With protein intakes greater than 20% of energy intake there is an association between protein with increased albumin excretion rate.
Marion J et al. Current Diabetes Reports 2003, 3:412-417
Slightly Elevated UAE: at onset of diabetes already predicted the development of MA.
the risk of progression from normoalbuminuria to microalbuminuria and macroalbuminuria within 10 years was 70% if the patient had a combination of four risk factors, namely, retinopathy, urinary AER>10 mg/24 h, HbA1c>8.6% and smoking, as against only 10% risk of progression if none of these risk factors were present.
Rossing P et al. (2002). Diabetes Care 25: 859–864 .
is related to initiation of microalbuminuria and the presence of diabetic nephropathy.
Hovind P et al. (2004). Br Med J 328:1105
Oral Contraceptive : activate RAS and increase risk of developing DN.
Ahmed SB et al (2005). Diabetes Care 28:1988–1994.
Cardiovascular Risk Markers
DN: Susceptibility / Risk Factors
Diabetic Patient IN Development Of In The Presence Of Diabetic Retinopathy Hypertension Progressive Renal Deterioration Absence of other causes P ersistant Proteinuria > 300 mg / day DN: Diagnostic Criteria Type 1> 10 Y Type 2 at Diagnosis
1. Duration of Diabetes in DN Average Type 1: Overt DN Rarely occur before 10 yrs. Type 2: May be present in newly diagnosed patients . Peak Peak incidence 10 to 20 y duration If duration > 30 y + Normoalbuminuria Risk is Very Low DN: Diagnostic Criteria Decline After 20 y Progressive decline in incidence takes place.
Normal Protein in urine should not exceed 150 mg /day 2. Abnormal Urinary Albumin Excretion DN: Diagnostic Criteria
Higher levels of blood pressure are associated with more rapid progression of diabetic kidney disease Most patients with diabetic kidney disease are hypertensive Hypertension is both a cause and a consequence of renal disease and the kidney is both villain and victim in hypertension. Critchley JA et al. Chin Med J (Engl). 2002 Jan;115(1):129-35. 4. Hypertension DN: Diagnostic Criteria
4. Hypertension DN: Diagnostic Criteria With Macroalbuminuria: >90% With Microalbuminuria: 80% At Diagnosis: 50% Type 2 With Macroalbuminuria: 65-88% With Microalbuminuria: 30-50% At Diagnosis: 20-40% Type 1
6. Exclusion of Other Causes DN: Diagnostic Criteria
Lack of Retinopathy or Neuropathy Persistent Hematuria (microscopic or macroscopic) Signs or symptoms of Systemic Disease Rapidly Rising Creatinine High SCr with little or no Proteinuria F/H of Nondiabetic Renal Disease (e.g. polycystic kidney disease or Alport syndrome) Short Duration of Diabetes 6. Exclusion of Other Causes Markers of Non Diabetic Renal Diseases Indications of Renal Biopsy in Diabetes 1 2 3 4 5 6 7
Natural History of Type 1 Diabetic Nephropathy DN: Natural History
Susceptibility Silent Silent Incipient Overt ESRD DN: Natural History Natural History of Type 2 Diabetic Nephropathy
Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD C V D E A T H The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated Adler et al. Kid Int, 2003 Elevated Serum Creatinine 19% No albuminruia 1.4% Microalbuminruia 3.0% Macroalbuminruia 4.6%
Diabetic Nephropathy Death Rate In Diabetic Patients on RRT 54.1
Causes of Death DN: Causes of Death Stroke Myocardial Infarction Heart Failure Sudden Death
Not all patients with Microalbuminuria will develop Macroalbuminuria.
Not all patients with Macroalbuminuria will develop ESRD.
Microalbuminuria Macroalbuminuria 80%/10-15y Macroalbuminuria ESRD 50%/ 10y 75%/ 20y Without Specific Interventions in type 1 DM Microalbuminuria Macroalbuminuria Macroalbuminuria ESRD 20%/ 20y Without Specific Interventions in type 2 DM 20-40 % American Diabetic Association. Diab Care 2004 DN: Prognosis
DN: Where to Meet the Patients? Susceptibility Silent Silent Incipient Overt ESRD Screening and Prevention of Type 2 Diabetes Screening and Prevention of Diabetic Nephropathy Natural History of Type 2 Diabetic Nephropathy Prevention of progression of MiA to overt DN
Preventive/ Pre-emptive Strategies Screening For DN Prevention Of DN
1 American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004 BP UAE Lipid At Least Annually < 150mg/dl TG < 100 mg/dl LDL > 40mg/dl HDL DN: Screening
Screening for microalbuminuria can be performed by three methods:
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.
The first method 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.
Measurement of microalbuminuria:
Specific assays :
Enzyme-linked immunosorbent assay
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.
There is also marked day-to-day variability in albumin excretion, so at least two of three collections done in a 3- to 6-month period should show elevated levels before designating a patient as having microalbuminuria.
High doses of thiamine and its derivate benfotiamine: retard the development of microalbuminuria in experimental diabetic nephropathy, probably due to decreased activation of protein kinase C, decreased protein glycation, and oxidative stress.
ALT-711 (cross-link breaker of the advanced glycation end products) : has been shown to result in a significant reduction in UAE, blood pressure, and renal lesions in experimental diabetes.
Protein kinase C ß inhibitor (ruboxistaurin): normalized GFR, decreased albumin excretion rate, and ameliorated glomerular lesions in diabetic rodents.
Sulodexide (a glycosaminoglycan): significantly reduced albuminuria in micro- or macroalbuminuric type 1 and type 2 diabetic patients.
Pimagedine (second-generation inhibitor of advanced glycation end products): reduced urinary protein excretion and the decline in GFR in proteinuric type 1 diabetic patients in a randomized, placebo-controlled study.
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ: Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52:2110–2120, 2003.
Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME: The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J 17:1762–1764, 2003.
Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, Wilkinson-Berka JL, Gilbert RE: Protein kinase C ß inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes 52:512–518, 2003
Gambaro G, Kinalska I, Oksa A, Pont’uch P, Hertlova M, Olsovsky J, Manitius J, Fedele D, Czekalski S, Perusicova J, Skrha J, Taton J, Grzeszczak W, Crepaldi G: Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol 13:1615–1625, 2002.
Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP: Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 24:32–40, 2004.
Addition of spironolactone (25-50 mg OD) to an ACE inhibitor or AngII receptor blocker is associated with a marked and sustained antiproteinuric effect, which in part relates to the more pronounced reduction in GFR.
van den Meiracker et al. J Hypertens. 2006 Nov;24(11):2285-92.