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Diabetic nephropathy
Updated 2014 Jan 22 08:29:00 AM: ADA position statement on standards of medical care in diabetes (Diabetes Care 2014 Jan) view update Show more updates Related Summaries: Diabetes (list of topics) Diabetes mellitus type 2 Diabetes mellitus type 1 Chronic kidney disease Physician Quality Reporting System Quality Measures General Information Description: microvascular diabetic complication involving the kidney(1) Also called: diabetic glomerulosclerosis diabetic kidney disease Definitions: glomerular classification of diabeticnephropathy Class I - mild or nonspecific light microscopy changes and electron microscopy-proven glomerular basement membrane thickening Class IIa - mild mesangial expansion (in > 25% of observed mesangium) Class IIb - severe mesangial expansion (in > 25% of observed mesangium) Class III - nodular sclerosis (at least one convincing Kimmelstiel-Wilson lesion) Class IV - advanced diabetic glomerulosclerosis (global glomerular sclerosis in > 50% of glomeruli) Reference - J Am Soc Nephrol 2010 Apr;21(4):556 full-text Kidney Disease Improving Global Outcomes (KDIGO) recommends CKD staging based on cause, GFR category, and albuminuria category(3) GFR categories G1 - GFR > 90 mL/minute/1.73 m2 (normal or high) G2 - GFR 60-89 mL/minute/1.73 m2 (mildly decreased compared to young adult level) G3a - GFR 45-59 mL/minute/1.73 m2 (mild-to-moderately decreased) G3b - GFR 30-44 mL/minute/1.73 m2 (moderate-to-severely decreased) G4 - GFR 15-29 mL/minute/1.73 m2 (severely decreased) G5 - GFR < 15 mL/minute/1.73 m2 (kidney failure) albuminuria categories A1 - albumin excretion rate (AER) < 30 mg/24 hours, albumin:creatinine ratio (ACR) < 30 mg/g (3 mg/mmol) (normal to mildly increased) A2 - AER 30-300 mg/24 hours, ACR 30-300 mg/g (3-30 mg/mmol) (moderately increased compared to young adult level) A3 - AER > 300 mg/24 hours, ACR > 300 mg/g (30 mg/mmol) (severely increased [including nephrotic syndrome]) Reference - KDIGO 2013 Jan PDF Who is most affected: more common in patients with type 1 diabetes, more cases of patients with type 2 diabetes (N Engl J Med 1989 Oct 19;321(16):1074) Incidence/Prevalence: occurs in 20%-40% of patients with diabetes(1) prevalence of diabetic kidney disease in United States 3.3% during 2005-2008 based on cross-sectional analyses of Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994, NHANES 1999-2004 and NHANES 2005-2008 diabetic kidney disease defined as diabetes with albuminuria (ratio of urine albumin-to-creatinine 30 mg/g), impaired glomerular filtration rate (< 60 mL/min/1.73 m2 estimated using Chronic Kidney Disease Epidemiology Collaboration formula) or both prevalence of diabetic kidney disease in United States 2.2% in 15,073 persons from NHANES III
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2.8% in 13,045 persons from NHANES 1999-2004 3.3% in 9,588 persons from NHANES 2005-2008 prevalence of diabetic kidney disease increased in direct proportion to prevalence of diabetes without change in prevalence of diabetic kidney disease among those with diabetes Reference - JAMA 2011 Jun 22;305(24):2532 full-text cumulative incidence of end-stage renal failure with diabetes mellitus type 1 2.2% at 20 years and 7.8% at 30 years based on cohort of 20,005 patients diagnosed with type 1 diabetes before age 30 years in Finland and followed for up to 37 years (median 17 years) Reference - JAMA 2005 Oct 12;294(14):1782, commentary can be found in ACP J Club 2006 Mar-Apr;144(2):51 < 1% at median 21 years based on retrospective cohort of 12,032 patients diagnosed with type 1 diabetes before age 15 years in Sweden and followed for up to 27 years (median 21 years) 33 (0.27%) developed end-stage renal disease due to diabeticnephropathy, all of whom had diabetes duration > 15 years 33 (0.7%) of 4,414 patients who had diabetes duration > 15 years developed end-stage renal disease due to diabeticnephropathy Reference - Diabetes Care 2006 Mar;29(3):538 prevalence of nephropathy (defined as urinary albumin-creatinine ratio 30 mg/kg or higher) was 28% in 271 persons with diagnosed diabetes, 24.9% in 132 persons with undiagnosed diabetes, and 9.6% in 2,168 persons without diabetes in national United States survey of 2,571 persons > 40 years old 1999-2002 (Ann Fam Med 2006 Sep-Oct;4(5):427 full-text), commentary can be found in Am Fam Physician 2006 Dec 1;74(11):1960 23% of 3,893 Australian general practice patients with type 2 diabetes had estimated glomerular filtration rate < 60 mL/minute/1.73 m2, and 35% had elevated urinary albumin-creatinine ratio (Med J Aust 2006 Aug 7;185(3):140) Causes and Risk Factors Causes: hyperglycemia leads to diabetic glomerulosclerosis in subset of patients with diabetes (develops mean 15 years after onset of metabolic abnormalities) (Contrib Nephrol 2011;170:36) many patients with diabetes and chronic renal insufficiency may have renal parenchymal disease and not classic diabetic glomerulosclerosis; study of 1,197 adults > 40 years old with diabetes mellitus type 2, 171 (13%) had chronic renal insufficiency defined as glomerular filtration rate < 60 mL/minute/1.73 m2 body surface area; among these 171 subjects, 30% had neither diabetic retinopathy nor albuminuria (including microalbuminuria), suggesting causes other than diabetic glomerulosclerosis (JAMA 2003 Jun 25;289(24):3273), commentary can be found in JAMA 2003 Oct 8;290(14):1855 Pathogenesis: multiple mechanisms(2) early hemodynamic changes of glomerular hyperperfusion and hyperfiltration lead to albumin leakage from glomerular capillaries and structural changes, such as glomerular basement membrane thickening glomerular hypertrophy glomerulosclerosis mesangial cell expansion podocyte injury and loss activated inflammatory mediators (due to poorly controlled glucose, blood pressure, and cholesterol) in patients with genetic predisposition may increase risk of progression to advanced stage nephropathy Likely risk factors: hypertension(2) poorly controlled diabetes(1) poorly controlled cholesterol(2) microalbuminuria microalbuminuria may be marker for increased mortality and future nephropathy microalbuminuria as marker for increased mortality microalbuminuria associated with increased risk of mortality based on systematic review without methodological analysis 11 European cohort studies defined microalbuminuria as albumin excretion 0.03-0.3 g/day consistent finding across studies showed that presence of microalbuminuria associated with 2 times risk of all-cause and cardiovascular mortality unclear if treating microalbuminuria in type 2 diabetes reduces risk Reference - Arch Intern Med 1997 Jul 14;157(13):1413 in J Fam Pract 1997 Nov;45(5):379 microalbuminuria associated with increased risks for overall mortality, major cardiovascular events, and hospitalization for heart failure based on cohort study
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5,545 persons > 55 years old with cardiovascular disease and 3,498 persons > 55 years old with diabetes followed for median 4.5 years Reference - JAMA 2001 Jul 25;286(4):421, commentary can be found in ACP J Club 2002 Jan-Feb;136(1):34 microalbuminuria and gross proteinuria associated with increased risks for death from all causes, cardiovascular causes, coronary heart disease, or stroke cohort study of 840 patients with older-onset diabetes followed for 12 years; 43% cardiovascular mortality in cohort, based on death certificates increased risks significant after controlling for known cardiovascular risk factors and diabetes-related variables relative risks were 1.68-2.2 for microalbuminuria and 2.33-2.73 for gross proteinuria Reference - Arch Intern Med 2000 Apr 24;160(8):1093 microalbuminuria associated with 17.5 times the risk of developing proteinuria in 4.5-year follow-up of 7,674 subjects in HOPE trial (J Am Soc Nephrol 2003 Mar;14(3):641) albumin-to-creatinine ratio > 30 mg/g in random urine specimens predicts development of overt nephropathy study of 439 Pima Indians aged 25-84 years with diabetes, with no overt nephropathy at baseline mean follow-up 4.2 years overt nephropathy defined as protein-to-creatinine ratio > 1 g/g at baseline, 140 patients had albumin/creatinine ratio > 30 mg/g and 299 had ratio < 30 mg/g overt nephropathy developed in 34% with vs. 4% without albumin/creatinine ratio > 30 mg/g other independent predictors of nephropathy were duration of diabetes and 2-hour postload glucose concentration albumin-to-creatinine ratio > 30 mg/g had 80% sensitivity, 76% specificity, 34% positive predictive value, and 96% negative predictive value Reference - Arch Intern Med 1991 Sep;151(9):1761, commentary can be found in ACP J Club 1992 JanFeb;116(1):19 microalbuminuria associated with increased risk for diabeticnephropathy but most patients with microalbuminuria do not develop nephropathy based on prospective cohort study 23 patients with diabetes with persistent microalbuminuria and 209 patients with diabetes without microalbuminuria followed for 7 years microalbuminuria regressed in 56% of those with it and developed in 16% of those without it microalbuminuria had 43% positive predictive value and 77% negative predictive value for diabeticnephropathy Reference - Diabetes Care 2001 Sep;24(9):1560 microalbuminuria frequently regresses over 2-6 years in patients with type 1 diabetes study of 386 patients with type 1 diabetes and persistent microalbuminuria (urinary albumin excretion 30-299 mcg/minute) followed for 6 years 58% had regression of microalbuminuria defined as 50% reduction in urinary albumin excretion from one 2-year period to the next regression more likely if microalbuminuria of short duration, HbA1c < 8%, systolic blood pressure < 115 mm Hg, or low cholesterol and triglyceride levels angiotensin-converting enzyme inhibitors did not affect likelihood of regression Reference - N Engl J Med 2003 Jun 5;348(23):2285, commentary can be found in N Engl J Med 2003 Aug 28;349(9):906, Am Fam Physician 2004 Feb 1;69(3):695 Possible risk factors: vitamin D deficiency may be associated with increased risk of diabeticnephropathy based on cross-sectional study 1,216 adults 20 years old with diabetes evaluated for vitamin D deficiency and insufficiency and diabeticnephropathy nephropathy in 30.7% (more prevalent in minorities) vitamin D deficiency in 48.9%, vitamin D insufficiency in 36.6% vitamin D deficiency in 53.2% with nephropathy vs. 47% without nephropathy (p = 0.03) Reference - J Am Board Fam Med 2009 Sep-Oct;22(5):521 full-text Complications and Associated Conditions Complications: end-stage renal disease(1) anemia(2) avoid contrast material (IV pyelogram, computed tomography dye) especially if creatinine > 2, else prior hydration is extremely important (see Chronic kidney disease for additional information) see Chronic kidney disease for comprehensive list of nephropathy-associated complications Associated conditions: arteriosclerotic disease(1)
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(2)
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cardiovascular disease , especially hypertension diabetic foot ulcer diabetic retinopathy diabetic peripheral neuropathy diabetic ketoacidosis (DKA) in adults diabetic ketoacidosis (DKA) in children and adolescents hyperosmolar hyperglycemic crisis gastroparesis
(2)
History and Physical History: Chief concern (CC): usually asymptomatic identified upon screening patient with diabetes Review of systems (ROS): associated with diabetic retinopathy, ask about blurry or decreased vision diabetic neuropathy, ask about numbness, pain, and/or tingling in extremities Physical: General physical: edema if nephrotic syndrome, hypertension HEENT: most have retinopathy(3), assess for aneurysms, proliferation, and hemorrhages of retinal vasculature cotton wool spots Diagnosis Making the diagnosis: diabetic kidney disease (presumptive diagnosis of kidney disease caused by diabetes) can be diagnosed in most patients with diabetes if any of(1, 3) albuminuria of 300 mg/24 hours or albumin-creatinine ratio > 300 mg/g (also called macroalbuminuria) (NKF KDOQI Grade B) albuminuria of 30-299 mg/24 hours or albumin-creatinine ratio 30-300 mg/g (also called microalbuminuria) plus retinopathy (NKF KDOQI Grade B) microalbuminuria plus type 1 diabetes of 10 years duration (NKF KDOQI Grade A) albuminuria based on elevated albumin-creatinine ratio should be confirmed with additional 2 first-voided urine specimens during subsequent 3-6 months (NKF KDOQI Grade B)(3) consider nondiabetic causes of chronic kidney disease if any of (NKF KDOQI Grade B)(3) absence of diabetic retinopathy low or rapidly decreasing glomerular filtration rate rapidly increasing proteinuria or nephrotic syndrome refractory hypertension active urinary sediment signs or symptoms of other systemic disease > 30% reduction in glomerular filtration rate within 2-3 months after starting angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy Differential diagnosis: other causes of renal failure, see Acute renal failure - differential diagnosis Chronic kidney disease other causes of elevated serum creatinine (blood urea nitrogen/creatinine ratio usually < 8) acute upper gastrointestinal bleeding malnutrition liver disease rhabdomyolysis laboratory artifact (chemical interference with creatinine determination due to presence of ketones, proteins, sugars) medication-induced inhibition of tubular secretion of creatinine cimetidine pyrimethamine trimethoprim
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acetoacetate Reference - Arch Intern Med 1998 Dec 7-21;158(22):2509 causes of falsely elevated serum creatinine medications (for example, cefoxitin) toxic ingestion such as methanol poisoning or nitromethane ingestion ketoacidosis, such as diabetic ketoacidosis (DKA) see Acute renal failure - differential diagnosis for details causes of transient increases in albuminuria(2) fever high-salt diet vigorous exercise in previous 24 hours infection dehydration hematuria significant hyperglycemia very high blood pressure heart failure Testing overview: annual screening for diabetic kidney disease recommended starting(1, 3) at diagnosis with type 2 diabetes (ADA Grade B, NKF KDOQI Grade B) 5 years after diagnosis with type 1 diabetes (ADA Grade B, NKF KDOQI Grade A) screening should include(1, 3) measurement of urine albumin excretion (ADA Grade B), such as urine albumin-to-creatinine ratio in spot urine sample (NKF KDOQI Grade B) measurement of serum creatinine and estimation of glomerular filtration rate (ADA Grade E, NKF KDOQI Grade B) additional testing if abnormal urine albumin excretion 2 additional urine specimens in following 3-6 months for confirmation (NKF KDOQI Grade B)(1, 3) testing to rule out nondiabetic causes of kidney disease if suspicion exists(3) renal biopsy if uncertain diagnosis (such as patient with normoalbuminuria and decreased glomerular filtration rate)(3) Blood tests: serum creatinine levels (to estimate glomerular filtration rate [eGFR])(2, 3) Modification of Diet in Renal Disease (MDRD) calculator recommended by National Kidney Foundation for evaluating renal function in patients with chronic kidney disease 4-variable MDRD equation may have higher diagnostic accuracy than Cockcroft-Gault formula for chronic kidney disease (CKD) in elderly patients with diabetes (level 2 [mid-level] evidence) based on prospective cohort study without results of MDRD and reference standard blinded to each other 69 patients with diabetes 72 years old and serum creatinine ranging from 54-367 mcmol/L (0.61-4.15 mg/dL) had comparison of eGFR calculated using 4-variable MDRD and Cockcroft-Gault equations actual GFR measured using chromium-51-ethylenediaminetetraacetic acid (EDTA) clearance formulas using (standard definition of CKD) GFR < 60 mL/minute/1.73 m2 had 98% sensitivity and 61% specificity for MDRD equation 82% sensitivity and 44% specificity for Cockcroft-Gault equation Reference - J Am Geriatr Soc 2006 Jun;54(6):1007 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and MDRD equations each underestimate GFR more frequently in patients with type 2 diabetes than in healthy persons (level 1 [likely reliable] evidence) based on diagnostic cohort study 56 patients with type 2 diabetes and normal renal function and 55 healthy volunteers (mean age 58 years) had GFR estimated using MDRD and CKD-EPI equations and measured by Cr-EDTA single-injection method misclassification of CKD (estimated GFR < 60 mL/minute/1.73 m2) in patients with diabetes, false positive in 16% with CKD-EPI equation vs. 21% with MDRD equation (not significant) in healthy volunteers, false positive in 2% with CKD-EPI vs. 2% with MDRD equation Reference - Diabet Med 2011 Jan;28(1):90 review of measuring renal function in clinical practice can be found in BMJ 2006 Oct 7;333(7571):733 full-text, commentary can be found in BMJ 2006 Oct 28;333(7574):918 full-text, BMJ 2006 Nov 18;333(7577):1072 full-text review of measured and estimated glomerular filtration rate for assessing kidney function can be found in N Engl J Med 2006 Jun 8;354(23):2473, commentary can be found in N Engl J Med 2006 Sep 7;355(10):1067 Urine studies: urinary albumin-to-creatinine ratio in random spot sample(3) microalbuminuria defined as 30-300 mg/g (generally associated with stable kidney function)
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macroalbuminuria defined as > 300 mg/g confirm abnormal result in absence of urinary tract infection with 2 additional first-void specimens in following 3-6 months (2 of 3 samples falling in microalbuminuric or macroalbuminuric range confirms diagnosis) (NKF KDOQI Grade B) urine dipstick or immunoassay for albumin alone (without measuring urine creatinine) is less expensive but may have more false negative and false positive test results(1) Biopsy and pathology: renal biopsy(3) risks of percutaneous native kidney biopsy similar in patients with diabeticnephropathy and chronic kidney disease of other etiology required to definitely diagnose diabetic glomerulopathy (possibility exists of serious diabetic glomerular lesions in patients with normoalbuminuria and normal glomerular filtration rate) usually only done if unclear diagnosis or other cause suspected typical findings in patients with type 1 diabetes and macroalbuminuria include advanced diabetic lesions of increased mesangial volume increased glomerular basement membrane thickness tubulointerstitial pathologies findings in patients with type 1 diabetes and microalbuminuria are generally less severe in patients with type 2 diabetes and microalbuminuria about 40% show changes similar to type 1 diabetes about 30% show tubulointerstitial, vascular, and/or glomerulosclerotic lesions unrelated to classic diabetic glomerulopathy about 30% have normal or near normal biopsy results Treatment Treatment overview: dietary protein restriction for patients with any degree of chronic kidney disease, limit protein intake to improve renal function (ADA Grade C, NKF KDOQI Grade B) protein restricted diet may slightly slow progression of diabeticnephropathy (level 3 [lacking direct] evidence) and might reduce risk of end-stage renal disease or death (level 2 [mid-level] evidence) low-carbohydrate, low-iron diet enriched with polyphenols may delay progression of nephropathy (level 3 [lacking direct] evidence) and reduce renal replacement therapy or death compared to conventional protein-restricted diet in patients with type 2 diabetes (level 2 [mid-level] evidence) angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) ACE inhibitor or ARB recommended in patients with diabetes if urinary albumin excretion 300 mg/day (ADA Grade A, KDIGO Level 1 Grade B) or 30-299 mg/day (ADA Grade C, KDIGO Level 2 Grade D) urine albumin-creatinine ratio 30 mg/g (NKF KDOQI Grade 2C) chronic kidney disease and hypertension (NKF KDOQI Grade A) in patients with diabeticnephropathy ACE inhibitors may reduce risk for end-stage kidney disease (level 2 [mid-level] evidence), and ACE inhibitors at maximum tolerable dose (but not at lower doses) may reduce all-cause mortality (level 2 [mid-level] evidence) ARBs may reduce risk for end-stage kidney disease in hypertensive patients with type 2 diabetes (level 1 [likely reliable] evidence) addition of ARB to ACE inhibitor may further reduce albuminuria (level 3 [lacking direct] evidence) but may not reduce risk for end-stage kidney disease (level 2 [mid-level] evidence) other medications combination of perindopril plus indapamide (Preterax) reduces mortality in patients with type 2 diabetes (level 1 [likely reliable] evidence) spironolactone (Aldactone) or eplerenone (Inspra) may reduce albuminuria (level 3 [lacking direct] evidence) other medications reported to reduce albuminuria in single or few trials include pitavastatin (Livalo), pentoxifylline (Trental), paricalcitol (Zemplar), and astragalus membranaceus (a traditional Chinese herb) (level 3 [lacking direct] evidence) treatment targets for cardiovascular risk factors include target blood pressure recommendations in patients with diabetes vary, but range from < 130/80 mm Hg to < 140/90 mm Hg, however, most are not specific to patients with diabetes and kidney disease National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines recommend target blood pressure < 130/80 mm Hg for patients with diabetes and chronic kidney disease (NKF KDOQI Grade B) Kidney Disease: Improving Global Outcomes (KDIGO) guideline for adults with chronic kidney disease and diabetes recommend target blood pressure 140/90 mm Hg if urine albumin excretion < 30 mg/24 hours (KDIGO Level 1, Grade B) target blood pressure 130/80 mm Hg if urine albumin excretion > 30 mg/24 hours (KDIGO Level 2, Grade D) HbA1c < 7% (ADA Grade B, NKF KDOQI Grade 1A) but less stringent target (such as < 8%) if risk for hypoglycemia or
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comorbidities (ADA Grade B, NKF KDOQI Grade 2C) low-density lipoprotein (LDL) cholesterol level < 100 mg/dL (2.6 mmol/L) (ADA Grade B, NKF KDOQI Grade B) monitor estimated glomerular filtration rate every 3-6 months and consider need to adjust medication doses early vaccination against hepatitis B indicated in patients likely to progression to end-stage kidney disease(1) avoid nephrotoxic therapies, such as contrast material, to prevent progression of chronic kidney disease Diet: Protein restriction: American Diabetes Association (ADA) recommendations on protein intake in patients with diabetes and chronic kidney disease (ADA Grade C)(1) limit protein intake to 0.8-1 g/kg/day at earlier stages of chronic kidney disease limit protein intake to 0.8 g/kg/day at later stages of chronic kidney disease reducing protein intake to these limits may improve measures of renal function (urine albumin excretion and glomerular filtration rate) National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) recommends target dietary protein intake 0.8 g/kg/day for people with diabetes and chronic kidney disease stages 1-4 (NKF KDOQI Grade B)(3) protein restricted diet may slightly slow progression of diabeticnephropathy (level 3 [lacking direct] evidence) and might reduce risk of end-stage renal disease or death (level 2 [mid-level] evidence) based on Cochrane review of trials with methodologic limitations and only 1 trial reporting clinical outcomes systematic review of 9 randomized trials and 3 before and after studies evaluating effect of protein modified or restricted diet for at least 4 months on diabetic renal function in patients with type 1 or type 2 diabetes only 2 randomized trials used intention-to-treat analysis, none of the before and after studies detailed selection criteria actual protein intake in intervention groups ranged from 0.7-1.1 g/kg/day only 1 trial reported clinical outcomes 10% low protein diet vs. 27% usual protein diet patients progressed to end-stage renal disease or death in 1 trial with 82 patients with type 1 diabetes (p = 0.042, NNT 6) intervention was protein 0.6 g/kg/day, actual protein intake 0.89 g/kg/day mean declines in glomerular filtration rate did not differ (3.8 vs. 3.9 mL/minute/year) so differences in clinical outcomes may be related to other factors Reference - Kidney Int 2002 Jul;62(1):220 full-text rate of decline of glomerular filtration rate was slightly reduced (but not statistically significant) with low-protein diet in meta-analysis of 7 trials with 222 patients with type 1 diabetes 2 trials in patients with type 2 diabetes no data on the effects of low protein diets on health-related quality of life and costs Reference - Cochrane Database Syst Rev 2007 Oct 17;(4):CD002181 DynaMed commentary -- low protein diet is < 0.8 g/kg/day, so actual intake was not low protein for most intervention groups low-protein diet may reduce proteinuria and HbA1c but may not improve glomerular filtration rate (level 3 [lacking direct] evidence) based on systematic review without clinical outcomes systematic review of 8 randomized trials evaluating low vs. normal protein diets in 519 participants with type 1 or type 2 diabeticnephropathy significantly lower proteinuria or albuminuria in low-protein diet groups in meta-analysis of 8 trials with significant heterogeneity significantly reduced HbA1c levels in low-protein groups in meta-analysis of 7 trials no significant differences in glomerular filtration rates Reference - Am J Clin Nutr 2008 Sep;88(3):660 full-text Other dietary considerations: low-carbohydrate, low-iron diet enriched with polyphenols may delay progression of nephropathy (level 3 [lacking direct] evidence) and reduce composite outcome of renal replacement therapy or death compared to conventional protein-restricted diet in patients with type 2 diabetes (level 2 [mid-level] evidence) based on randomized trial without intention-to-treat analysis 191 patients with type 2 diabetes and nephropathy randomized to carbohydrate-restricted, low-iron, polyphenol-enriched (CR-LIPE) diet vs. conventional protein-restricted diet (0.8 g/kg/day) CR-LIPE diet included 50% reduction from previous carbohydrate intake substitution of iron-enriched meats with iron-poor meats and protein-enriched items that inhibit iron absorption (dairy, eggs, soy) beverage intake limited to water, tea, and red wine, plus milk for breakfast exclusive use of polyphenol-enriched extra virgin olive oil for dressings and cooking mean follow-up 3.9 years loss to follow-up in 21 patients (11%) comparing CR-LIPE diet vs. protein-restricted diet in 170 patients
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renal replacement therapy or death in 20% vs. 39% (p < 0.01, NNT 5) doubling of serum creatinine level in 21% vs. 39% (p < 0.01, NNT 5) difference in outcomes was independent of HbA1c, baseline proteinuria, and use of angiotensin system inhibitors Reference - Diabetes 2003 May;52(5):1204 full-text, commentary can be found in J Fam Pract 2003 Sep;52(9):672, Am Fam Physician 2003 Sep 15;68(6):1176 replacing half of animal protein with soy protein may improve cardiovascular risk factors and kidney-related biomarkers (level 3 [lacking direct] evidence) based on small randomized trial without clinical outcomes 41 patients with diabetes type 2 with nephropathy randomized to soy protein diet (0.8 g protein/kg body weight containing 35% animal, 35% textured soy, and 30% vegetable proteins) vs. control diet (70% animal and 30% vegetable proteins) for 4 years mean changes comparing soy protein vs. control diet fasting plasma glucose -18 vs. +11 mg/dL (p = 0.03) total cholesterol -23 vs. +10 mg/dL (p = 0.01) low-density lipoprotein cholesterol -20 vs. +6 mg/dL (p = 0.01) serum triglyceride levels -24 vs. -5 mg/dL (p = 0.01) serum C-reactive protein levels -1.31 vs. -0.33 mg/L (p = 0.02) proteinuria -0.15 vs. +0.02 g/day (p = 0.001) urinary creatinine -1.5 vs. +0.6 mg/dL (p = 0.01) Reference - Diabetes Care 2008 Apr;31(4):648 Medications: see also Hypertension treatment in patients with diabetes Renin angiotensin system (RAS) antagonists: Recommendations (RAS antagonist use): American Diabetes Association (ADA) recommendations: use either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in nonpregnant patients with(1) modestly elevated levels of urinary albumin excretion (30-299 mg/day) (ADA Grade C) higher levels of urinary albumin excretion ( 300 mg/day) (ADA Grade A) monitor serum creatinine and potassium levels for development of increased creatinine and hyperkalemia if using ACE inhibitors, ARBs, or diuretics (ADA Grade E)(1) National Kidney Foundation (NKF KDOQI) recommendations: angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) recommended for hypertensive patients with diabetes and chronic kidney disease stages 1-4, usually in combination with a diuretic (NKF KDOQI Grade A)(3) suggested for normotensive patients with diabetes and albuminuria (urine albumin/creatinine ratio 30 mg/g) who are at high risk of diabetic kidney disease or its progression (NKF KDOQI Grade 2C)(4) NOT recommended for primary prevention of diabetic kidney disease in normotensive normoalbuminuric patients with diabetes (NKF KDOQI Grade 1A)(4) in pregnant women with diabetes and chronic kidney disease (NKF KDOQI Grade C)(3) ACE inhibitors and ARBs before pregnancy may improve fetal and maternal outcomes, but discontinue as soon as a menstrual period is missed or after a positive pregnancy test use insulin to control hyperglycemia if pharmacologic therapy needed Kidney Disease: Improving Global Outcomes (KDIGO) recommendations: angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for patients with chronic kidney disease and diabetes suggested if urine albumin excretion 30-300 mg/24 hours (KDIGO Level 2 Grade D) recommended if urine albumin excretion > 300 mg/24 hours (KDIGO Level 1 Grade B) Reference - KDIGO 2012 Dec PDF or at National Guideline Clearinghouse 2012 Dec 19:39430, appendix can be found at KDIGO Appendix 2012 Dec PDF, supplementary tables can be found at KDIGO Tables 2012 Dec PDF, commentary can be found at Am J Kidney Dis 2013 Aug;62(2):201 Angiotensin-converting enzyme (ACE) inhibitors: in patients with diabeticnephropathy, ACE inhibitors may reduce risk for end-stage kidney disease (level 2 [mid-level] evidence), and ACE inhibitors at maximum tolerable dose (but not at lower doses) may reduce allcause mortality (level 2 [mid-level] evidence) based on Cochrane review of trials with methodological limitations systematic review of 49 trials of ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with diabeticnephropathy (microalbuminuria or macroalbuminuria) 38 trials compared ACE inhibitors vs. placebo in 8,970 patients with type 1 or type 2 diabetes only 1 trial (HOPE trial) had both adequate allocation concealment and blinding of outcome assessors, and data analyzed
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for this trial represents subgroup analysis of a much larger trial compared to placebo, ACE inhibitors associated with reduced risk of end-stage kidney disease in analysis of 10 trials with 6,189 patients RR 0.6 (95% CI 0.39-0.93) NNT 164-1,429 with 1% risk of end-stage kidney disease in control group reduced all-cause mortality at maximum tolerable dose in analysis of 10 trials with 2,034 patients risk ratio (RR) 0.78 (95% CI 0.61-0.98) NNT 19-358 with 14% risk of mortality in control group no significant difference in all-cause mortality at half or less the maximum dose in analysis of 11 trials with 5,261 patients Reference - Cochrane Database Syst Rev 2006 Oct 18;(4):CD006257 earlier review (36 trials with 4,008 patients) did not separate mortality outcome by dose of ACE inhibitor (BMJ 2004 Oct 9;329(7470):828 full-text), also published in J Am Soc Nephrol 2006 Apr;17(4 Suppl 2):S153 full-text, commentary can be found in Am Fam Physician 2005 Feb 1;71(3):564, Evidence-Based Medicine 2005 May-Jun;10(3):77, ACP J Club 2006 Sep-Oct;145(2):35 ACE inhibitors reduce progression to macroalbuminuria in patients with diabetes mellitus type 1 and microalbuminuria (level 3 [lacking direct] evidence) based on systematic review without clinical outcomes systematic review of 12 controlled trials with 698 patients with type 1 diabetes and microalbuminuria given ACE inhibitor vs. placebo or no treatment for at least 1 year ACE inhibitors reduced progression to macroalbuminuria and increased regression to normoalbuminuria Reference - Ann Intern Med 2001 Mar 6;134(5):370 recommended parameters for stopping ACE inhibitor (grade B recommendation [inconsistent or limited evidence]) hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L]) rise in creatinine > 30% above baseline (even for patients with elevated baseline creatinine > 1.4 mg/dL [123.8 mcmol/L]) based on analysis of 705 patients taking ACE inhibitors in 12 trials patients with increase in creatinine (but increase < 30%) had stable long-term renal function Reference - Arch Intern Med 2000 Mar 13;160(5):685 Angiotensin II receptor blockers (ARBs): in patients with diabeticnephropathy, angiotensin II receptor blockers (ARBs) may reduce risk for end-stage kidney disease in hypertensive patients with type 2 diabetes (level 2 [mid-level] evidence) based on Cochrane review of trials with methodologic limitations systematic review of 49 trials of ACE inhibitors and ARBs in patients with diabeticnephropathy 5 trials compared ARBs to placebo in 3,409 patients (all including patients with hypertension), 7 trials compared ARBs to ACE inhibitors in 557 patients all trials assessing ARBs had 1 methodologic limitation including allocation concealment not stated outcome assessors not blinded no intention-to-treat analysis compared to placebo, ARBs associated with reduced risk of end-stage kidney disease in analysis of 3 trials with 2,251 patients risk ratio (RR) 0.78 (95% CI 0.67-0.91) NNT 16-59 with 19% risk of end-stage kidney disease in control group reduced risk of doubling of serum creatinine in analysis of 3 trials with 2,251 patients RR 0.79 (95% CI 0.67-0.93) NNT 14-65 with 22% risk of doubling of serum creatinine in control group no significant difference in all-cause mortality (RR 0.99, 95% CI 0.85-1.17) in analysis of 5 trials with 3,409 patients comparing ARBs vs. ACE inhibitors no significant differences in all-cause mortality in analysis of 3 trials with 307 patients outcomes of end-stage kidney disease and doubling of serum creatinine not reported no significant differences in progression or regression of microalbuminuria in single trials Reference - Cochrane Database Syst Rev 2006 Oct 18;(4):CD006257 earlier review (36 trials with 4,008 patients) can be found in (BMJ 2004 Oct 9;329(7470):828 full-text), also published in J Am Soc Nephrol 2006 Apr;17(4 Suppl 2):S153 full-text, commentary can be found in Am Fam Physician 2005 Feb 1;71(3):564, Evidence-Based Medicine 2005 May-Jun;10(3):77, ACP J Club 2006 Sep-Oct;145(2):35 details of individual randomized trials losartan slows progression of diabeticnephropathy and reduces risk for end-stage renal disease (level 2 [mid-level] evidence) based on randomized trial with allocation concealment not stated 1,513 patients aged 31-70 years with diabetes mellitus type 2 and nephropathy were randomized to losartan 50 mg (increased to 100 mg after 4 weeks if blood pressure > 140/90 mm Hg) vs. placebo orally once daily for
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mean 3.4 years nephropathy defined as urinary albumin to creatinine ratio > 300 or urinary protein excretion > 500 mg/24 hours, and serum creatinine 1.3-3 mg/dL (115-265 mcmol/L) or 1.5-3 mg/dL in men > 60 kg (132.6-265 mcmol/L) other antihypertensive agents were used as needed to reach target blood pressure < 140/90 mm Hg primary endpoint was composite of doubling of baseline serum creatinine level, end-stage renal disease (defined as dialysis or renal transplantation) or death comparing losartan vs. placebo 43.5% vs. 47.1% reached primary endpoint (p = 0.02, NNT 28) 21.6% vs. 26% doubling of serum creatinine (p = 0.0006, NNT 23) 19.6% vs. 25.5% end-stage renal disease (p = 0.002, NNT 17) 21% vs. 20.3% mortality (p = 0.88) no significant differences in cardiovascular outcomes adverse effects not reported Reference - RENAAL trial (N Engl J Med 2001 Sep 20;345(12):861 full-text), editorial can be found in N Engl J Med 2001 Sep 20;345(12):910, commentary can be found in J Fam Pract 2001 Dec;50(12):1083, commentary can be found in ACP J Club 2002 May-Jun;136(3):82 DynaMed commentary -- study funded by drug manufacturer subgroup analyses stratified by age found significant reductions in primary outcome and in end-stage renal disease in each of 3 age groups (< 58 years, 58-65 years, and > 65 years) (Diabetes Care 2006 Oct;29(10):2210) irbesartan but not amlodipine slows progression of diabeticnephropathy (level 3 [lacking direct] evidence) based on randomized trial without significant differences in clinical outcomes 1,715 patients aged 30-70 years with diabetes mellitus type 2, hypertension, and diabeticnephropathy were randomized to irbesartan titrated from 75 to 300 mg vs. amlodipine titrated from 2.5 to 10 mg vs. placebo orally once daily for mean 2.6 years hypertension defined as blood pressure > 135/85 mm Hg or use of antihypertensive agents diabeticnephropathy defined as proteinuria (urinary protein excretion > 900 mg/24 hours) with serum creatinine 1-3 mg/dL (88.4-265.2 mcmol/L) in women and 1.2-3 mg/dL (106-265.2 mcmol/L) in men other antihypertensive agents were used as needed to reach target blood pressure < 135/85 mm Hg primary end point was composite of doubling of baseline serum creatinine level, end-stage renal disease (defined as dialysis, renal transplantation, or serum creatinine > 6 mg/dL [530.4 mcmol/L]) or death from any cause comparing irbesartan vs. amlodipine vs. placebo primary end point in 32.6% vs. 41.1% vs. 39% (p = 0.02, NNT 16 for irbesartan vs. placebo) doubling of serum creatinine in 16.9% vs. 25.4% vs. 23.7% (p = 0.003, NNT 15 for irbesartan vs. placebo) no significant differences in end-stage renal disease (14.2% vs. 18.3% vs. 17.8%, p = 0.07), mortality, or cardiovascular outcomes hyperkalemia leading to discontinuation of medication in 1.9% vs. 0.5% vs.0.4% (p = 0.01, NNH 66 for irbesartan) Reference - IDNT trial (N Engl J Med 2001 Sep 20;345(12):851), editorial can be found in N Engl J Med 2001 Sep 20;345(12):910, commentary can be found in N Engl J Med 2002 Feb 28;346(9):705, ACP J Club 2002 MayJun;136(3):82 (correction can be found in ACP J Club 2002 Jul-Aug;137(1):A17) DynaMed commentary -- study funded by drug manufacturer neither irbesartan nor amlodipine reported to reduce cardiovascular outcomes compared to placebo in this trial composite outcome of cardiovascular death, myocardial infarction, heart failure, stroke, or coronary revascularization procedure occurred in 28.4%-29.7% treatment groups and 32.5% placebo group (no significant differences) individual outcome analysis suggests irbesartan may reduce heart failure while amlodipine may reduce myocardial infarction Reference - Ann Intern Med 2003 Apr 1;138(7):542, commentary can be found in Am Fam Physician 2003 Aug 1;68(3):534, J Fam Pract 2003 Aug;52(8):593 irbesartan may slow progression of diabeticnephropathy in patients with type 2 diabetes with microalbuminuria (level 3 [lacking direct] evidence) based on randomized trial without clinical outcome 590 patients aged 30-70 years with type 2 diabetes, hypertension (blood pressure > 135/85 mm Hg), persistent microalbuminuria (urinary albumin excretion 20-200 mcg/minute in at 2 of 3 overnight samples), and serum creatinine < 1.5 mg/dL (132.6 mcmol/L) in men and 1.1 mg/dL (97.2 mcmol/L) in women were randomized to irbesartan 150 mg/day vs. irbesartan 300 mg/day vs. placebo for 2 years, other antihypertensive agents were used as needed to reach target blood pressure < 135/85 mm Hg primary outcome was onset of diabeticnephropathy defined as persistent albuminuria in overnight specimens, plus urinary albumin excretion rate > 200 mcg/minute and at least 30% higher than baseline
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nephropathy developed in 14.9% with placebo vs. 9.7% with irbesartan 150 mg/day (p = 0.08) vs. 5.2% with irbesartan 300 mg/day (p = 0.08 for 150 mg; p < 0.001, NNT 11 for 300 mg) renoprotective effect appeared independent of antihypertensive effect serious adverse events (not defined in the article) reported in 22.8% placebo patients vs. 15.4% combined irbesartan groups (p = 0.02, NNT 14) Reference - N Engl J Med 2001 Sep 20;345(12):870 full-text, commentary can be found in ACP J Club 2002 MayJun;136(3):82 (correction can be found in ACP J Club 2002 Jul-Aug;137(1):A17), N Engl J Med 2001 Sep 20;345(12):910, N Engl J Med 2002 Feb 28;346(9):705 DynaMed commentary -- study funded by drug manufacturer other ARBs (telmisartan, valsartan) reported to slow progression of diabeticnephropathy (level 3 [lacking direct] evidence) based on 6 small randomized trials without clinical outcomes telmisartan reported to be as renoprotective as enalapril 250 patients with type 2 diabetes and early nephropathy randomized to telmisartan (Micardis) 80 mg vs. enalapril 20 mg once daily for 5 years (half dose for first 4 weeks) no significant differences in change in glomerular filtration rate (-17.9 vs. -14.9 mL/minute/1.73 m2) Reference - DETAIL trial (N Engl J Med 2004 Nov 4;351(19):1952), correction can be found in N Engl J Med 2005 Apr 21;352(16):1731, commentary can be found in J Fam Pract 2005 Feb;54(2):108, J Fam Pract 2005 May;54(5):453, Am Fam Physician 2005 Mar 15;71(6):1178, N Engl J Med 2005 Feb 24;352(8):835, Ann Intern Med 2005 Nov 1;143(9):675; also published in J Am Soc Nephrol 2006 Apr;17(4 Suppl 2):S132 full-text DynaMed commentary -- no significant differences in rates of end-stage renal disease, cardiovascular events, or overall mortality but study too small to reliably assess these outcomes valsartan reported to be as effective as captopril in slowing progressive albumin excretion 122 patients with "incipient diabeticnephropathy," type 2 diabetes, microalbuminuria, and either normotension or treated hypertension were randomized to valsartan 80 mg orally once daily vs. valsartan 160 mg orally once daily vs. captopril 25 mg orally 3 times daily vs. placebo for 1 year 84% completed follow-up comparing valsartan 80 mg vs. valsartan 160 mg vs. captopril 25 mg vs. placebo change in albumin excretion rate at 1 year was -28% vs. -21% vs. -27% vs. +18% progression to clinical proteinuria occurred in 4% vs. 0% vs. 3% vs. 11% cough noted in 3% vs. 10% vs. 21% vs. 3% Reference - Curr Ther Res 1999 Dec;60:650 in QuickScan Reviews in Fam Pract 2000 Dec;25(10):5 valsartan reported to be more effective than amlodipine at reducing microalbuminuria in 24-week randomized trial of 332 patients with type 2 diabetes, 30% vs. 15% returned to normoalbuminuria (NNT 7) (Circulation 2002 Aug 6;106(6):672 full-text in QuickScan Reviews in Fam Pract 2003 Feb;28(2):24) losartan reduces urinary albumin excretion in normotensive patients with type 2 diabetes and microalbuminuria in randomized trial of 147 patients (Ann Intern Med 2003 Jul 15;139(2):90), commentary can be found in Ann Intern Med 2004 Apr 20;140(8):668 losartan may reduce albuminuria more than quinapril (level 3 [lacking direct] evidence) based on randomized crossover trial without clinical outcomes 41 Asian patients with type 2 diabetes and albuminuria (> 30 mg/g creatinine) were randomized to losartan 50 mg vs. quinapril 20 mg for 4 weeks each with 4-week washout comparing losartan vs. quinapril mean reduction in albuminuria 93 vs. 42 mg/g creatinine (p = 0.02) mean blood pressure reduction 3/1 vs. 2/2 mm Hg (not significant) Reference - Diabetes Obes Metab 2007 Jul;9(4):477 losartan appeared as effective as enalapril in reducing albuminuria (level 2 [mid-level] evidence) in randomized crossover trial of 16 patients with type 1 diabetes (Kidney Int 2000 Feb;57(2):601 full-text) telmisartan may be more effective than losartan in reducing proteinuria in patients with type 2 diabetes (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 860 patients with type 2 diabetes were randomized to telmisartan 80 mg vs. losartan 100 mg patients included if blood pressure > 130/80 mm Hg or taking antihypertensive medications, and if morning spot urinary protein to creatinine ratio 700 80% completed trial comparing telmisartan vs. losartan at 1 year 29.8% vs. 21.4% mean reduction of urinary protein-to-creatinine ratio (p = 0.03) 33.5% vs. 27% mean reduction in urinary albumin-to-creatinine ratio (p = 0.04) adverse events in 84% vs. 82.1% (statistics not reported) severe events in 15.5% vs. 22.4% (statistics not reported) no significant difference in effect on systolic or diastolic blood pressure Reference - Kidney Int 2008 Aug;74(3):364
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Combination ACE inhibitor plus ARB: addition of olmesartan to antihypertensive therapy may not reduce end-stage renal disease in patients with type 2 diabetes and overt nephropathy (level 2 [mid-level] evidence) based on randomized trial with high dropout rate 577 patients aged 30-70 years (65% Japanese and 35% Chinese) with type 2 diabetes and overt nephropathy receiving antihypertension therapy (angiotensin-converting enzyme [ACE] inhibitors in 74%, with target blood pressure to 130/85 mm Hg) randomized to olmesartan 10-40 mg once daily vs. placebo and followed for mean 3.2 years 76% completed trial and 98% analyzed comparing olmesartan vs. placebo end-stage renal disease in 26.2% vs. 27.5% (not significant) all-cause mortality in 6.7% vs. 7% (not significant) cardiovascular mortality 3.5% vs. 1.1% (not significant) doubling of serum creatinine in 37.6% vs. 41.3% (not significant) discontinuation due to hyperkalemia in 9.2% vs. 5.3% (no p value reported) discontinuation due to any adverse events in 25.9% vs. 22.5% (no p value reported) Reference - ORIENT trial (Diabetologia 2011 Dec;54(12):2978 full-text) combination of lisinopril plus irbesartan may not improve outcomes compared to either drug alone in patients with type 2 diabeticnephropathy (level 2 [mid-level] evidence) based on randomized trial without blinding 133 patients > 35 years old (mean age 66 years, 76% men) with type 2 diabeticnephropathy randomized to combination of lisinopril 20 mg plus irbesartan 300 mg vs. lisinopril 40 mg vs. irbesartan 600 mg once daily at baseline mean estimated glomerular filtration rate 49 mL/minute/1.73 m2 and mean blood pressure 153/81 mm Hg median follow-up 32 months no significant difference among groups in mortality, progression to end-stage renal disease or > 50% increase in serum creatinine, proteinuria, or adverse events Reference - Am J Kidney Dis 2013 Feb;61(2):211 addition of lisinopril to losartan may increase risk of acute kidney injury and hyperkalemia in older men with diabeticnephropathy (level 2 [mid-level] evidence) based on randomized trial with early termination 1,448 patients (mean age 65 years, 99% male) with diabeticnephropathy receiving losartan 50-100 mg/day for 30 days randomized to lisinopril 10 mg orally once daily (titrated to 40 mg over 4 weeks) vs. placebo all patients had type 2 diabetes, estimated glomerular filtration rate (GFR) 30-89.9 mL/minute/1.73 m2, and urinary albumin to creatinine ratio 300 at baseline losartan was continued in all patients trial terminated early without planned stopping rule due to increased adverse event rates in lisinopril group median follow-up 2.2 years primary end point was composite of death, end-stage renal disease, or reduction in estimated GFR of 30 mL/minute/1.73 m2 if baseline estimated GFR > 60 mL/minute/1.73 m2 50% if baseline estimated GFR < 60 mL/minute/1.73 m2 hyperkalemia defined as increase in potassium level > 6 mmol/liter or requiring emergency department visit, hospitalization, or dialysis comparing lisinopril vs. placebo acute kidney injury requiring hospitalization or during hospitalization in 18% vs. 11% (p < 0.001, NNH 14) hyperkalemia in 9.9% vs. 4.4% (p < 0.001, NNH 18) serious adverse event in 57.5% vs. 52.5% (p = 0.06) end-stage renal disease in 3.7% vs. 5.9% (p = 0.07) death in 8.7% vs. 8.3% (not significant) no significant difference in rates of primary outcome at time of termination, or in rates of myocardial infarction, heart failure, or stroke Reference - VA NEPHRON-D trial (N Engl J Med 2013 Nov 14;369(20):1892), editorial can be found in N Engl J Med 2013 Nov 14;369(20):1960 addition of ARB to ACE inhibitor may further reduce albuminuria (level 3 [lacking direct] evidence) addition of irbesartan to enalapril may further reduce albuminuria (level 3 [lacking direct] evidence) in small study with 24 patients in Kidney Int 2003 May;63(5):1874 addition of candesartan 16 mg/day to ACE inhibitor may reduce albuminuria (level 3 [lacking direct] evidence) based on small randomized trial of 20 patients no significant differences in glomerular filtration rate, creatinine, or ambulatory blood pressures Reference - Diabetes Care 2003 Aug;26(8):2268 combination of losartan plus enalapril reported to reduce albuminuria more than monotherapy in patients diabeticnephropathy (level 3 [lacking direct] evidence) based on small randomized trial without clinical outcomes 34 patients with type 2 diabetes and nephropathy randomized to enalapril 20 mg vs. losartan 100 mg once daily for 8
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weeks Reference - Singapore Med J 2010 Feb;51(2):151 full-text Aldosterone antagonists: Spironolactone: spironolactone (Aldactone) may reduce albuminuria (level 3 [lacking direct] evidence) based on 3 randomized trials without clinical outcomes spironolactone may reduce urine albumin-to-creatinine ratio (ACR) in patients taking lisinopril (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 81 patients with diabetes, hypertension, and albuminuria randomized to 1 of 3 treatments for 48 weeks spironolactone 25 mg daily losartan 100 mg daily placebo all patients had lisinopril 80 mg once daily change in urine ACR vs. placebo at week 48 -34% for spironolactone (95% CI -51% to -11.2%) -16.8% for losartan (not significant) serum potassium was significantly increased in both spironolactone and losartan groups compared to placebo Reference - J Am Soc Nephrol 2009 Dec;20(12):2641 full-text, editorial can be found in J Am Soc Nephrol 2009 Dec;20(12):2487 full-text spironolactone may decrease albuminuria and blood pressure (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 21 patients with type 2 diabetes, hypertension and overt albuminuria randomized to spironolactone 25 mg vs. placebo once daily for 8 weeks each in crossover trial outcomes significantly lower with spironolactone vs. placebo mean urine albumin level 1.1 vs. 1.6 g/24 hours mean 24-ambulatory blood pressure 132/67 vs. 138/71 mm Hg 1 patient developed severe hyperkalemia on spironolactone Reference - Diabetes Care 2005 Sep;28(9):2106 in J Watch Online 2005 Sep 23, also published in Kidney Int 2006 Aug;70(3):536 spironolactone may decrease albuminuria in patients with type 1 diabetes (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 21 patients (mean age 58 years) with type 1 diabetes, hypertension, and persistent microalbuminuria randomized to spironolactone 25 mg/day orally vs. placebo for 60 days each in crossover trial with no washout period all patients taking individual antihypertensive medication comparing spironolactone vs. placebo mean albumin excretion rate was 35 mg/24 hours vs. 90 mg/24 hours (p = 0.011) mean glomerular filtration rate (ml/min/1.73 m2) 72 vs. 78 (p = 0.003) no significant differences in blood pressure Reference - Diabet Med 2012 Aug;29(8):e184 Eplerenone: eplerenone (Inspra) may reduce albuminuria in patients with type 2 diabetes taking enalapril (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 268 patients with type 2 diabetes and urine albumin/creatinine ratio 50 mg/g taking enalapril 20 mg once daily were randomized to 1 of 3 treatments for 12 weeks eplerenone 50 mg once daily eplerenone 100 mg once daily placebo once daily reduction in urinary albumin/creatinine ratio by 41% with eplerenone 50 mg (p < 0.001 vs. placebo) by 48.4% with eplerenone 100 mg (p < 0.001 vs. placebo) by 7.4% with placebo Reference - Clin J Am Soc Nephrol 2006 Sep;1(5):940 full-text Other antihypertensive drugs and combinations: combination of perindopril plus indapamide (Preterax) reduces mortality in patients with type 2 diabetes (level 1 [likely reliable] evidence) based on randomized trial 12,877 patients > 55 years old with type 2 diabetes diagnosed after age 30 years and with history of or risk factor for cardiovascular disease entered 6-week run in period with fixed combination tablet of perindopril 2 mg (an angiotensinhttp://web.b.ebscohost.com/dynamed/delivery/printcitation?expand=sec-General-Information,sec-Causes-and-Risk-Factors,sec-Complications-and-Asso 13/29
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converting enzyme [ACE] inhibitor) plus indapamide 0.625 mg (a diuretic) 11,140 (86.5%) who adhered to and tolerated study drug were randomized to combination tablet vs. placebo, dose doubled after 3 months patients also randomized to intensive glucose control with gliclazide modified release-based regimen (target HbA1c 6.5%) vs. standard glucose control mean follow-up 4.3 years, range 1 month to 5.6 years major macrovascular events defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke major microvascular events defined as new or worsening nephropathy (macroalbuminuria, doubling of serum creatinine to 200 mcmol/L [2.26 mg/dL], renal replacement therapy, or death from renal disease) or retinopathy (proliferative retinopathy, macular edema, diabetes-related blindness, or retinal photocoagulation therapy) comparing perindopril/indapamide vs. placebo for adherence 83% vs. 87% continued treatment during follow-up 73% vs. 74% adherent to treatment at end of follow-up 3.3% vs. 1.3% discontinued due to cough (NNH 50) 1.2% vs. 0.4% discontinued due to hypotension or dizziness (NNH 125) comparing perindopril/indapamide vs. placebo for mortality and macrovascular outcomes all-cause mortality 7.3% vs. 8.5% (p = 0.025, NNT 79 over 5 years, 95% CI 43-483) cardiovascular mortality 3.8% vs. 4.6% (p = 0.027, NNT 125) major macrovascular event in 8.6% vs. 9.3% (not significant) total coronary event rate (major events plus hospitalization for unstable angina, coronary revascularization, or silent myocardial infarction) 8.4% vs. 9.6% (p = 0.02, NNT 75 over 5 years, 95% CI 41-453) total cerebrovascular event rate 5.1% vs. 5.4% (not significant) comparing perindopril/indapamide vs. placebo for microvascular outcomes major microvascular event in 7.9% vs. 8.6% (not significant) new or worsening nephropathy in 3.3% vs. 3.9% (p = 0.055) new microalbuminuria in 19.6% vs. 23.6% (p < 0.0001, NNT 25) new or worsening retinopathy in 5.2% vs. 5.1% (not significant) visual deterioration in 43.9% vs. 45.1% (p = 0.1) major macrovascular or major microvascular event in 15.5% vs. 16.8% (p = 0.041, NNT 66 over 5 years, 95% CI 34-1,068) Reference - ADVANCE trial (Lancet 2007 Sep 8;370(9590):829), editorial can be found in Lancet 2007 Sep 8;370(9590):804, Ann Intern Med 2008 Mar 4;148(5):400, commentary can be found in Lancet 2008 Jan 5;371(9606):25, Evid Based Med 2008 Apr;13(2):49 cost-effectiveness analysis can be found in Med J Aust 2010 Sep 20;193(6):320 effects of perindopril/indapamide and intensive glucose lowering were independent and additive (Diabetes Care 2009 Nov;32(11):2068 full-text) in subgroup of 847 patients with atrial fibrillation (7.6% patients in ADVANCE trial), reduction in 5-year cardiovascular mortality with perindopril/indapamide was greater (NNT 42) because of higher overall risk (Eur Heart J 2009 May;30(9):1128 full-text) combination perindopril plus indapamide may reduce risk of developing microalbuminuria or progression of albuminuria in adults with type 2 diabetes (level 3 [lacking direct] evidence) based on secondary analysis of ADVANCE trial comparing perindopril-indapamide vs. placebo during mean 4.3-year follow-up new-onset microalbuminuria in 27.4% vs. 33% (p < 0.001, NNT 18) new-onset macroalbuminuria in 2.1% vs. 3% (p = 0.0027, NNT 112) regression of 1 albuminuria stage in 55.4% vs. 50.2% (p = 0.0017, NNT 20) progression of 1 albuminuria stage in 21.7% vs. 26.6% (p < 0.0001, NNT 21) no significant differences in doubling of serum creatinine or end-stage kidney disease Reference - J Am Soc Nephrol 2009 Apr;20(4):883 full-text combination perindopril plus indapamide may reduce risk of cardiovascular mortality in patients 75 years old with type 2 diabetes (level 2 [mid-level] evidence) based on post hoc analysis of ADVANCE trial comparing perindopril-indapamide vs. placebo in patients 75 years old during mean 4.3-year follow-up all-cause mortality 18.2% vs. 19.8% (not significant) cardiovascular mortality 7.9% vs. 11.8% (p < 0.05, NNT 26) major macrovascular events in 14.1% vs. 17.5% (not significant) Reference - J Hypertens 2010 Jun;28(6):1141 ARB plus non-ACE inhibitor hypertensive agent associated with reduced cardiovascular mortality compared to combination of ARB and ACE inhibitor patients on chronic hemodialysis (level 2 [mid-level] evidence) based on cohort study 28,628 patients who started treatment with ACE inhibitor or ARB after 60 days of chronic hemodialysis were assessed 9,325 patients started additional antihypertensive medication 701 patients were given ARB and ACE inhibitor
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6,866 patients were given ACE inhibitor and non-ARB antihypertensive agent or ARB and non-ACE inhibitor antihypertensive agent mean follow-up was 1.46 years compared to ARB and ACE inhibitor, ARB and non-ACE inhibitor associated with reduced cardiovascular mortality (hazard ratio [HR] 0.69, 95% CI 0.57-0.84) nonsignificant trend toward reduced all-cause mortality (HR 0.93, 95% CI 0.81-1.07) nonsignificant trend toward reduced falls (HR 0.98, 95% CI 0.92-1.04) compared to ARB and ACE inhibitor, ACE inhibitor and non-ARB not significantly associated with reduced cardiovascular mortality (HR 0.87, 95% CI 0.72-1.06) hyperkalemia (HR 0.98, 95% CI 0.89-1.08) risk of falls (HR 0.98, 95% CI 0.92-1.04) Reference - Kidney Int 2011 Nov;80(9):978 full-text, editorial can be found in Kidney Int 2011 Nov;80(9):911 calcium channel blockers may be as effective as ACE inhibitors for improving makers of diabeticnephropathy (level 3 [lacking direct] evidence) based on 2 small randomized trials without clinical outcomes 52 patients (mean age 63 years) with type 2 diabetes randomized to lisinopril, calcium channel blocker (verapamil SR or diltiazem SR), or atenolol and followed for mean of 63 months comparing lisinopril vs. calcium channel blockers no significant difference in rate of decline of creatinine clearance no significant difference in reduction of proteinuria rate of decline of creatinine clearance greatest and reduction of proteinuria least affected with atenolol Reference - Kidney Int 1996 Nov;50(5):1641 51 hypertensive patients with type 1 diabetes and diabeticnephropathy randomized to lisinopril 10-20 mg/day vs. nisoldipine 20-40 mg/day for 4 years 3 patients dropped out in first month lisinopril improved albuminuria and glomerular filtration rate in the first 6 months no significant differences in glomerular filtration rates over 6-48 months Reference - Diabetes Care 2000 Dec;23(12):1725 PDF addition of amlodipine or hydrochlorothiazide to benazepril reported to reduce albuminuria in patients with diabetes mellitus type 2 (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 332 patients (mean age 57 years) with diabetes mellitus type 2, albuminuria and hypertension randomized to benazepril plus amlodipine vs. benazepril plus hydrochlorothiazide both treatments significantly reduced urinary albumin-to-creatinine ratio and sitting blood pressure compared to baseline Reference - Kidney Int 2008 Jun;73(11):1303 aliskiren (Tekturna in United States, Rasilez in Canada and United Kingdom) addition of aliskiren to angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker may not improve cardiovascular mortality or renal disease in patients with type 2 diabetes and chronic kidney disease and/or cardiovascular disease (level 2 [mid-level] evidence) based on randomized trial with low adherence 8,606 patients 35 years old with type 2 diabetes randomized to aliskiren vs. placebo initial dose of aliskiren 150 mg once daily was increased at 4 weeks to 300 mg once daily if deemed safe all patients received angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker all patients had chronic kidney disease and/or cardiovascular disease at baseline at 2 years adherence was 74.1% with aliskiren and 78.7% with placebo trial terminated early due to increase in adverse events with aliskiren without improvement in major cardiovascular or renal outcomes at second interim efficacy analysis comparing aliskiren vs. placebo at median follow-up of 32.9 months cardiovascular-related mortality 5.8% vs. 5% (not significant) all-cause mortality 8.8% vs. 8.4% (not significant) cardiac arrest with resuscitation in 0.4% vs. 0.2% (p = 0.04, NNH 500) fatal or nonfatal myocardial infarction in 3.4% vs. 3.3% (not significant) fatal or nonfatal stroke in 3.4% vs. 2.8% (not significant) unplanned hospitalization for heart failure in 4.8% vs. 5.1% (not significant) end-stage renal disease, death from kidney failure, or loss of kidney function in 2.8% vs. 2.6% (not significant) doubling of serum creatinine in 4.9% vs. 5.1% (not significant) hyperkalemia (serum potassium 6 mmol/L) in 11.2% vs. 7.2% (p < 0.001, NNH 25) hypotension in 12.1% vs. 8.3% (p < 0.001, NNH 26) aliskiren associated with lower systolic and diastolic blood pressure, and greater mean reduction in urinary albumin-tocreatinine ratio (p < 0.05 for each) Reference - ALTITUDE trial (N Engl J Med 2012 Dec 6;367(23):2204) addition of aliskiren to losartan may reduce albumin-creatinine ratio in patients with type 2 diabetes and nephropathy (level 3 [lacking direct] evidence)
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based on randomized trial without clinical outcomes 599 patients with diabetes and nephropathy randomized to aliskiren vs. placebo for 6 months all patients received losartan 100 mg daily throughout trial beginning 3 months prior to randomization aliskiren 150 mg daily for 3 months then 300 mg daily for 3 months comparing aliskiren plus losartan vs. losartan alone at 6 months mean reduction in albumin-creatinine ratio 20% vs. 0% (p = 0.001) 50% reduction in albumin-creatinine ratio in 24.7% vs. 12.5% (p < 0.001, NNT 9) Reference - N Engl J Med 2008 Jun 5;358(23):2433, editorial can be found in N Engl J Med 2008 Jun 5;358(23):2503, commentary can be found in N Engl J Med 2008 Sep 4;359(10):1068, cost-effectiveness analysis can be found in J Am Soc Nephrol 2009 Oct;20(10):2205 full-text Statins: National Kidney Foundation (NKF KDOQI) recommendations regarding lipid-lowering medications(4) LDL cholesterol-lowering medication (such as statin or statin/ezetimibe combination) recommended for patients with diabetes and chronic kidney disease, including those who have received a kidney transplant (NKF KDOQI Grade 1B) do not start statin therapy in patients with diabetes who are treated by dialysis (NKF KDOQI Grade 1B) pitavastatin may reduce albumin-to-creatinine ratio compared to pravastatin in patients with type 2 diabetes and macroalbuminuria (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 87 patients (mean age 65 years) with type 2 diabetes and early stage diabeticnephropathy randomized to pitavastatin 2 mg/day orally vs. pravastatin 10 mg/day orally mean change in albumin-creatinine ratio -67.2% pitavastatin vs. +14.5% with pravastatin (p = 0.004) in patients with macroalbuminuria (albumin-creatinine ratio 600 mg/g) no significant difference in patients with microalbuminuria no significant differences in estimated glomerular filtration rate Reference - Diabetes Obes Metab 2012 Jul;14(7):666 dose of atorvastatin does not appear to affect progression of nephropathy in patients with type 2 diabetes and early renal disease (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 119 patients (mean age 64 years) with type 2 diabetes and microalbuminuria or proteinuria randomized to atorvastatin 80 mg/day vs. 10 mg/day and followed for mean 2 years no significant difference in glomerular filtration rate, creatinine clearance, serum creatinine, cystatin C, urine protein or albumin excretion between high- or low-dose atorvastatin no significant difference in death or adverse events Reference - PANDA trial (Diabet Med 2011 Jan;28(1):100) Other medications: pentoxifylline may decrease amount of albuminuria and proteinuria in patients with diabetic kidney disease (level 3 [lacking direct] evidence) based on non-clinical outcomes from Cochrane review systematic review of 17 randomized and quasi-randomized trials evaluating pentoxifylline in 991 patients with diabetic kidney disease comparing pentoxifylline to placebo in patients receiving routine treatment pentoxifylline associated with decreased albuminuria in analysis of 2 trials with 117 patients overt proteinuria (mean difference [MD] -428.58 g/minute, 95% CI -661.65 g/minute to -195.5 g/minute) in 1 trial with 46 patients serum creatinine levels (MD -0.1 mg/dL, 95% CI -0.17 mg/dL to -0.03 mg/dL [-8.84 mcmol/L, 95% CI -15 mcmol/L to -2.65 mcmol/L]) in analysis of 2 trials with 117 patients diastolic blood pressure (MD -5.75 mm Hg, 95% CI -9.56 mm Hg to -1.94 mm Hg) in analysis of 2 trials with 126 patients no significant difference in systolic blood pressure in analysis of 2 trials with 126 patients, but results limited by heterogeneity comparing pentoxifylline plus routine treatment to routine treatment alone pentoxifylline associated with decrease in albuminuria in analysis of 4 trials with 220 patients proteinuria in analysis of 5 trials with 192 patients (MD 0.46 g/24 hours, 95% CI 0.17-0.74 g/24 hours) no significant differences in serum creatinine levels in analysis of 5 trials with 199 patients blood pressure in analysis of 5 trials with 240 patients comparing pentoxifylline to captopril, no significant differences in serum creatinine in analysis of 2 trials with 166 patients albuminuria in analysis of 2 trials with 233 patients, but results limited by heterogeneity
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proteinuria in analysis of 2 trials with 145 patients blood pressure in analysis of 3 trials with 272 patients adverse effects mild; no serious adverse effects reported Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD006800 addition of paricalcitol 2 mcg to ACE inhibitor or ARB therapy may lower 24-hour urinary albumin excretion in patients with diabeticnephropathy (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 281 patients with type 2 diabetes and albuminuria receiving ACE inhibitor or ARB randomized to 1 of 3 treatments for 24 weeks paricalcitol 1 mcg/day orally paricalcitol 2 mcg/day orally placebo mean reduction in urinary albumin-creatinine ratio (comparison vs. placebo) 11% with 1 mcg paricalcitol (not significant) 20% with 2 mcg paricalcitol (p = 0.053) 3% with placebo mean reduction in 24-hour urinary albumin excretion (p vs. placebo) 10% with 1 mcg paricalcitol (not significant) 34% with 2 mcg paricalcitol (p = 0.009, NNT 5) 9% with placebo Reference - VITAL study (Lancet 2010 Nov 6;376(9752):1543), editorial can be found in Lancet 2010 Nov 6;376(9752):1521 ethylenediaminetetraacetic acid (EDTA) chelation therapy may slow decline in glomerular filtration rate in patients with diabeticnephropathy and high-normal body lead burden (level 3 [lacking direct] evidence) based on 2 small randomized trials without clinical outcomes 50 patients with diabeticnephropathy (and type 2 diabetes) and body lead burden 80-600 mcg were randomized to EDTA chelation therapy vs. placebo for 27 months EDTA chelation given once weekly for 3 months to reduce body lead burden to < 60 mcg and then given as needed for 24 months to maintain level baseline serum creatinine level 1.5-3.9 mg/dL (132.6-344.8 mmol/L) comparing EDTA chelation vs. placebo mean change in estimated glomerular filtration rate (eGFR) at 3 months +1 mL/minute/1.73 m2 vs. -1.5 mL/minute/1.73 m2 (p = 0.04) mean yearly decrease in eGFR over next 24 months 5.6 mL/minute/1.73 m2 vs. 9.2 mL/minute/1.73 m2 (p = 0.04) Reference - Am J Kidney Dis 2012 Oct;60(4):530 30 patients with type 2 diabetes, serum creatinine 1.5-3.9 mg/dL (132.6-344.8 mcmol/L) and high-normal body lead burden (80-600 mcg) were randomized to calcium disodium EDTA vs. placebo weekly until body lead burden < 60 mcg rate of decline in glomerular filtration rate over 12 months was 5 mL/minute/year/1.73 m2 with EDTA vs. 11.8 mL/minute/year/1.73 m2 with placebo (p = 0.0084) Reference - Kidney Int 2006 Jun;69(11):2049 pirfenidone 1,200 mg associated with improved estimated glomerular filtration rate (eGFR) in diabeticnephropathy (level 3 [lacking direct] evidence) based on small randomized trial without clinical outcomes 77 patients with diabeticnephropathy with elevated albuminuria and reduced eGFR (20-75 mL/min per 1.73 m2) randomized to pirfenidone 1,200 mg daily vs. pirfenidone 2,400 mg daily vs. placebo for 1 year 33% dropout rate with 44% of dropouts from pirfenidone 2,400 mg group mean change in eGFR at 1 year comparing pirfenidone vs. placebo +3.3 mL/min per 1.73 m2 in 1,200 mg group vs. -2.2 mL/min per 1.73 m2 (p = 0.026) -1.9 mL/min per 1.73 m2 in 2,400 mg group vs. -2.2 mL/min per 1.73 m2 (not significant) no significant difference in number of patients requiring hemodialysis Reference - J Am Soc Nephrol 2011 Jun;22(6):1144 full-text DynaMed commentary -- pirfenidone approved for use in Europe as Esbriet for idiopathic pulmonary fibrosis (InterMune) avosentan (an endothelin-A antagonist not FDA approved) addition of avosentan to ACE inhibitor/ARB therapy associated with decrease in urine albumin excretion in patients with diabeticnephropathy (level 3 [lacking direct] evidence) based on randomized trial without clinical outcomes 286 patients with diabeticnephropathy, macroalbuminuria (urinary albumin excretion rate 0.2-5.6 mg/minute), and blood pressure < 180/110 mm Hg randomized to avosentan (5, 10, 25, and 50 mg) vs. placebo for 12 weeks, in addition to standard angiotensin-converting-enzyme inhibitor (ACEI)/ARB therapy from baseline to week 12, mean relative decrease in urinary albumin excretion rate by 16.3%-29.9% with avosentan vs. 35.5% INCREASE with placebo (p < 0.01 for all avosentan dosages compared with placebo) no significant difference among groups in
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creatinine clearance blood pressure significantly more (dose-dependent) peripheral edema in those taking avosentan (p = 0.01) Reference - J Am Soc Nephrol 2009 Mar;20(3):655 full-text addition of avosentan to ACE inhibitor/ARB therapy associated with increased risk of fluid overload and heart failure (level 2 [mid-level] evidence) based on randomized trial with inadequate statistical power 1,402 patients with type 2 diabetes randomized to avosentan (25 or 50 mg) vs. placebo orally, in addition to continued ACE inhibition and/or ARB trial prematurely terminated at median 4-month follow-up due to excessive cardiovascular events with avosentan discontinuation of trial medication (due mostly to fluid overload and heart failure) in 11.5% with placebo 19.6% with avosentan 25 mg (p = 0.001 vs. placebo) 18.2% with avosentan 50 mg (p = 0.02 vs. placebo) no significant difference between groups in composite primary outcome of time to doubling of serum creatinine, end stage renal disease or death at study termination Reference - J Am Soc Nephrol 2010 Mar;21(3):527 full-text, editorial can be found in J Am Soc Nephrol 2010 Mar;21(3):392 full-text high-dose B vitamin therapy associated with increased vascular events and decreased glomerular filtration rate (GFR) in patients with diabeticnephropathy (level 2 [mid-level] evidence) based on randomized trial with composite outcome and modified intention to treat analysis 252 patients 18 years old with diabetes type 1 or 2 and diabeticnephropathy randomized to high-dose B vitamin therapy vs. placebo orally B vitamin therapy was folic acid (2.5 mg), vitamin B6 (25 mg) and vitamin B12 (1 mg) daily patients followed for mean 31.9 months 4 randomized patients excluded for not meeting inclusion criteria (no diabeticnephropathy), 10 lost to follow-up modified intention-to-treat population included 238 patients (94%) who had first medication tablet and had 1 GFR measurement after randomization comparing B vitamin therapy vs. placebo at 36 months mean decrease in radionuclide GFR 16.5 mL/minute/1.73 m2 vs. 10.7 mL/minute/1.73 m2 (p = 0.02) composite of myocardial infarction, stroke, revascularization, all-cause mortality in 23.5% vs. 14.4% (p = 0.04, NNH 11) myocardial infarction in 7.8% vs. 4.6% (not significant) stroke in 7.2% vs. 1.3% (p = 0.08) revascularization in 6.3% vs. 6.1% (not significant) all-cause mortality 6.7% vs. 6.6% (not significant) mean change in plasma total homocysteine -2.2 mcmol/L vs. +2.6 mcmol/L (p < 0.001) 1 adverse event in 88.2% vs. 89.9% (not significant) no significant differences in dialysis requirement, mean HbA1c, or mean diastolic or systolic blood pressure Reference - DIVINe trial (JAMA 2010 Apr 28;303(16):1603) pyridoxamine may not improve serum creatinine levels in patients with type 2 diabetes and diabeticnephropathy (level 3 [lacking direct] evidence) based on nonclinical outcome from randomized trial 317 patients (mean age 64 years) with type 2 diabetes and diabeticnephropathy randomized to pyridoxamine 150 mg vs. 300 mg vs. placebo twice daily for 1 year no significant difference among groups in serum creatinine levels Reference - J Am Soc Nephrol 2012 Jan;23(1):131 full-text astragalus membranaceus (traditional Chinese herb) may improve kidney-related biomarkers in patients with diabeticnephropathy (level 3 [lacking direct] evidence) based on systematic review without clinical outcomes systematic review of 25 trials (21 randomized, 4 nonrandomized) comparing astragalus membranaceus vs. control in 1,804 patients with diabeticnephropathy astragalus associated with significant improvement in blood urea nitrogen (BUN) in analysis of 8 trials, results limited by heterogeneity serum creatinine in analysis of 12 trials, results limited by heterogeneity creatinine clearance in analysis of 3 trials urine protein in analysis of 13 trials urine microalbumin in analysis of 6 trials, results limited by heterogeneity serum albumin in analysis of 5 trials, results limited by heterogeneity analysis of adverse effects not performed due to lack of reporting of severe side effects in all clinical trials Reference - J Ethnopharmacol 2011 Jan 27;133(2):412 omega-3 fatty acids may not improve kidney-related biomarkers in patients with type 2 diabetes and proteinuria (level 3 [lacking direct] evidence)
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based on randomized crossover trial without clinical outcomes 31 patients (mean age 67 years) with type 2 diabetes and proteinuria randomized to omega-3 fatty acids 4 g/day orally vs. placebo for 6 weeks followed by crossover to other treatment after 2-week washout period at baseline median estimated GFR was 76.9 mL/minute/1.73 m2 and median 24-hour urine albumin excretion was 161 mg/day no significant differences in urine albumin excretion, serum markers of kidney function, or estimated GFR omega-3 fatty acids associated with decreased urine neutrophil gelatinase-associated lipocalin excretion (p = 0.04) Reference - GO-FISH trial (Diabetes Care 2013 Jun;36(6):1462) Surgery and procedures: see Chronic kidney disease for information on renal transplant see also Dialysis for chronic kidney disease pancreas transplantation can reverse lesions of diabeticnephropathy, but reversal requires > 5 years of normoglycemia, clinical outcomes (need for dialysis, mortality) not assessed, based on serial biopsies of 8 patients with diabetes type 1 (N Engl J Med 1998 Jul 9;339(2):69) Consultation and referral: consider referral to physician experienced in care of kidney disease if uncertain etiology, difficult management issues, or advanced kidney disease (ADA Grade B)(1) specialists in high-risk pregnancy and kidney disease should co-manage pregnancy in women with diabetes and chronic kidney disease (NKF KDOQI Grade C)(3) Other management: treatment targets for cardiovascular risk factors (blood pressure, glycemic control, lipid profile, body weight) blood pressure target recommendations in patients with diabetes vary, but range from < 130/80 mm Hg to < 140/90 mm Hg, however, most are not specific to patients with diabetes and chronic kidney disease National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines recommend target blood pressure < 130/80 mm Hg for patients with diabetes and chronic kidney disease (NKF KDOQI Grade B)(3) Kidney Disease: Improving Global Outcomes (KDIGO) guideline for adults with chronic kidney disease and diabetes recommend target blood pressure 140/90 mm Hg if urine albumin excretion < 30 mg/24 hours (KDIGO Level 1 Grade B) target blood pressure 130/80 mm Hg if urine albumin excretion > 30 mg/24 hours (KDIGO Level 2 Grade D) Reference - KDIGO 2012 Dec PDF or at National Guideline Clearinghouse 2012 Dec 19:39430, appendix can be found at KDIGO Appendix 2012 Dec PDF, supplementary tables can be found at KDIGO Tables 2012 Dec PDF, commentary can be found at Am J Kidney Dis 2013 Aug;62(2):201 American Diabetes Association (ADA) recommends diastolic blood pressure target < 80 mm Hg (ADA Grade B) and systolic blood pressure < 140 mm Hg for patients with diabetes and hypertension (ADA Grade B), and did not make recommendation specific to patients with chronic kidney disease(1) Eighth Joint National Committee (JNC 8) recommended target blood pressure < 140/90 mm Hg for patients with diabetes (JNC8 Expert opinion) and for patients with chronic kidney disease (JNC8 Expert opinion), but did not make recommendation specific to combination of diabetes and chronic kidney disease (JAMA 2013 Dec 18 early online fulltext) see also Hypertension treatment in patients with diabetes and Hypertension treatment in patients with chronic kidney disease glycemic goals HbA1c < 7% recommended for most nonpregnant adults with type 1 or type 2 diabetes (ADA Grade B)(1) HbA1c about 7% recommended to prevent or delay progression of microvascular complications of diabetes including diabeticnephropathy (NKF KDOQI Grade 1A)(4) less stringent target HbA1c (such as < 8%) may be appropriate for patients with risk for hypoglycemia, comorbidities, or limited life expectancy (ADA Grade B, NKF KDOQI Grade 2C)(1, 4) see Glycemic goals in patients with type 1 diabetes or Glycemic goals in patients with type 2 diabetes for details low-density lipoprotein (LDL) cholesterol targets National Kidney Foundation KDOQI recommendations for LDL cholesterol targets in patients with diabetes and chronic kidney disease stages 1-4(3) LDL cholesterol target of < 100 mg/dL (2.6 mmol/L) (NKF KDOQI Grade B) LDL cholesterol target of < 70 mg/dL (1.8 mmol/L) is a therapeutic option (NKF KDOQI Grade B) American Diabetes Association recommendations for LDL cholesterol targets in patients with diabetes(1) in patients without overt cardiovascular disease, target is < 100 mg/dL (2.6 mmol/L) (ADA Grade B) in children with type 1 diabetes, target is < 100 mg/dL (2.6 mmol/L) (ADA Grade E) see Lipid-lowering in patients with diabetes for details target body mass index for people with diabetes and chronic kidney disease should be within the normal range - 18.5-24.9 kg/m2 (NKF KDOQI Grade C)(3) Follow-up: American Diabetes Association (ADA) recommendations(1)
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consider continued monitoring of urine albumin excretion to assess both response to therapy and progression of disease (ADA Grade E) evaluate and manage potential complications of chronic kidney disease if estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2 (ADA Grade E) for patients with diabetes and GFR 45-60 mL/minute/1.73 m2 referrals nephrologist if possibility of nondiabetic kidney disease (such as type 1 diabetes duration < 10 years, heavy proteinuria, abnormal findings on renal ultrasound, resistant hypertension, rapid fall in GFR, or active urinary sediment on ultrasound) dietary counseling monitoring every 6 months - estimated GFR annually - electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, and parathyroid hormone consider need to adjust medication doses confirm vitamin D sufficiency consider bone mineral density testing for patients with diabetes and GFR 30-44 mL/minute/1.73 m2 monitoring every 3 months - estimated GFR every 3-6 months - electrolytes, bicarbonate, calcium, phosphorus, parathyroid hormone, hemoglobin, albumin, and weight consider need to adjust medication doses for patients with diabetes and GFR < 30 mL/minute/1.73 m2, refer to nephrologist Prognosis disease process accelerated by hypertension (inconsistent evidence) systolic blood pressure stronger predictor than diastolic blood pressure of renal outcomes based on randomized trial 1,513 patients with nephropathy, hypertension and type 2 diabetes doubling of serum creatinine, end-stage renal disease, or death Reference - Arch Intern Med 2003 Jul 14;163(13):1555, commentary can be found in Arch Intern Med 2004 Jan 26;164(2):223 hypoalbuminemia, proteinuria, and black race (but not blood pressure, HbA1c or serum cholesterol) were independent predictors of progression of decline in glomerular filtration rate based on cohort study 343 patients with type 2 diabetes, chronic kidney disease and mean blood pressure 138/72 mm Hg Reference - BMC Nephrol 2005 Jun 28;6(1):8 full-text urinary obstruction infection nephrotoxic agents medication IV radiocontrast material low-level environmental lead exposure may accelerate progressive diabeticnephropathy based on cohort study 87 patients with type 2 diabetes and serum creatinine 1.5-3.9 mg/dL (132.6-344.8 mcmol/L) patients all had normal body lead burdens (< 600 mcg) but basal blood levels and body lead burden predicted elevation of serum creatinine during follow-up Reference - Kidney Int 2006 Jun;69(11):2049 low eGFR and high albumin-to-creatinine ratio each associated with increased risk of end-stage renal disease and mortality regardless of diabetes status based on systematic review of cohort studies systematic review of 43 cohort studies (30 general population or high-risk for cardiovascular disease cohorts and 13 CKD cohorts) with 1,024,977 persons including 896,472 without diabetes and 128,505 with diabetes overall, persons with diabetes had increased risk of all-cause mortality, cardiovascular mortality, and end stage renal disease compared to persons without diabetes decreasing estimated glomerular filtration rate (eGFR) and increasing albumin-creatinine ratio each associated with increasing risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease, with similar risks in persons with and without diabetes Reference - Lancet 2012 Nov 10;380(9854):1662 full-text, correction can be found in Lancet 2013 Feb 2;381(9864):374, editorial can be found in Lancet 2012 Nov 10;380(9854):1628 higher urinary albumin-to-creatinine ratio (ACR) associated with higher mortality in patients with diabetes based on cohort of 94,934 patients with diabetes (98% male, mean age 67 years) followed for median 6.4 years
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prevalence of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 11% in patients < 65 years old and 44% in patients 75 years old patients with elevated ACR 300 mg/g in 3.2% of patients < 65 years old and 3.7% in patients 75 years old 30-299 mg/g in 19% < 65 years old and 28% in patients 75 years old in analysis of 24,592 patients 75 years old, higher urinary ACR associated with increased risk of mortality independently of eGFR in analysis of patients < 65 years old, higher ACR associated with increased risk of mortality in patients with eGFR at levels > 30 mL/minute/1.73 m2 but not levels 30 mL/min/1.73 m2 Reference - Arch Intern Med 2010 Jun 14;170(11):930, correction can be found in Arch Intern Med 2010 Oct 11;170(18):1639, editorial can be found in Arch Intern Med 2010 Jun 14;170(11):926 Prevention and Screening Prevention: American Diabetes Association (ADA) recommendations to reduce risk or slow prevention of nephropathy, optimize(1) glucose control (ADA Grade A) blood pressure control (ADA Grade A) National Kidney Foundation recommendations for patients with diabetes blood pressure goal < 130/80 mm Hg in patients with diabetes and chronic kidney disease stages 1-4 (NKF KDOQI Grade B)(3) ACE inhibitor or ARB recommended for hypertensive patients with diabetes and chronic kidney disease stages 1-4, usually in combination with a diuretic (NKF KDOQI Grade A)(3) for normotensive patients with diabetes(4) angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) suggested for patients with diabetes and albuminuria (urine albumin/creatinine ratio 30 mg/g) who are at high risk of diabetic kidney disease or its progression (NKF KDOQI Grade 2C) ACE inhibitors or ARBs are NOT recommended for primary prevention of diabetic kidney disease in patients with normal albuminuria level (NKF KDOQI Grade 1A) Multiple risk factor management: lifestyle modifications which may lower blood pressure (BP) and cardiovascular risk and are recommended for patients with diabetes include weight loss if overweight or obese (ADA Grade B, ACC/AHA Class I, Level A) Dietary Approaches to Stop Hypertension (DASH) diet (fruits, vegetables, low-fat dairy, reduced fat) (ADA Grade B, ACC/AHA Class I, Level A) dietary sodium restriction (ADA Grade B, ACC/AHA Class I, Level A) aerobic physical activity (ADA Grade B, ACC/AHA Class IIa, Level A) see Hypertension treatment in patients with diabetes for details intensive management of multiple risk factors may reduce microvascular and macrovascular complications in patients with type 2 diabetes and microalbuminuria (level 2 [mid-level] evidence) based on randomized trial without attention control 160 patients aged 40-65 years with diabetes mellitus type 2 and microalbuminuria randomized to intensive treatment (of hyperglycemia, hyperlipidemia, hypertension, and microalbuminuria) vs. standard treatment (Danish guidelines) all patients had individualized dietary advice intensive treatment group had behavior modification therapy (low-fat diet, smoking cessation, exercise 30 minutes 3-5 times/week advised) angiotensin-converting enzyme (ACE) inhibitor plus other antihypertensive agents to keep blood pressure < 140/85 mm Hg vitamin C 250 mg, vitamin E 100 mg aspirin if ischemic cardiovascular disease diabetic treatment to keep HbA1c < 7% (oral hypoglycemic agents then insulin if necessary) antihyperlipidemic treatment comparing intensive treatment vs. standard treatment at 4 years (mean follow-up 3.8 years) nephropathy (based on urinary albumin excretion rate > 300 mg/24 hours) in 11% vs. 25% (p = 0.01, NNT 7) progression of retinopathy in 26% vs. 43% (p = 0.04, NNT 6) blindness in 1 eye in 1% vs. 9% (p = 0.03, NNT 13) progression of autonomic neuropathy in 11% vs. 29% (p = 0.01, NNT 6) combined outcome of death and macrovascular events (cardiovascular morbidity and mortality) in 34% vs. 54% (p = 0.03, NNT 5) Reference - STENO-2 trial (Lancet 1999 Feb 20;353(9153):617), editorial can be found in Lancet 1999 Feb 20;353(9153):606, commentary can be found in Lancet 1999 Jul 3;354(9172):74, Am Fam Physician 1999 May 1;59(9):2626, or in Evidence-Based Medicine 1999 Jul-Aug;4(4):107 longer follow-up (mean 7.8 years) reports reduction in cardiovascular disease, nephropathy, retinopathy, and autonomic neuropathy
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cardiovascular events defined as cardiovascular death, myocardial infarction, coronary artery bypass graft (CABG), percutaneous coronary intervention, stroke, amputation, or vascular surgery cardiovascular events occurred in 24% intensive treatment group vs. 44% control group (NNT 5) Reference - N Engl J Med 2003 Jan 30;348(5):383, editorial can be found in N Engl J Med 2003 Jan 30;348(5):457, commentary can be found in N Engl J Med 2003 May 8;348(19):1925, ACP J Club 2003 Sep-Oct;139(2):31 reduced mortality and adverse effects reported at mean 13.3 year follow-up follow-up included original trial for mean 7.8 years then further follow-up for mean 5.5 years comparing intensive treatment vs. usual care 30% vs. 50% died (p = 0.02, NNT 5) 11.3% vs. 23.8% died from cardiovascular causes (p = 0.03, NNT 8) 25% vs. 46% developed diabeticnephropathy (p = 0.004, NNT 5) 1.3% vs. 7.5% had progression to end-stage renal disease requiring dialysis (p = 0.04, NNT 16) 51% vs. 67.5% had progression of diabetic retinopathy (p = 0.01, NNT 6) 17.5% vs. 33.75% had laser treatment for proliferative retinopathy or macular edema (p = 0.02, NNT 6) number of cardiovascular events 51 (in 25 patients) vs. 158 (in 48 patients) (hazard ratio 0.41, p < 0.001) 2.5% vs. 8.8% developed blindness in 1 eye (not statistically significant) 1 patient in intensive treatment group developed bleeding gastric ulcer no significant differences in progression of peripheral neuropathy, hypoglycemia episodes, or cancer-related deaths Reference - N Engl J Med 2008 Feb 7;358(6):580, commentary can be found in N Engl J Med 2008 May 22;358(21):2292, ACP J Club 2008 Aug 19;149(2):4 tight target control of multiple factors associated with reduced risk of microalbuminuria in Chinese patients with diabetes (level 3 [lacking direct] evidence) based on prospective cohort study without clinical outcomes 1,290 adult Chinese patients with type 2 diabetes and normal urine albumin levels at baseline were followed for 4.5 years patients treated to reach targets recommended by American Diabetes Association (ADA) HbA1c < 7% systolic blood pressure < 130 mm Hg, diastolic blood pressure < 80 mm Hg low-density lipoprotein cholesterol < 100 mg/dL (< 2.6 mmol/L) triglycerides < 150 mg/dL (< 1.7 mmol/L) high-density lipoprotein (HDL) cholesterol > 40 mg/dL (> 1.0 mmol/L) in men and > 50 mg/dL (1.3 mmol/L) in women 16.4% developed microalbuminuria during follow-up significantly reduced risk of microalbuminuria associated with reaching targets for HbA1c systolic blood pressure HDL cholesterol Reference - Arch Intern Med 2010 Jan 25;170(2):155 intensive blood pressure control (target systolic blood pressure < 120 mm Hg) and intensive glycemic control (target HbA1c < 6%) may not prevent renal failure or retinopathy in patients with type 2 diabetes (level 2 [mid-level] evidence) based on secondary analysis of ACCORD trial 4,726 adults aged 40-82 years with type 2 diabetes and 2 other cardiovascular risk factors enrolled in randomized trial and followed for mean 4.7 years intensive blood pressure therapy (systolic blood pressure target < 120 mm Hg) vs. standard therapy (systolic blood pressure target < 140 mm Hg) intensive glycemic control (target HbA1c < 6%) vs. standard treatment (target HbA1c 7-7.9%) comparing intensive vs. standard blood pressure therapy renal failure in 2.6% vs. 2.7% (not significant) retinopathy requiring retinal photocoagulation or vitrectomy in 9.6% vs. 9.1% (not significant) comparing intensive vs. standard glycemic control renal failure in 2.7% vs. 2.5% (not significant) retinopathy requiring retinal photocoagulation or vitrectomy in 9.2% vs. 9.5% (not significant) no significant interaction between intensive blood pressure and intensive glycemic control on renal failure Reference - Kidney Int 2012 Mar;81(6):586 Antihypertensive medications: effects of antihypertensive medications in patients with diabetes mellitus and no diabetic kidney disease (combining normotensive and hypertensive patients, but all patients had normoalbuminuria) angiotensin-converting enzyme (ACE) inhibitors may decrease all-cause mortality, but do not appear to reduce risk for end-stage kidney disease (level 2 [mid-level] evidence) despite decreasing albuminuria (level 3 [lacking direct] evidence) compared to placebo or no treatment angiotensin II receptor blockers (ARBs) may not decrease all-cause mortality or risk for end-stage kidney disease (level 2 [mid-level] evidence) compared to placebo or no treatment ACE inhibitors and ARBs may have similar all-cause mortality (level 2 [mid-level] evidence) compared to
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each other based on Cochrane review of trials with methodologic limitations systematic review of 26 randomized trials evaluating antihypertensive medications for prevention of kidney disease in 61,264 normotensive or hypertensive patients with diabetes and normal urine albumin levels (albumin excretion rate < 30 mg/day) all but 1 trial had methodologic limitations including randomization method inadequate or unclear allocation concealment unclear blinding unclear for trial without methodologic limitations the data analyzed was limited to subgroup of patients without kidney disease all-cause mortality ACE inhibitors (compared to placebo or no treatment) associated with reduced all-cause mortality in analysis of 6 trials with 11,350 patients risk ratio (RR) 0.84 (95% CI 0.73-0.97) NNT 53-477 with 7% risk in control group no significant differences in all-cause mortality in analyses comparing ARBs vs. placebo or no treatment (RR 1.12, 95% CI 0.88-1.41) in analysis of 5 trials with 7,653 patients ACE inhibitors vs. ARBs (RR 1.02, 95% CI 0.85-1.22) in analysis of 2 trials with 4.303 patients ACE inhibitors vs. calcium channel blockers (RR 0.84, 95% CI 0.26-2.73) in analysis of 5 trials with 1,519 patients end-stage kidney disease no significant differences in risk of end-stage kidney disease in analyses comparing ACE inhibitors vs. placebo or no treatment (RR 1.94, 95% CI 0.66-5.7) in analysis of 3 trials with 10,504 patients ARBs vs. placebo or no treatment (RR 0.5, 95% CI 0.09-2.71) in analysis of 3 trials with 6,217 patients combination of ACE inhibitor plus ARB associated with nonsignificantly lower risk for end-stage kidney disease than ACE inhibitor alone (RR 0.88, 95% CI 0.78-1) in analysis of 2 trials with 4,171 patients onset of microalbuminuria or macroalbuminuria (from normoalbuminuria) ACE inhibitors (compared to placebo or no treatment) reduced risk in analysis of 8 trials with 11,906 patients RR 0.71 (95% CI 0.56-0.89) NNT 10-38 with 24% risk in control group ACE inhibitors (compared to calcium channel blockers) associated with reduced risk in analysis of 5 trials with 1,253 patients RR 0.6 (95% CI 0.42-0.85) NNT 15-56 with 12% risk in control group no significant difference in comparisons of ARBs vs. placebo or no treatment (RR 0.9, 95% CI 0.68-1.19) in analysis of 5 trials with 7,653 patients ACE inhibitors vs. ARBs (RR 0.57, 95% CI 0.14-2.23) in analysis of 2 trials with 4,303 patients Reference - Cochrane Database Syst Rev 2012 Dec 12;12:CD004136 (review updated 2013 Aug 20) DynaMed commentary -- apparent inconsistencies (ACE inhibitors effective and ARBs ineffective, but ACE inhibitors and ARBs having similar efficacy in direct comparisons) may be due to relatively limited data rather than clear understanding of drug class effects in patients without kidney disease in patients with diabetes and microalbuminuria, ACE inhibitors and angiotensin receptor blockers each appear to reduce likelihood for progression to macroalbuminuria and increase likelihood of regression to normoalbuminuria (level 3 [lacking direct] evidence) based on nonclinical outcome from Cochrane review of trials with methodological limitations systematic review of 49 trials of ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with diabeticnephropathy Cochrane review included populations with any degree of diabeticnephropathy (including microalbuminuria) 38 trials compared ACE inhibitors vs. placebo in 8,970 patients with type 1 or type 2 diabetes 5 trials compared ARBs to placebo in 3,409 patients (all including patients with hypertension) 7 trials compared ARBs to ACE inhibitors in 557 patients only 1 trial (HOPE trial) had both adequate allocation concealment and blinding of outcome assessors, and data analyzed for this trial represents subgroup analysis of a much larger trial compared to placebo, ACE inhibitors associated with reduced likelihood of progression from microalbuminuria to macroalbuminuria (risk ratio 0.45, 95% CI 0.29-0.69) in analysis of 17 trials with 2,036 patients increased likelihood of regression from microalbuminuria to normoalbuminuria (risk ratio 3.06, 95% CI 1.76-5.35) in analysis of 16 trials with 1,910 patients compared to placebo, ARBs associated with reduced likelihood of progression from microalbuminuria to macroalbuminuria (risk ratio 0.49, 95% CI 0.32-0.75) in analysis of 3 trials with 761 patients increased likelihood of regression from microalbuminuria to normoalbuminuria (risk ratio 1.42, 95% CI 1.05-1.93) in analysis of 2 trials with 670 patients
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no significant differences comparing ACE inhibitors vs. ARBs in progression to macroalbuminuria (1 trial with 41 patients) or regression to normoalbuminuria (2 trials with 65 patients) in this review ACE inhibitors and ARBs were each associated with reduced risk for end-stage kidney disease but these analyses were not limited to patients with microalbuminuria (that is, these analysis included patients with any degree of diabeticnephropathy) Reference - Cochrane Database Syst Rev 2006 Oct 18;(4):CD006257 for treatment of hypertension in patients with diabetes mellitus target blood pressure (BP) in patients with diabetes guidelines vary but range from < 130/80 mm Hg to < 140/90 mm Hg diastolic blood pressure (DBP) DBP target 80 mm Hg may reduce mortality, myocardial infarction, and stroke compared to target 90 mm Hg in patients with type 2 diabetes and baseline DBP 100-115 mm Hg (level 2 [mid-level] evidence) DBP target of 75 mm Hg may reduce mortality compared to target of 80-89 mm Hg in patients with type 2 diabetes and baseline DBP 90 mm Hg (level 2 [mid-level] evidence) DBP < 70 mm Hg associated with increased risk for cardiovascular disease events in patients with type 2 diabetes (level 2 [mid-level] evidence) systolic blood pressure (SBP) achieving SBP 135 mm Hg associated with reduced mortality and nephropathy in patients with type 2 diabetes (level 2 [mid-level] evidence) achieving SBP 130 mm Hg associated with reduced stroke and nephropathy in patients with type 2 diabetes (level 2 [mid-level] evidence), but may increase mortality in patients with diabetes and coronary artery disease (level 2 [mid-level] evidence) SBP target < 120 mm Hg does not reduce mortality or myocardial infarction but does reduce nonfatal stroke compared to target < 140 mm Hg in patients with type 2 diabetes and high risk for cardiovascular events (level 1 [likely reliable] evidence) selection of antihypertensive agents guidelines recommend initial antihypertensive therapy in patients with diabetes include one of angiotensin-converting enzyme (ACE) inhibitor (JNC8 Moderate recommendation for nonblack patients, ADA Grade C, CHEP Grade A, ESH/ESC Class I, Level A) angiotensin receptor blocker (ARB) (JNC8 Moderate recommendation for nonblack patients, ADA Grade C, CHEP Grade B, ESH/ESC Class I, Level A) calcium channel blocker (JNC8 Moderate recommendation for nonblack patients, JNC8 Weak recommendation for black patients, CHEP Grade A, ESH/ESC Class I, Level A) thiazide-like diuretic (JNC8 Moderate recommendation for nonblack patients, JNC8 Weak recommendation for black patients, CHEP Grade A, ESH/ESC Class I, Level A) some guidelines (ADA, ESH/ESC) state preference for ACE inhibitor or ARB for hypertensive patients with diabetes (ADA Grade C, ESH/ESC Class I, Level A), while JNC8 recommends thiazide-like diuretic or calcium channel blocker in black patients with diabetes (JNC8 Weak recommendation) most patients will require 2 or more drugs to achieve target blood pressure (ADA Grade B) comparative efficacy ACE inhibitors, calcium channel blockers, thiazide-type diuretics, and beta blockers appear to have similar effects on myocardial infarction and stroke in patients with hypertension and diabetes (level 2 [mid-level] evidence); calcium channel blockers may have increased risk for heart failure (level 2 [mid-level] evidence) comparative efficacy for all-cause mortality is unclear in patients with diabetes compared to placebo, all-cause mortality appears reduced with ACE inhibitors (level 2 [mid-level] evidence) but not with ARBs (level 2 [mid-level] evidence), while ACE inhibitors and ARBs have similar all-cause mortality in direct comparisons (level 2 [mid-level] evidence) atenolol (a beta blocker) may be less effective than ACE inhibitors (and as effective as calcium channel blockers) for reducing cardiovascular mortality and all-cause mortality (level 2 [mid-level] evidence) specific drugs shown to reduce mortality in large trials include ramipril (an ACE inhibitor) 10 mg/day (but not 1.25 mg/day) decreases mortality and cardiovascular outcomes in patients with diabetes (level 1 [likely reliable] evidence) combination of perindopril plus indapamide (Preterax) reduces mortality in patients with type 2 diabetes (level 1 [likely reliable] evidence) in patients with diabeticnephropathy ACE inhibitors may reduce risk for end-stage kidney disease (level 2 [mid-level] evidence), and ACE inhibitors at maximum tolerable dose (but not at lower doses) may reduce all-cause mortality (level 2 [mid-level] evidence) ARBs may reduce risk for end-stage kidney disease in hypertensive patients with type 2 diabetes (level 2 [midlevel] evidence) combination ACE inhibitor plus ARB does not reduce mortality or cardiovascular morbidity compared to ACE inhibitor alone (level 1 [likely reliable] evidence) and may worsen renal impairment despite greater efficacy for reducing blood pressure and urinary albumin excretion (level 3 [lacking direct] evidence) see Hypertension treatment in patients with diabetes for details
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Heparin: no randomized trials identified evaluating heparin and related substances for prevention of diabeticnephropathy based on Cochrane review Reference - Cochrane Database Syst Rev 2010 Sep 8;(9):CD005631 Screening: microalbuminuria screening albuminuria screening recommendations annual screening for diabetic kidney disease recommended starting at diagnosis with type 2 diabetes (ADA Grade B, NKF KDOQI Grade B) 5 years after diagnosis with type 1 diabetes (ADA Grade B, NKF KDOQI Grade A) screening should include measurement of urine albumin excretion (ADA Grade B), such as urine albumin-to-creatinine ratio in spot urine sample (NKF KDOQI Grade B) if abnormal urine albumin excretion, 2 additional urine specimens in following 3-6 months recommended for confirmation (NKF KDOQI Grade B) References American Diabetes Association (ADA) 2014 standards of medical care in diabetes (Diabetes Care 2014 Jan;37 Suppl 1:S14 full-text) National Kidney Foundation KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease (Am J Kidney Dis 2007 Feb;49(2 Suppl 2):S12 PDF) screening for microalbuminuria in patients with diabetes may be effective in preventing nephropathy, but may not be cost-effective (level 3 [lacking direct] evidence) based on systematic review of 31 studies no controlled trials directly evaluating effect of screening on progression to nephropathy repeated testing does not improve diagnostic certainty screening probably cost-effective in patients with type 1 diabetes, but may not be cost-effective in patients with type 2 diabetes (routine use of angiotensin-converting enzyme [ACE] inhibitors may be more cost-effective than microalbuminuria screening) Reference - J Fam Pract 2001 Aug;50(8):661, editorial can be found in J Fam Pract 2001 Aug;50(8):674 random urine albumin/creatinine ratio sensitive for microalbuminuria in adults with diabetes based on diagnostic cohort study 314 adults aged 18-84 years with diabetes provided random morning urine sample and 24-hour urine collection urine albumin-creatinine ratio > 22.1 mg/g (2.5 mg/mmol) in men had 95.7% sensitivity and 68%-84% specificity (declining with age) urine albumin-creatinine ratio > 30.9 mg/g (3.5 mg/mmol) in women had 93.4% sensitivity and 72%-89.5% specificity (declining with age) Reference - Am J Kidney Dis 2002 Jun;39(6):1183 in Ann Intern Med 2004 Jan 20;140(2):106 microalbuminuria may be prognostic marker for increased mortality and future nephropathy diabetes mellitus type 2 associated with elevated albuminuria and progression from micro- to macroalbuminuria in children (level 2 [mid-level] evidence) based on noninception prognostic cohort study 3,959 Pima Indian children aged 5-19 years assessed for micro- and macroalbuminuria and diabetes mellitus type 2 microalbuminuria defined as urinary albumin-to-creatinine ratio (ACR) 30 mg/g and macroalbuminuria defined as ACR 300 mg/g diabetes in 103 children (2.6%) at baseline comparing children with vs. without diabetes elevated albuminuria in 21% vs. 7% (p < 0.0001) microalbuminuria in 18.5% vs. 6.5% (p value not reported) macroalbuminuria in 2.9% vs. 0.6% (p value not reported) regression to normal on later exam in 1 of 14 (7.1%) vs. 141 of 187 (75.4%) children with follow-up macroalbuminuria incidence risk ratios comparing children with vs. without diabetes in subset of 2,666 children with median 8-year follow-up 15.9 (95% CI 11.1-22.6) adjusted for ACR 7.6 (95% CI 1.8-32.8) vs. 8.2 (95% CI 2.1-32.4) in children with microalbuminuria at baseline (adjusted for age and gender) Reference - Pediatrics 2010 Apr;125(4):e844 full-text benefit of monitoring or screening for microalbuminuria in patients already taking ACE inhibitors or angiotensin II receptor blockers not researched (J Fam Pract 2007 Feb;56(2):145, J Fam Pract 2003 Mar;52(3):229), commentary can be found in J Fam Pract 2007 May;56(5):343 serum creatinine measurement (and estimation of glomerular filtration rate) recommended at least annually for all adults with diabetes, regardless of degree of urine albumin excretion (ADA Grade E)(1) all patients with type 2 diabetes from time of diagnosis and type 1 diabetes 5 years after diagnosis (NKF KDOQI Grade B)
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diabetic retinopathy may have limited utility for identifying diabeticnephropathy in patients with type 2 diabetes and renal disease (level 2 [mid-level] evidence) based on systematic review limited by heterogeneity systematic review of 26 cohort studies evaluating diabetic retinopathy for differentiating diabeticnephropathy from nondiabetic renal diseases in patients with type 2 diabetes and renal disease in 2,012 patients pooled predictive performance of diabetic retinopathy for identifying diabeticnephropathy in patients with type 2 diabetes and renal disease sensitivity 65% (range 33%-100%) specificity 75% (range 27%-100%) positive predictive value 72% (range 34%-100%) negative predictive value 69% (range 19%-100%) all results limited by significant heterogeneity Reference - Diabetologia 2013 Mar;56(3):457 Quality Improvement Physician Quality Reporting System Quality Measures: 119. Diabetes Mellitus: Medical Attention for Nephropathy Percentage of patients aged 18-75 years with diabetes mellitus who received urine protein screening or medical attention for nephropathy during at least one office visit within 12 months see Physician Quality Reporting System Quality Measures for additional information Quality and Outcomes Framework Indicators: DM5 (NM59). Percentage of patients with diabetes on the register who have record of albumin:creatinine ratio test in preceding 12 months DM6. Percentage of patients with diabetes on the register with diagnosis of nephropathy (proteinuria) or micro-albuminuria who are treated with ACE inhibitor or angiotensin receptor blocker see Quality and Outcomes Framework Indicators for additional information Guidelines and Resources Guidelines: United States guidelines: American Diabetes Association (ADA) American Diabetes Association (ADA) position statement on standards of medical care in diabetes can be found in Diabetes Care 2014 Jan;37 Suppl 1:S14 full-text, executive summary can be found in Diabetes Care 2014 Jan;37 Suppl 1:S5 full-text ADA 2011 recommendations on chronic complications of diabetes mellitus: prevention and management can be found in Rev Enferm 2012 Sep;35(9):46 [Spanish] ADA position statement on nephropathy in diabetes from can be found in Diabetes Care 2004 Jan;27 Suppl 1:S79 full-text National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) clinical practice recommendations on diabetes and chronic kidney disease can be found in Am J Kidney Dis 2012 Nov;60(5):850 PDF, correction can be found in Am J Kidney Dis 2013 Jun;61(6):1049, previous version can be found at NKF KDOQI 2007 National Kidney Foundation (NKF) recommendation on preserving renal function in adults with hypertension and diabetes can be found in Am J Kidney Dis 2000 Sep;36(3):646 Canadian guidelines: Canadian Diabetes Association (CDA) guideline on prevention and management of diabetes can be found at CDA CDA 2008 Sep PDF Review articles: review can be found in Am Fam Physician 2005 Jul 1;72(1):96 review can be found in N Engl J Med 1999 Oct 7;341(15):1127 (summarized in Am Fam Physician 2000 Mar 1;61(5):1486), commentary can be found in N Engl J Med 2000 Feb 10;342(6):441 review can be found in N Engl J Med 2002 Apr 11;346(15):1145, commentary can be found in N Engl J Med 2002 Sep 19;347(12):947 review can be found in Lancet 1998 Jul 18;352(9123):213, summarized in Am Fam Physician 1998 Nov 15;58(8):1845 review can be found in J Fam Pract 1998 Jan;46(1):21 review can be found in Mayo Clin Proc 2000 Jan;75(1):49 editorial review can be found in BMJ 2002 Jul 13;325(7355):59 full-text review of family physician's role in diabeticnephropathy can be found in Am Fam Physician 2012 May 1;85(9):883 full-text review of early screening for microalbuminuria can be found in Mayo Clin Proc 2008 Dec;83(12):1373 full-text American Diabetes Association (ADA) literature review on diabeticnephropathy can be found in Diabetes Rev 1995;3:510 MEDLINE search: to search MEDLINE for (Diabeticnephropathy) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis
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Patient Information handout can be found in Am Fam Physician 2005 Jul 1;72(1):100 ICD-9/ICD-10 Codes ICD-9 codes: first code underlying disease 249.40 secondary diabetes mellitus with renal manifestations, not stated as uncontrolled, or unspecified 249.41 secondary diabetes mellitus with renal manifestations, uncontrolled 250.40 diabetes mellitus with renal manifestations, type II or unspecified type, not stated as uncontrolled 250.41 diabetes mellitus with renal manifestations, type I not stated as uncontrolled 250.42 diabetes mellitus with renal manifestations, type II or unspecified type, uncontrolled (blood glucose > 200) 250.43 diabetes mellitus with renal manifestations, type I, uncontrolled (blood glucose > 200) 581.81 nephrotic syndrome in diseases classified elsewhere 583.81 nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere ICD-10 codes: E10.2 insulin-dependent diabetes mellitus with renal complications E11.2 non-insulin-dependent diabetes mellitus with renal complications E12.2 malnutrition-related diabetes mellitus with renal complications E13.2 other specified diabetes mellitus with renal complications E14.2 unspecified diabetes mellitus with renal complications N08.3 glomerular disorders in diabetes mellitus References General references used: 1. American Diabetes Association. Standards of medical care in diabetes--2013. Diabetes Care. 2013 Jan;36 Suppl 1:S1166 full-text 2. Bakris GL. Recognition, pathogenesis, and treatment of different stages of nephropathy in patients with type 2 diabetes mellitus. Mayo Clin Proc. 2011 May;86(5):444-56 full-text 3. KDOQI. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007 Feb;49(2 Suppl 2):S12-154 PDF 4. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease: 2012 update Am J Kidney Dis. 2012 Nov;60(5):850-86 PDF, correction can be found in Am J Kidney Dis 2013 Jun;61(6):1049 Recommendation grading systems used: American Diabetes Association (ADA) evidence grading system for clinical practice recommendations Grade A clear evidence from well-conducted, generalizable, randomized controlled trials (RCTs) that are adequately powered, including evidence from well-conducted multicenter trial or meta-analysis that incorporated quality ratings in analysis compelling nonexperimental evidence, specifically, "all or none" rule developed by Center for Evidence Based Medicine at Oxford supportive evidence from well-conducted RCTs that are adequately powered, including evidence from well-conducted trial at 1 institution or meta-analysis that incorporated quality ratings in analysis Grade B supportive evidence from well-conducted cohort studies, including evidence from well-conducted prospective cohort study or registry or meta-analysis of cohort studies supportive evidence from a well-conducted case-control study Grade C supportive evidence from poorly controlled or uncontrolled studies evidence from randomized clinical trials with 1 major or 3 minor methodologic flaws that could invalidate results evidence from observational studies with high potential for bias (such as case series with comparison to historical controls) evidence from case series or case reports conflicting evidence with weight of evidence supporting recommendation Grade E - expert consensus or clinical experience Reference - ADA 2014 position statement on standards of medical care in diabetes (Diabetes Care 2014 Jan;37 Suppl 1:S14 full-text) Eighth Joint National Committee (JNC 8) 2014 grades of recommendation Strong recommendation - Grade A - high certainty based on evidence that net benefit is substantial Moderate recommendation - Grade B - moderate certainty based on evidence that net benefit is moderate to substantial OR high certainty that net benefit is moderate Weak recommendation - Grade C - at least moderate certainty based on evidence that there is small net benefit
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Recommendation against - Grade D - at least moderate certainty based on evidence that no net benefit or that risks/harms outweigh benefits Expert opinion - Grade E - "There is insufficient evidence or evidence is unclear or conflicting, but this is what the committee recommends", net benefit unclear No recommendation for or against - Grade N - "There is insufficient evidence or evidence is unclear or conflicting", net benefit unclear Reference - JAMA 2013 Dec 18 early online full-text National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) grading systems for guidelines and clinical practice recommendations NKF KDOQI grading system used in 2012 strength of recommendation Level 1 - most patients should receive the recommended course of action Level 2 - different choices appropriate for different patients, varies with values and preferences quality of evidence A - High-quality evidence B - Moderate-quality evidence C - Low-quality evidence D - Very low-quality evidence Reference - NKF KDOQI clinical practice recommendations for diabetes and chronic kidney disease 2012 update (Am J Kidney Dis 2012 Nov;60(5):850 PDF) NKF KDOQI grading system used in 2007 Grade A strongly recommended that clinicians routinely follow guideline for eligible patients strong evidence that practice improves health outcomes Grade B recommended that clinicians routinely follow guideline for eligible patients moderately strong evidence that practice improves health outcomes Grade C recommended that clinicians consider following clinical practice recommendation for eligible patients based on weak evidence or opinions of the work group and reviewers that practice might improve health outcomes Reference - NKF KDOQI clinical practice recommendations for diabetes and chronic kidney disease (NKF KDOQI 2007) Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommendations strength of recommendation Level 1 ("we recommend") - most patients should receive recommended course of action Level 2 ("we suggest") - different choices appropriate for different patients, based on patient's values and preferences Not Graded - topic does not allow adequate application of evidence, not meant to be interpreted as being stronger recommendations than Level 1 or 2 quality of evidence Grade A - high-quality evidence, true effect lies close to that of estimate of effect Grade B - moderate-quality evidence, true effect likely to be close to estimate of effect, but there is possibility it is substantially different Grade C - low-quality evidence, true effect may be substantially different from estimate of effect Grade D - very low-quality evidence, estimate of effect very uncertain and often far from truth Kidney Disease: Improving Global Outcomes (KDIGO) guideline on management of blood pressure in chronic kidney disease can be found at KDIGO 2012 Dec PDF or at National Guideline Clearinghouse 2012 Dec 19:39430 European Society of Hypertension/European Society of Cardiology (ESH/ESC) grading system classifications of recommendations Class I - evidence and/or general agreement that procedure or treatment is beneficial, useful, effective Class II - conflicting evidence and/or divergence of opinion about usefulness/efficacy of given treatment of procedure Class IIa - weight of evidence/opinion in favor of usefulness/efficacy Class IIb - usefulness/efficacy less well established by evidence/opinion Class III - evidence or general agreement that procedure or treatment is not useful/effective, and in some cases may be harmful levels of evidence Level A - data derived from multiple randomized clinical trials or meta-analyses Level B - data derived from single randomized trial or large nonrandomized studies Level C - consensus opinions of experts, and/or small studies, retrospective studies, or registries Reference - European Society of Hypertension/European Society of Cardiology (ESH/ESC) guideline on management of arterial hypertension (Eur Heart J 2013 Jul;34(28):2159 full-text) DynaMed editorial process:
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DynaMed topics are created and maintained by the DynaMed Editorial Team. Over 500 journals and evidence-based sources (DynaMed Content Sources) are monitored directly or indirectly using a 7-Step evidence-based method for systematic literature surveillance. DynaMed topics are updated daily as newly discovered best available evidence is identified. The participating members of the DynaMed Editorial Team have declared that they have no financial or other competing interests related to this topic. The participating reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated. McMaster University is a partner that provides support in identifying Practice-Changing DynaMed Updates. Over 1,000 practicing physicians from 61 disciplines in 77 countries rate these articles to help you find the most useful new evidence affecting your practice. F1000 is a partner that provides support in identifying Practice-Changing DynaMed Updates. Over 2,000 practicing clinicians from 20 disciplines in 60 countries rate these articles to help you find the most useful new evidence affecting your practice. Special acknowledgements: Atul Kalanuria, MD, MBBS (Hahnemann University Hospital, Drexel University College of Medicine; Pennsylvania, United States) provides peer review. Yedatore Swamy Venkatesh, MD, FRCP (Edin), DM, FAAN (Clinical Professor of Neurology, Drexel University College of Medicine; Director of Neurology and Director of Stroke Program, Mercy Catholic Medical Center; Pennsylvania, United States) provides peer review. How to cite: For attribution in other publications see How to Cite Information from DynaMed. You are viewing a DynaMed summary. Use of DynaMed indicates acceptance of DynaMed Terms of Use. Limitations of DynaMed are contained in the DynaMed Terms of Use. Please give us your feedback by e-mailing DynaMed at: DynaMedEditor@ebscohost.com
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