random spot collectionrandom spot collection 2.2. 24-h Urine Collection24-h Urine Collection withwith creatinine, allowing the simultaneouscreatinine, allowing the simultaneous measurement of creatinine clearancemeasurement of creatinine clearance 3.3. TimedTimed (e.g., 4-h or overnight)(e.g., 4-h or overnight) collection.collection.
    13. 13. 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. 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 MAUrine Tests for MA
    14. 14. Measurement of MAMeasurement of MA 1.1. Specific assaysSpecific assays :: a.a. RadioimmunoassayRadioimmunoassay b.b. Enzyme-linked immunosorbent assayEnzyme-linked immunosorbent assay c.c. NephelometryNephelometry 2.2. Reagent tablets or dipsticksReagent tablets or dipsticks forfor microalbumin may be carried out, sincemicroalbumin may be carried out, since they show acceptable sensitivity (95%) andthey show acceptable sensitivity (95%) and specificity (93%) when carried out byspecificity (93%) when carried out by trained personnel.trained personnel.  All positive tests by reagent strips or tablets shouldAll positive tests by reagent strips or tablets should be confirmed by more specific methods.be confirmed by more specific methods.
    15. 15. MA: SusceptibleMA: Susceptible diabeticsdiabetics  If the urine albumin excretion is in the upperIf the urine albumin excretion is in the upper range of normal (20–30 mg/d).range of normal (20–30 mg/d).  If the systolic blood pressure is greater thanIf the systolic blood pressure is greater than 130 mm Hg.130 mm Hg.  If the glycosylated hemoglobin level isIf the glycosylated hemoglobin level is greater than 8. orgreater than 8. or  If the total cholesterol level is greater thanIf the total cholesterol level is greater than 5.24 mmol/L.5.24 mmol/L. SheldonSheldon et al; 2002CMAJ • September 3, 2002;et al; 2002CMAJ • September 3, 2002; 167 (5)167 (5)
    16. 16. MA: PREVALENCES inMA: PREVALENCES in the General Populationthe General Population normal 0-10mg/lnormal 0-10mg/l macroproteinuriamacroproteinuria >200 mg/l>200 mg/l microalbuminuriamicroalbuminuria 20-200 mg/l (~7%)20-200 mg/l (~7%) high-normalhigh-normal albuminuriaalbuminuria 10-20 mg/l10-20 mg/l Hillege HL et al. J Int Med 2001;249:519-26Hillege 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.
    17. 17. Incidence of MAIncidence of MA  Microalbuminuria is likely to be foundMicroalbuminuria is likely to be found in one-third or more of diabeticin one-third or more of diabetic patients.patients. Sheldon et al; 2002 CMAJ • September 3, 2002; 167Sheldon et al; 2002 CMAJ • September 3, 2002; 167 (5)(5)
    18. 18. MA: PathogenesisMA: Pathogenesis Metabolic ChangesStructural Changes Functional Changes Macroalbuminuria Hyperglycemi a CKDCVD Microalbuminuria
    19. 19. MA: PathogenesisMA: Pathogenesis
    20. 20. MA: PathogenesisMA: Pathogenesis Structural Changes 1) Mesangial Expansion 2) GBM Thickening 3) Renal Hypertrophy 4) Glomerulosclerosis Functional Changes 1) Incresed Renal Plasma Flow 2) Hyperperfusion 3) Afferent Arterioar VD, Efferent Arteriolar VC 4) Increase Intraglomerular Pressure 5) Increased Glomerular Hydrostatic Pressure 6) Hyperfiltration Metabolic Changes 1) Advanced glycosylation end products 2) GF, Cytokines (TGF-B) 3) Protein Kinase C 4) Polyol pathway 5) Reactive Oxygen Species 6) Endothelial Dysfunction
    21. 21. Pathogenesis:Pathogenesis: Role of Endothelial DysfunctionRole of Endothelial Dysfunction  MA is thought to be the consequence ofMA is thought to be the consequence of generalized endothelial damage along thegeneralized endothelial damage along the vascular tree, including the glomerulus .vascular tree, including the glomerulus .  Enzymes involved in the metabolism ofEnzymes involved in the metabolism of anionic components of the extracellularanionic components of the extracellular matrix (e.g. heparan sulphate proteoglycan)matrix (e.g. heparan sulphate proteoglycan) vulnerable to hyperglycaemia, seem tovulnerable to hyperglycaemia, seem to constitute the primary cause of albuminuriaconstitute the primary cause of albuminuria and the associated complications.and the associated complications.  Genetic polymorphism of such enzymes isGenetic polymorphism of such enzymes is possibly the main reason for variation inpossibly the main reason for variation in susceptibility.susceptibility. DeckertDeckert
    22. 22. Natural History in DM 1Natural History in DM 1  Microalbuminuria is not usually aMicroalbuminuria is not usually a presenting finding at the onset of DM1.presenting finding at the onset of DM1.  After a 5- to 10-yr duration of diabetes,After a 5- to 10-yr duration of diabetes, susceptible patients developsusceptible patients develop intermittent microalbuminuria beforeintermittent microalbuminuria before having persistent microalbuminuriahaving persistent microalbuminuria
    23. 23. Natural History in DM 1Natural History in DM 1
    24. 24. Natural History in DM 2Natural History in DM 2  Because of the insidious onset of DM2, theBecause of the insidious onset of DM2, the true duration of the disease is often nottrue duration of the disease is often not known. It has been reported that a durationknown. It has been reported that a duration of >6 yr of diabetes may have existed beforeof >6 yr of diabetes may have existed before diagnosisdiagnosis  Subjects often present with microalbuminuriaSubjects often present with microalbuminuria at that point.at that point.  However, diabetic nephropathy in DM2 isHowever, diabetic nephropathy in DM2 is similar to nephropathy in DM1 with similarsimilar to nephropathy in DM1 with similar pathology, response to interventions ofpathology, response to interventions of glucose control and anti-angiotensin IIglucose control and anti-angiotensin II
    25. 25. Significance of MA inSignificance of MA in Diabetic PatientsDiabetic Patients  MA predicts clinical nephropathy.MA predicts clinical nephropathy.  MA predicts an increased incidence ofMA predicts an increased incidence of cardiovascular disease andcardiovascular disease and cardiovascular mortality.cardiovascular mortality.  In other words, MA doubled the risk ofIn other words, MA doubled the risk of having a cardiovascular event in diabetichaving a cardiovascular event in diabetic pts.pts.
    26. 26.  MA is a marker of early stage renalMA is a marker of early stage renal damage.damage.  The degree of microalbuminuria isThe degree of microalbuminuria is proportional to the degree of damage.proportional to the degree of damage.  Regression of MA decreases the risk.Regression of MA decreases the risk. MA Predicts OvertMA Predicts Overt NephropathyNephropathy
    27. 27.  In type 1 Diabetes withoutIn type 1 Diabetes without specific intervention:specific intervention: – Only 80 % of microalbuminuric patients willOnly 80 % of microalbuminuric patients will develop macroalbuminuria.develop macroalbuminuria. – Only 50 % at 10 y and 75% at 20 y ofOnly 50 % at 10 y and 75% at 20 y of macroalbuminuric patients willdevelopmacroalbuminuric patients willdevelop ESRD.ESRD. MA Predicts OvertMA Predicts Overt NephropathyNephropathy American Diabetic Association. Diab Care 2004
    28. 28.  In type 2 Diabetes withoutIn type 2 Diabetes without specific intervention:specific intervention: – Only 20 – 40 % of microalbuminuricOnly 20 – 40 % of microalbuminuric patients will develop macroalbuminuria.patients will develop macroalbuminuria. – Only 20% of macroalbuminuric patientsOnly 20% of macroalbuminuric patients over 20 y will develop ESRD.over 20 y will develop ESRD. MA Predicts OvertMA Predicts Overt NephropathyNephropathy American Diabetic Association. Diab Care 2004
    29. 29. MA and CV RisksMA and CV Risks  MA is the strongestMA is the strongest independent determinant ofindependent determinant of ischaemic heart disease sinceischaemic heart disease since confers a two to four-foldconfers a two to four-fold increased risk for this illnessincreased risk for this illness among diabetic andamong diabetic and hypertensive or borderlinehypertensive or borderline hypertensive subjects.hypertensive subjects.Jensen JS et al. Hypertension.2000; 35: 898–903.
    30. 30. All CV Risks Are RelatedAll CV Risks Are Related to MAto MA  Microalbuminuria is related to aMicroalbuminuria is related to a number of clinical variables such as:number of clinical variables such as:  Practically, all recognisedPractically, all recognised cardiovascular risk factors are relatedcardiovascular risk factors are related to microalbuminuria.to microalbuminuria. 1. Age 2. Male gender 3. Race 4. Hyperglycaemia 5. Hyperlipaemia 6. Hyperinsulinaemia 7. Hypertension 8. Obesity 9. LVH 10.Smoking habits 11.Diet
    31. 31.  Microalbuminuria could simply reflectMicroalbuminuria could simply reflect an augmented susceptibility toan augmented susceptibility to atherosclerosis linked to commonatherosclerosis linked to common pathogenetic factors (for instancepathogenetic factors (for instance endothelial dysfunction).endothelial dysfunction). MA and CV RisksMA and CV Risks
    32. 32.  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.Jensen JS et al. J Hum Hypertens 1997; 11: 727–732. Agrawal B et al. J Hypertens 1996; 14: 223– 228. MA and CV RisksMA and CV Risks
    33. 33.  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%). Agrawal B et al.Agrawal B et al. J Hyperten 1996; 14:223–228.J Hyperten 1996; 14:223–228. MA and CV RisksMA and CV Risks
    34. 34. 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 RisksMA and CV Risks
    35. 35. 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.
    36. 36.  In type 1 diabetes, in contrast to type 2In type 1 diabetes, in contrast to type 2 diabetes, the relation betweendiabetes, the relation between microalbuminuria and cardiovascularmicroalbuminuria and cardiovascular morbidity and mortality has been mainlymorbidity and mortality has been mainly attributed to the later development of overtattributed to the later development of overt nephropathy.nephropathy.  However, in adults with type 1 diabetes,However, in adults with type 1 diabetes, microalbuminuria alone has beenmicroalbuminuria alone has been associated with excess cardiovascularassociated with excess cardiovascular mortality.mortality. Is the risk due to later overt nephropathy? Agardh CDet al. Diab Res Clin Pract 1997; 35(suppl):113–121.
    37. 37. MA in EssentialMA in Essential HypertensionHypertension  Microalbuminuria can be detected in up toMicroalbuminuria can be detected in up to 40% of the population with established40% of the population with established hypertension, particularly in those patientshypertension, particularly in those patients not controlled satisfactorily by anti-not controlled satisfactorily by anti- hypertensive therapy.hypertensive therapy.  Even blood pressure levels between 130Even blood pressure levels between 130 and 139/80 and 89 mmHg are significantlyand 139/80 and 89 mmHg are significantly associated with microalbuminuriaassociated with microalbuminuria Ruilope LM. Nephrol Dial Transplant (2004) 19: 524-528
    38. 38. MA and Metabolic Syndrome  Hyperinsulinaemia and peripheralHyperinsulinaemia and peripheral resistance to insulin action seem to beresistance to insulin action seem to be features of microalbuminuric patientsfeatures of microalbuminuric patients Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14
    39. 39.  Microalbuminuria is also associated withMicroalbuminuria is also associated with the metabolic syndrome, which includesthe metabolic syndrome, which includes insulin resistance, low HDL cholesterolinsulin resistance, low HDL cholesterol levels, high triglyceride levels, and truncallevels, high triglyceride levels, and truncal obesity.obesity.  Current evidence strongly suggests thatCurrent evidence strongly suggests that hyperinsulinemia is associated with ahyperinsulinemia is associated with a greater risk for cardiovascular disease.greater risk for cardiovascular disease.  Patients with type 1 and type 2 diabetesPatients with type 1 and type 2 diabetes mellitus with microalbuminuria are moremellitus with microalbuminuria are more insulin-resistant than those withoutinsulin-resistant than those without MA and Metabolic Syndrome
    40. 40. 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 actionMA could be the result of insulin action at the renal level.at the renal level.
    41. 41. Palaniappan et al. NHANES III. Am J Hypertens 2003;16:952-8.Palaniappan et al. NHANES III. Am J Hypertens 2003;16:952-8. Prevalence of MetS in subjects with microalbuminuria or normoalbuminuria MA and Metabolic Syndrome
    42. 42. MicroalbuminuriaMicroalbuminuria CVD Risk FactorsCVD Risk Factors CKD Risk FactorsCKD Risk Factors Metabolic SyndromeMetabolic Syndrome MA and MetabolicMA and Metabolic SyndromeSyndrome
    43. 43. MA and Salt Sensitivity  Salt-sensitive hypertensive patients showSalt-sensitive hypertensive patients show higher albumin excretion rates than salt-higher albumin excretion rates than salt- resistant patients.resistant patients.  Furthermore, when salt sensitive patientsFurthermore, when salt sensitive patients are given a high-sodium diet they show anare given a high-sodium diet they show an increase in fitration fraction, glomerularincrease in fitration fraction, glomerular pressure, and albumin excretion rate.pressure, and albumin excretion rate. Bigazzi et al; NephrolDial Transplant 1995; 10 [suppl 6]: 10-14
    44. 44. MA and Atherogenic Serum Lipid Profile  Microalbuminuria is associated with anMicroalbuminuria is associated with an increased LDL:HDL cholesterol ratio andincreased LDL:HDL cholesterol ratio and lower HDL cholesterol, as well as with higherlower HDL cholesterol, as well as with higher uric acid levels.uric acid levels.  Furthermore, age, BMI, diastolic bloodFurthermore, age, BMI, diastolic blood pressure, LDL cholesterol and uric acidpressure, LDL cholesterol and uric acid independently and significantly influence theindependently and significantly influence the variation of microalbuminuria.variation of microalbuminuria.  The relationship between these classicalThe relationship between these classical atherogenic risk factors andatherogenic risk factors and microalbuminuria suggest that the lattermicroalbuminuria suggest that the latter could be a reflection of atherogenic vascularcould be a reflection of atherogenic vascular damage.damage.
    45. 45. MA & EndothelialMA & Endothelial DysfunctionDysfunction  Data support the concept that theData support the concept that the presence of MA warning that there is apresence of MA warning that there is a problem with the vasculature.problem with the vasculature.  The presence of MA is a marker ofThe presence of MA is a marker of extensive endothelial dysfunction andextensive endothelial dysfunction and a predictor of increased cardiovasculara predictor of increased cardiovascular risk.risk. Chugh A, Bakris GL. J Clin Hypertens (Greenwich). 2007 Mar;9(3):196-200.
    46. 46. Recent Report ofRecent Report of Stehouwer and Smulders 2006Stehouwer and Smulders 2006  The most likely possibility is that aThe most likely possibility is that a common pathophysiologic process, suchcommon pathophysiologic process, such as endothelial dysfunction, chronic low-as endothelial dysfunction, chronic low- grade inflammation, or increasedgrade inflammation, or increased transvascular leakage oftransvascular leakage of macromolecules, underlies themacromolecules, underlies the association between microalbuminuriaassociation between microalbuminuria and cardiovascular disease.and cardiovascular disease. Stehouwer CD, Smulders YM.J Am Soc Nephrol. 2006 Aug;17(8):2106-11.
    47. 47. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 6 Albuminuria and CV Risk inAlbuminuria and CV Risk in Diabetics PtsDiabetics 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
    48. 48. Days 0 200 400 600 800 1000 1200 1400 Fractionofsubjectsalive 0,00 0,85 0,90 0,95 1,00 0-10 mg/L 10-20 mg/L 20-200 mg/L > 200 mg/L Hillege HL et al Circulation 2002;106:1777-82Hillege HL et al Circulation 2002;106:1777-82 MORTALITY with albuminuriaMORTALITY with albuminuria Normo albuminuria High Normal Microalbuminuria Macroalbuminuri a
    49. 49. RISK FACTORS andRISK FACTORS and ALL CAUSE MORTALITYALL CAUSE MORTALITY Diercks J et al. JACC 2002;40:1401Diercks J et al. JACC 2002;40:1401 Microalbuminuria Hypertension Hypercholest. Smoking Overweight Diabetes
    50. 50. Mortality rate according to urine albumin and proteinuria status Valmadrid et al. Arch Intern Med. 2000; 160:1093-1100.
    51. 51. Verhave et alVerhave et al.. JASN 2003;14:1330-5JASN 2003;14:1330-5 Age (yrs)Age (yrs) 2020 3030 4040 5050 6060 7070 8080 UAE(mg/24h)UAE(mg/24h) 66 77 88 99 1010 1111 1212 1313 MaleMale FemaleFemale MA and AgeMA and Age Urinary Albumin Excretion Increase with Age
    52. 52. Verhave J.C. et al. JASNVerhave J.C. et al. JASN 2003; 14:1330-52003; 14:1330-5 MA and BMIMA and BMI BMI (kg/mBMI (kg/m22 )) 2020 2222 2424 2626 2828 3030 3232 UAE(mg/24h)UAE(mg/24h) 66 77 88 99 1010 1111 1212 1313 MaleMale FemaleFemale Urinary Albumin Excretion Increase with  BMI
    53. 53. MA and SMOKINGMA and SMOKING Pinto-Sietsma SJ et al. Ann Int Med 2000;133:585-91Pinto-Sietsma SJ et al. Ann Int Med 2000;133:585-91 0 1 2 3 4 Microalbuminuria nonsmokers current smokers ≤20 >20 former smokers Odds ratio (95% CI) High normal albuminuria nonsmokers current smokers ≤20 >20 former smokers
    54. 54. MA and HormonalMA and Hormonal TherapyTherapy Oral contraceptivesOral contraceptives Second generationSecond generation Third generationThird generation Hormone Replacement TherapyHormone Replacement Therapy ≤≤5 year used5 year used >5 year used>5 year used PremenopausalPremenopausal 1.90 (1.23 - 2.93)1.90 (1.23 - 2.93) 2.04 (1.28 - 3.25)2.04 (1.28 - 3.25) 1.39 (0.63 - 3.06)1.39 (0.63 - 3.06) PostmenopausalPostmenopausal 2.05 (1.12 - 3.77)2.05 (1.12 - 3.77) 1.28 (0.37 - 4.50)1.28 (0.37 - 4.50) 2.56 (1.32 - 4.97)2.56 (1.32 - 4.97) MonsterTBM et al. Arch Int Med 2001;161:2000-2005MonsterTBM et al. Arch Int Med 2001;161:2000-2005
    55. 55. So…So…  Microabuminuria is a sign of early renalMicroabuminuria is a sign of early renal damagedamage  More importantlyMore importantly, it is an independent, it is an independent sign of significantly increased risk of MI,sign of significantly increased risk of MI, CVA and vascular death.CVA and vascular death.  Microalbuminuria should be looked forMicroalbuminuria should be looked for in all pts with DM and hypertension.in all pts with DM and hypertension.
    56. 56. MA: PracticalMA: 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.
    57. 57. MA: PracticalMA: 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
    58. 58. MA: PracticalMA: Practical Perspective
    59. 59. 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 PreventivePreventive StrategyStrategy MA: PracticalMA: Practical Perspective
    60. 60. Management StrategyManagement Strategy ProteinuriaProteinuria MAMA Later HypertensionHypertension ObesityObesityGlycemiaGlycemia LipidsLipids SmookingSmooking
    61. 61. Management StrategyManagement Strategy ProteinProtein < 1g/d< 1g/dMAMA Later BPBP < 125/75< 125/75 WeightWeightStrict BGStrict BG ControlControl NormaliseNormalise LipidsLipids StopStop SmookingSmooking
    62. 62. Management StrategyManagement Strategy ACE-I/ARBACE-I/ARBACE-I/ARBACE-I/ARB Later ControlControl DietDiet Strict BGStrict BG ControlControl NormaliseNormalise LipidsLipids StopStop SmookingSmooking ACE-I/ARBACE-I/ARB
    63. 63. Management StrategyManagement Strategy
    64. 64.  Among available antihypertensive drugs,Among available antihypertensive drugs, angiotensin-converting enzyme (ACE)angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptorinhibitors and the angiotensin II receptor antagonists seem to be superior to otherantagonists seem to be superior to other antihypertensive drugs in reducing UAE.antihypertensive drugs in reducing UAE.  The dual blockade of the renin-angiotensinThe dual blockade of the renin-angiotensin system with an ACE inhibitor and ansystem with an ACE inhibitor and an angiotensin II receptor antagonist is a newangiotensin II receptor antagonist is a new and promising approach to control UAE inand promising approach to control UAE in hypertensive patientshypertensive patients Verdecchia P, Reboldi G P. Blood Pressure. Volume 13, Number 4/August 2004 Management StrategyManagement Strategy
    65. 65. MA: Primary PreventionMA: Primary Prevention 1.1. Patients with family history of HTN and/ orPatients with family history of HTN and/ or cardiovascular events in 1st degree relatives.cardiovascular events in 1st degree relatives. 2.2. Hypertensive patients or even have smallHypertensive patients or even have small increase in systemic BP, within the normalincrease in systemic BP, within the normal range or loss of nocturnal dipping.range or loss of nocturnal dipping. Hovind P et al. (2004). Br Med J 328:1105Hovind P et al. (2004). Br Med J 328:1105 Daneman D et al (1994) Kidney Int 46:1154–1159Daneman D et al (1994) Kidney Int 46:1154–1159 3.3. Patients with poor glycemic control:Patients with poor glycemic control: Sustained hyperglycemia HbA1c > 8.6.Sustained hyperglycemia HbA1c > 8.6. 4.4. Patients who have retinopathy.Patients who have retinopathy. 5.5. Dyslipidemic patients.Dyslipidemic patients. 6.6. Smokers.Smokers. 1.1. Patients with family history of HTN and/ orPatients with family history of HTN and/ or cardiovascular events in 1st degree relatives.cardiovascular events in 1st degree relatives. 2.2. Hypertensive patients or even have smallHypertensive patients or even have small increase in systemic BP, within the normalincrease in systemic BP, within the normal range or loss of nocturnal dipping.range or loss of nocturnal dipping. Hovind P et al. (2004). Br Med J 328:1105Hovind P et al. (2004). Br Med J 328:1105 Daneman D et al (1994) Kidney Int 46:1154–1159Daneman D et al (1994) Kidney Int 46:1154–1159 3.3. Patients with poor glycemic control:Patients with poor glycemic control: Sustained hyperglycemia HbA1c > 8.6.Sustained hyperglycemia HbA1c > 8.6. 4.4. Patients who have retinopathy.Patients who have retinopathy. 5.5. Dyslipidemic patients.Dyslipidemic patients. 6.6. Smokers.Smokers. Target Diabetic PopulationsTarget Diabetic Populations
    66. 66. 7.7. Patients with protein intakes greater thanPatients with protein intakes greater than 20% of energy intake.20% of energy intake. Marion J et al.Marion J et al. Current Diabetes Reports 2003, 3:412-417Current Diabetes Reports 2003, 3:412-417 8.8. Patients who have slightly elevated urinaryPatients who have slightly elevated urinary albumin excretion: upper limit of normal.albumin excretion: upper limit of normal. Rossing P et al. (2002). Diabetes Care 25: 859Rossing P et al. (2002). Diabetes Care 25: 859––864864.. 9.9. Patients with short stature or History of LowPatients with short stature or History of Low Birth weight.Birth weight. Hovind P et al. (2004). Br Med J 328:1105Hovind P et al. (2004). Br Med J 328:1105 10.10. Women using Oral contraceptive.Women using Oral contraceptive. Ahmed SB et al (2005). Diabetes Care 28:1988Ahmed SB et al (2005). Diabetes Care 28:1988––1994.1994. 11.11. Presence of Cardiovascular risk markers.Presence of Cardiovascular risk markers. 7.7. Patients with protein intakes greater thanPatients with protein intakes greater than 20% of energy intake.20% of energy intake. Marion J et al.Marion J et al. Current Diabetes Reports 2003, 3:412-417Current Diabetes Reports 2003, 3:412-417 8.8. Patients who have slightly elevated urinaryPatients who have slightly elevated urinary albumin excretion: upper limit of normal.albumin excretion: upper limit of normal. Rossing P et al. (2002). Diabetes Care 25: 859Rossing P et al. (2002). Diabetes Care 25: 859––864864.. 9.9. Patients with short stature or History of LowPatients with short stature or History of Low Birth weight.Birth weight. Hovind P et al. (2004). Br Med J 328:1105Hovind P et al. (2004). Br Med J 328:1105 10.10. Women using Oral contraceptive.Women using Oral contraceptive. Ahmed SB et al (2005). Diabetes Care 28:1988Ahmed SB et al (2005). Diabetes Care 28:1988––1994.1994. 11.11. Presence of Cardiovascular risk markers.Presence of Cardiovascular risk markers. Target Diabetic PopulationsTarget Diabetic Populations MA: Primary PreventionMA: Primary Prevention
    67. 67. MA: 1ry PreventiveMA: 1ry Preventive MeasuresMeasures 1.1. Glycaemic controlGlycaemic control should be optimised,should be optimised, with FBSwith FBS << 6 mmol/l and/or HbA1c6 mmol/l and/or HbA1c << 7%7% 2.2. Mentain Target BPMentain Target BP << 130/80130/80 3.3. ACE-I/ ARBs:ACE-I/ ARBs: 4.4. Cigarette smokingCigarette smoking should be activelyshould be actively discourageddiscouraged 5.5. Mentian Lipid ProfileMentian Lipid Profile:: a.a. LDL<100 mg/dl (<2.6 mmol/l)    LDL<100 mg/dl (<2.6 mmol/l)     b.b. Triglycerides<150 mg/dl (<1.7 mmol/l)    Triglycerides<150 mg/dl (<1.7 mmol/l)     c.c. HDL>40 mg/dl (>1.0 mmol/l)HDL>40 mg/dl (>1.0 mmol/l) 1.1. Glycaemic controlGlycaemic control should be optimised,should be optimised, with FBSwith FBS << 6 mmol/l and/or HbA1c6 mmol/l and/or HbA1c << 7%7% 2.2. Mentain Target BPMentain Target BP << 130/80130/80 3.3. ACE-I/ ARBs:ACE-I/ ARBs: 4.4. Cigarette smokingCigarette smoking should be activelyshould be actively discourageddiscouraged 5.5. Mentian Lipid ProfileMentian Lipid Profile:: a.a. LDL<100 mg/dl (<2.6 mmol/l)    LDL<100 mg/dl (<2.6 mmol/l)     b.b. Triglycerides<150 mg/dl (<1.7 mmol/l)    Triglycerides<150 mg/dl (<1.7 mmol/l)     c.c. HDL>40 mg/dl (>1.0 mmol/l)HDL>40 mg/dl (>1.0 mmol/l)
    68. 68. MA: 1ry PreventiveMA: 1ry Preventive MeasuresMeasures
    69. 69. 6.6. Protein IntakeProtein Intake – Not to exceed a protein intake of 20% of total energy.Not to exceed a protein intake of 20% of total energy. Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26.Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26. – FishFish:: Diet including a high amount of fish protein lessen the risk of DN.Diet including a high amount of fish protein lessen the risk of DN. Mollsten AV et al. Diabetes Care 24:805–810, 2001Mollsten AV et al. Diabetes Care 24:805–810, 2001 – ChickenChicken:: A normoproteic diet with chicken as the only source of meatA normoproteic diet with chicken as the only source of meat may represent an alternative strategy for treatment of patients with typemay represent an alternative strategy for treatment of patients with type 2 diabetes and microalbuminuria.2 diabetes and microalbuminuria. Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651.Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651. – Fish and ChickenFish and Chicken:: A normoproteic diet with chicken and fish as theA normoproteic diet with chicken and fish as the only meat protein source decreases the GFR in the hyperfilteringonly meat protein source decreases the GFR in the hyperfiltering normoalbuminuric IDDM patients. The GFR reduction after this diet isnormoalbuminuric IDDM patients. The GFR reduction after this diet is similar to that observed after an LPD.similar to that observed after an LPD. Pecis M et al. Diabetes Care 17:665–672, 1994Pecis M et al. Diabetes Care 17:665–672, 1994 6.6. Protein IntakeProtein Intake – Not to exceed a protein intake of 20% of total energy.Not to exceed a protein intake of 20% of total energy. Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26.Toeller et al. Diabetologia. 1997 Oct;40(10):1219-26. – FishFish:: Diet including a high amount of fish protein lessen the risk of DN.Diet including a high amount of fish protein lessen the risk of DN. Mollsten AV et al. Diabetes Care 24:805–810, 2001Mollsten AV et al. Diabetes Care 24:805–810, 2001 – ChickenChicken:: A normoproteic diet with chicken as the only source of meatA normoproteic diet with chicken as the only source of meat may represent an alternative strategy for treatment of patients with typemay represent an alternative strategy for treatment of patients with type 2 diabetes and microalbuminuria.2 diabetes and microalbuminuria. Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651.Gross JL et al. Diabetes Care, April 1, 2002; 25(4): 645 - 651. – Fish and ChickenFish and Chicken:: A normoproteic diet with chicken and fish as theA normoproteic diet with chicken and fish as the only meat protein source decreases the GFR in the hyperfilteringonly meat protein source decreases the GFR in the hyperfiltering normoalbuminuric IDDM patients. The GFR reduction after this diet isnormoalbuminuric IDDM patients. The GFR reduction after this diet is similar to that observed after an LPD.similar to that observed after an LPD. Pecis M et al. Diabetes Care 17:665–672, 1994Pecis M et al. Diabetes Care 17:665–672, 1994 MA: 1ry PreventiveMA: 1ry Preventive MeasuresMeasures
    70. 70. 7.7. Sodium IntakeSodium Intake:: High sodium intake should beHigh sodium intake should be avoided.avoided. 8.8. Avoidance of Oral Contraceptive.Avoidance of Oral Contraceptive. 9.9. Correction of CV Risk Factors.Correction of CV Risk Factors. 10.10. Life Style ChangesLife Style Changes::  Moderate weight loss (7% body weight)Moderate weight loss (7% body weight)  Regular physical activity (150 min/week)Regular physical activity (150 min/week)  Dietary fiber (14 g fiber/1,000 kcal) and foodsDietary fiber (14 g fiber/1,000 kcal) and foods containing whole grainscontaining whole grains  Reduced intake of fat to reduce calories.Reduced intake of fat to reduce calories. 7.7. Sodium IntakeSodium Intake:: High sodium intake should beHigh sodium intake should be avoided.avoided. 8.8. Avoidance of Oral Contraceptive.Avoidance of Oral Contraceptive. 9.9. Correction of CV Risk Factors.Correction of CV Risk Factors. 10.10. Life Style ChangesLife Style Changes::  Moderate weight loss (7% body weight)Moderate weight loss (7% body weight)  Regular physical activity (150 min/week)Regular physical activity (150 min/week)  Dietary fiber (14 g fiber/1,000 kcal) and foodsDietary fiber (14 g fiber/1,000 kcal) and foods containing whole grainscontaining whole grains  Reduced intake of fat to reduce calories.Reduced intake of fat to reduce calories. MA: 1ry PreventiveMA: 1ry Preventive MeasuresMeasures

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