Approach To MicroalbuminuriaIn a Diabetic patients

Dr M M KapoorConsultant Nephrologist

Al Amiri HospitalKuwait.

What Is Micro-albuminuria?• Test Urine –Dip stiks protein is positive only urinary proteinuria is

more than 300 mg a day.• Micro-albuminuria • Micral Test II Test Strip• High performance Liquid Chromatography.• It is a specific assay for albumin • Normal rate of albumin excretion is < 30mg/day or 20mcg/min• MA 20-30mg/l ( <20mcg/min)• Alb/ Creat ratio > 30mg/g.• Three Occasions or early morning Void Specimen.• Spot Specimen.• No Fever, UTI or Heavy Exercise in the past 24 hours.

Situation in kuwait• N Abdella et al, Dia Res Clin Prac1998,187-9

– 20-39 years - 5.7%; 40-59 - 18.3%; overall -14.8%.– Obesity,family history & hypertension were positively associated with

it.– N Abdella Et all Sept 1999 Acta Diabetologica– Incidence 15.8%.

• Taha et al Diabetologia 1983 306-308, – Incidence of type I DM from 0-29 yrs = 22.09 /100,000; 0-14, &

0-19 = 3.96,& 5.87/100,000 respectively.– 30% to 40 % develop Diabetic nephropathy .– Moosa et al Med Prin Pract 2005 14(2) 87-91.– Incidence oy type I DM in 6-18 years old children 269.9/100,000 – Incidence of type 2 DM in 6-18

Case

Stages of Diabetic Nephropathy

1. Hyperfiltration GFR-- 30to 35%, Filteration area , glomerular size.

2. Microalbuminuria 30to 300mg/day in 2to3 Consecutive Non Ketotic Urine samples

OR 30 to 300mg/g of creatinine. OR 20 to 200mug/min . Transient microalbuminuria can occur in

fever,exercise,hyperglycemia

Stages of Diabetic Nephropathy

Persistent micro-albuminuric patients have increase in filtration fraction both at rest & exercise . It decreases with BP controlStage I & II are REVERSIBLE.

3. OVERT NEPHROPATHY More Than 300 mg/day -to a Nephrotic State

4.Chronic Renal Failure

Diagnosis of Diabetic Nephropathy

• Micro-albuminuria - Overt-proteinuria without active sediments in urine.

• A/C ratio best screening test for micro-alb, with high specificity & Sensi 2-3mg/mmol.

• Retinopathy Type I (100%) , Type II (80%).• Normal sized kidneys• Duration of Diabetes • Mogenson CE, Diabetes Care 1988;11(S1)10-15

Why Treat Microalbuminuria?• Prevents Cardiovascular Diseases .• Strokes.• CAD.• Progression of Renal disease.

Association of MA in Diabetic patients

Long-term Renal Outcomes of Patients WithType 1 Diabetes Mellitus and

Microalbuminuria

• Arch Intern Med. 2011;171(5):412-420• After development of persistent Microalbuminuria,

progression and regression of kidney disease each commonly occur.

• Intensive glycemic control, lower BP, and a favourable lipid profile are associated with improved outcomes.

Case Scenario ONE

• 28 Years Old Diabetic Type 1 On Insulin• HBA1C 7.2%• Micro-albuminuria 90mg/l.• Fever • Clinically Normal Weight Normotensive. No

Retinopathy No Edema• Systemic Exam NAD• RFT CBC Lipid are Normal• Urine R/ M Normal• Ultrasound Kidneys are Normal• What Is Your Advise to HIM?

Case scenario 1

• Start ACE• Reassure Him• Repeat urine Test

Case scenario 2• 42 years Obese BMI 32 ,Diabetic Type 2• DM .Is On Amaryl 6 MG OD and Glucophage 1gm TID HBA1C 8.3%.• Hypertensive -150/95 Mm Of HG is on Zestril 20 MG BID.• Hyperlipidemic -Atrvostatin 20Mg OD serum Total Chol 5.4 Mmol/l

LDL 3.2 Mmol/l. TG 2.84.• Bun and Creat electrolytes are all Normal. Urates are 576umol/l ( N

150-400)• MA 220mg/l and Alb/ Creat ratio is 250mg/g• Low Vitamin D levels of 28nmol/l ( sufficient is > 75 nmol/l)• Smoker • Snoring a lot

Case Scenario 2

Case Scenario 2

• 42 years Obese BMI 33 Diabetic Type 2• DM Uncontrolled Is On Amaryl 6 MG OD and Glucophage

1gm TID HBA1C 8.3%.• Hypertensive -150/95 Mm Of HG is on Zestril 20 MG BID.• Hyperlipidemic -Atrvostatin 20Mg OD serum Total Chol 5.4

Mmol/l LDL 3.2 Mmol/l. TG 2.84.• Bun and Creat electrolytes are all Normal. Urates are

576umol/l ( N 150-400)• MA 220mg/l and Alb/ Creat ratio is 250mg/g• Low Vitamin D levels of 28nmol/l ( sufficient is > 75 nmol/l)• Smoker• SNORES

Obesity and Microalbuminuria

• Lifestyle-Related Factors, Obesity, and Incident• Microalbuminuria: The CARDIA (Coronary Artery Risk• Development in Young Adults) Study• Alex Chang, MD, MS,1 Linda Van Horn, PhD, RD,2 David R. Jacobs Jr, PhD,3

• American journal Of kidney diseases 2013;62;267-275

Obesity OSA and Microalbuminuria

Smoking and Albuminuria

• SMOKING. Christiansen 1978 D.care 1:146-9.-A factor promotes D. Neph in both type I & II-It affects renal Hemodynamics , Increases Catecholamines production. Patients With DM I & II who smoke have a greater risk of Ualb , and progression to ESRD is about twice as rapid than non-smokers

Diabetic care 1994;17;126-9.

Nemon A, et al. Bull.WHO 2000:78(11):1306-15. Pevalance of Smoking 34.4% In adult KuwaitisEur, J Epid: 50.8%of married couples smoke

Smoking and MA

Life Style Education

Glycemic Control

Good glycemic control, Glycos HBA1c 7.1% A. Primary (DCCT NEJM 1993:329(14):977-86.)

Near Normal blood glucose in type I stab GFR, renal plasma flow& decreases Ualb excretion

It reduces development of ualb in 35% of Pat.

B. Secondary All long term trials have shown beneficial on rate of rise of

Ualb & Overt Neph.

Glycemia

DCCT tight glycemic control sig reduces Ualb 43% & macroalbumin 56% in Type I

Type II , studies have revealed a similar situation. By tight glycemic control developmentment and progression of albuminuria can be substantially reduced.UKPDS showed this irrespective of drugs insulin/ oral Sulh,Met.

Lancet UKPDS 1998:352:837 NEJM DCCT. 329;997-986,1993.

Glycemic Control• Meta analysis Wang Lancet.341;1306-9,1993

• Intensive versus conventional blood glucose control , The risk of progression of nephro pathy is decreased by 80% both in I & II DM. Glycoslated Hb 7.I%./ 9.4% . Mean B.Glucose 155mg/230mg.

• It takes a few ~3 years the effect of intensive glucose control to appear evident in overt nephropathy

• Pancreatic Trans takes more than five years of normoglycemia for reversal of glomer-disease.

• Sykler etal Microvascular complication . Endo & Met Clinics 30;4; Dec2001

Glycemic Control• What should e do In This patient For Glycemic

Control?• He is already on Glucophage and Amaryl• ADD DPP4 inhibitors• Incretin based Therapies

Glycemia Control• Int J Endocrinol. 2013; 2013: 895102.• Published online Sep 5, 2013. doi: 10.1155/2013/895102• PMCID: PMC3780627

• Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria• Martin Haluzík, 1 ,* Jan Frolík, 2 and Ivan Rychlík 3

• Author information ► Article notes ► Copyright and License information ►• Go to:• Abstract• Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment

owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1) dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

GLP1 receptor agonist• 2013;231(1):57-61.• The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of

overt diabetic nephropathy in type 2 diabetic patients.• Imamura S1, Hirai K, Hirai A.• Author information• Abstract• Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like

peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m² to 26.5 ± 0.8 kg/m² after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m²/year to 0.3 ± 1.9 mL/min/1.73 m²/year (p

= 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

Protein Intake• KANDELLA P. Lancet 1999, April 10: 853:2149

KUWAITI PASSION FOR FOOD CANNOT BE SHAKEN

• Strong evidence that high dietary protein intake increases risk of Diabetic Neph & its progression to ESRD. Lower intake of proteins has a lower incidence of Ualb. It reduces Hyperfiltration & intraglomerular pressure.

• ADA recommends .8Gm/Kg in Neph & .6Gm/kg in CRI. NEJM 1999: 324-:78-89. D Care 25:Sup1 :s85- . 9,2002

BP Control

•SALT

• Top Ten Worst McDonald's Menu Food Items for Fat Content and Fat Calories:

Big Breakfast with Hotcakes 2150 mg salt content 90% of the recommended daily salt intake for the average adult

Angus Bacon and Cheese 2070 mg salt content 86% of the recommended daily salt intake for the average adult

Angus Deluxe 1700 mg salt content 71% of the recommended daily salt intake for the average adult

Big Breakfast 1560 mg salt content 65% of the recommended daily salt intake for the average adult

Sausage, Egg & Cheese McGriddles 1360 mg salt content 57% of the recommended daily salt intake for the average adult

Double Quarter Pounder with Cheese 1360 mg salt content 57% of the recommended daily salt intake for the average adult

Bacon, Egg and Cheese Bagel 1300 mg salt content 54% of the recommended daily salt intake for the avera

SALT and Microalbuminuria• [Salt--hidden poison in everyday meal].• Jelaković B1, Premuzić V, Skupnjak B, Reiner Z.• Abstract Coratian Journal Lijec Vjesn 2009 May- june ;131(5-6):146-54• A large number of epidemiologic, evolutionary and clinical studies have confirmed that table salt is a significant

factor in determining the blood pressure (BP) level, and thereby in the prevalence of arterial hypertension (AH). It has been observed in epidemiologic studies that BP increases with age only if accompanied by excessive table salt intake. In addition to affecting BP, increased salt intake independently contributes to target organ damage. Correlation has also been observed between coronary artery disease, left ventricular hypertrophy, cerebrovascular insult, microalbuminuria. Table salt, i.e. NaCl, is directly involved in the process of atherothrombogenesis by changing the relation between vasoactive factors in the blood vessel wall, by affecting the expression of receptor for angiotensin II and, which is particularly important, by elevating platelet aggregability. From clinical and public health aspects, the data obtained in interventional studies are particularly important, as well as those that apparently confirm the benefit of restricting NaCl intake. This benefit is manifested not only in decreased BP and reduction in cardiovascular morbidity and mortality, but also in improved total health as it is known that excessive table salt intake is also a risk factor for osteoporosis, nephrolithiasis, gastric and nasopharyngeal carcinoma, etc. Although there were some studies that raised doubt about the fact that reduced table salt intake could be harmful due to activation of counter-regulative mechanisms, a substantially higher number of authors demonstrated that moderate intake reduction was not associated with the increased risk but rather the contrary. Table salt intake restriction should be performed as part of other lifestyle changes, primarily weight loss and increased physical activity. During NaCl intake reduction, it is necessary to pay attention to other electrolytes and microelements that are also important stones in the mosaic of healthy living. Gooverment authorities and food manufacturers bear heavy responsibility as ready or half-cooked food accounts for over 70% of NaCl intake into the body.

Serum Uric acid and Microalbuminuria DM• Journal Of Renal Nutrition 2011 Jan;21(1):124-7. doi: 10.1053/j.jrn.2010.10.024.• Serum uric acid as a new player in the development of diabetic nephropathy.• Hovind P1, Rossing P, Johnson RJ, Parving HH.• Author information• Abstract• The pathogenesis of diabetic nephropathy is complex and still not fully elucidated. Uric

acid has been associated with renal disease, even though hyperuricemia may be a marker of or by itself be responsible for microvascular disease in diabetes. In animal models, elevated level of uric acid can lead to arteriolopathy of preglomerular vessels, impaired autoregulation, glomerular hypertension, as well as endothelial dysfunction. Kidney damage in hyperuricemic rats is not dependent on blood pressure, and instead involves the renin-angiotensin system. In patients with diabetes, serum uric acid early in the course of diabetes is significantly, and independent of confounders, associated with later development of persistent macroalbuminuria. Therefore, uric acid may be a novel and important player in the pathogenesis of microvascular complications in diabetes. A dose-response relationship between serum uric acid and early decline in renal function has recently been demonstrated in patients with type-1 diabetes. Randomized controlled trials on drugs that lower uric acid need to be conducted to evaluate the causal relationship between serum uric acid and development and progression of diabetic kidney disease; in addition, large scale long-term treatment trials need to be performed, as they are still lacking.

ACE and ARBs and BP ControlACE inhibitors decrease intraglomerular pressure by reversing

vasoconstriction of efferent arteriole AnII .Bradykinin-Kalekerin system resulting in increasing amt. Of vasodialting PG and decreasing intra renal levels of growth factor- ANII

In microalbuminuric IDDM/NIDDM they PREVENT developing Overt nephropathy even in normotensives.

In overt nephropathy Ace inhibitors for BP Control or even in normotensives delays /decelerates the progression of renal failure and decreases Albu-ria

An II blockers have similar effect . & Combination of Ace & AnII blockers have additive effect Calm Study BMJ;321;1440-44,2000.

Parving et al Curr Opin Neph Hyper 1994:3(3):292-300 leheey et, kidney int 2000 ;58 (supp77):93-98

ACE BP Control• Meta analysis of 12 trials of DM N BP with Ualb . ACE

inhibitors reduced the risk of progression to macro alb by 62% compared placebo.

• Regresion to normal alb was THREE times more comman than placebo pat.

• Beneficial effect of ACE on prevention & progress- ion from Ualb to overt Neph is long lasting.

• LA Dihydropyridine CCB are as effective as ACE in delaying the occurrence of Macro alb in NORMOTENSIVE Type I DM who have persistent Ualb

• Parving H H , KID Int 60; 2041-55, Dec 2001.

ACE + ARBS

•ON TARGET•VA NEPHRON•ALTITUDE

Aldactone and Microalbuminuria

BP ControlNational Kidney foundation recommends Target BP of

125/75 mmof hg . Particulary with inclusion of ACE. Attempt to lowest tolerated. With aggressive treatment,the decline of RF can be reduced to half ie from 10% to 5% /year

BP lowering should with caution in elderly with carotid artery stenosis and autonomic neuropathy.

Comination of ACE+Non dihydropridine Ca channel blockers+ loop diuretics

ACE can cause increse K+ or det RFT in R. art Stenosis. It improves glucose control.

Bp in DM is Vol sensitive , Loop diuretics more than once a day.

Vit D Def and Microalbuminuria

Dyslipidemias• Incidence of MI increases many fold(4-40) in Type I & II

Dm in the presence of U Alb and overt Neph.• Presence of albuminuria as occurs in arterioles in

glomerulus suggests that large vessles are more permeable to lipoproteins and thus the macro vascular disease.

• Hyperlipidemia aggressively treated in DM prevents both macro and micro vascular abnormalities.

• Studies have shown that decreasing lipids with Statins results in improvement of retinopathy and stabilization of nephropathy. Statins have been demonstrated to decrease mesangial cell proliferation.

Diabetes :1994,43(4):552-557.

Lower advanced glyo-sylated end products level (AGE)

• Hyperglycemia results in increased levels of AGE which are formed when glucose is irreversibly attached to a protein.

• Increased levels of AGE results in their deposition in vessles causing Retinopathy, Nephropathy, CAD & PVD.

• AGE stimulate mesangial cell proliferation and production of proteoglycans

• Decreasing levels of AGE by AMINOGUANIDINE in experimental animals lowers the incidence of these complications.

• Studies in humans with type I DM resulted in amelioration of DM and a decline in proteinuria . Side effects Flu like , auto antibodies formation RPGN and Anemia Limited Success.

Post graduate med , 1999,105(20):1-11.

Endothelin 1 antogonist• Atrasentan Provides Health Benefits to Patients with Diabetic

Nephropathy• Low-dose atrasentan (0.75 mg/day) decreased albuminuria by

36% without major side effects in a randomized trial of 211 type 2 diabetic nephropathy patients who received a placebo, low-dose atrasentan, or 1.25 mg/day atrasentan for 12 weeks. The low dose of atrasentan also lowered blood pressure and cholesterol levels. The higher dose had similar benefits but caused more fluid retention. Patients in the JASN study had CKD stages 2 and 3 with albuminuria and were receiving maximum tolerated doses of RAS inhibitors. Atrasentan targets the endothelin receptor A and may have beneficial effects on kidney blood vessels while also reducing kidney inflammation and scarring.

• 2013 Dec 15;4(6):245-255.• Diabetic nephropathy: Is it time yet for routine kidney biopsy?• Gonzalez Suarez ML, Thomas DB, Barisoni L, Fornoni A.• Author information• Abstract• Diabetic nephropathy (DN) is one of the most important long-term complications of diabetes. Patients with

diabetes and chronic kidney disease have an increased risk of all-cause mortality, cardiovascular mortality, and kidney failure. The clinical diagnosis of DN depends on the detection ofmicroalbuminuria. This usually occurs after the first five years from the onset of diabetes, and predictors of DN development and progression are being studied but are not yet implemented into clinical practice. Diagnostic tests are useful tools to recognize onset, progression and response to therapeutic interventions. Microalbuminuria is an indicator of DN, and it is considered the only noninvasive marker of early onset. However, up to now there is no diagnostic tool that can predict which patients will develop DN before any damage is present. Pathological renal injury is hard to predict only with clinical and laboratory findings. An accurate estimate of damage in DN can only be achieved by the histological analysis of tissue samples. At the present time, renal biopsy is indicated on patients with diabetes under the suspicion of the presence of nephropathies other than DN. Results from renal biopsies in patients with diabetes had made possible the classification of renal biopsies in three major groups associated with different prognostic features: diabetic nephropathy, non-diabetic renal disease (NDRD), and a superimposed non-diabetic condition on underlying diabeticnephropathy. In patients with type 2 diabetes with a higher degree of suspicion for NDRD, it is granted the need of a renal biopsy. It is important to identify and differentiate these pathologies at an early stage in order to prevent progression and potential complications. Therefore, a more extensive use of biopsy is advisable.