Diabetic Nephropathynew horizonDr. Muhamed Al Rohani,MD
DefinitionClassical definition: progressive rise in urine albuminexcretion coupled with increasing BP and leadingto declining GFR and CKDAbnormal urine albumin excretion• >30 mg/24 hoursand/ordiabetic glomerular lesionsand/orloss of glomerular filtration rateADA recommendations, Diabetes Care, January 2012
EpidemiologyIncrease prevalence of DMIndia china USA4% 1995 – 5.4% 2025Worldwide:2.8 % 171 million 2000 –4.4% 366 million 2030Now: USA 7% (20.8 million) offpopulation has DMDN prevalenceIn India: 5.5% and 8.9%Asian Indians in UK 22.3%Increased mortality rateWith protinuriaWithout proteinuriaIncreased CV events
Harris MI. Clin Invest Med. 1995;18:231-239.Nelson RG, et al. Adv Nephrol Necker Hosp. 1995;24:145-156.World Health Organization. Diabetes Mellitus Fact Sheet 138. 2002.ADA. National diabetes fact sheet. Available at:http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp.Microvascular Complications Macrovascular ComplicationsComplications of Type 2 DiabetesAffect Every Part of the BodyPeripheralVascular DiseaseHeartDiseaseDiabetic RetinopathyLeading cause ofblindness inworking-age adultsDiabetic NephropathyLeading cause ofend-stage renal diseaseDiabetic NeuropathyLeading cause ofnontraumatic lowerextremity amputationsStroke2- to 4-fold increasein cardiovascularmortality and stroke
Type IDuration:Microalbuminuria after 20 yrs in 20 –30 % of DM patientsESRD after 10 yrs,Type 2Duration:CKD or ESRD in 1% of pts in the time ofdiagnosisESRD in 20 -30 % at 20 yrs.Poor glycemic controlStrict control reduce and slow the risk of microvascular and evenmacrovascular complications.Hypertension:Cause of and results of diabetic renal diseaseIn DM1 5% in 10 yrs33% in 20 yrs70% in 40 yrsRise with 3 yrs of microalbuminuria with Incidence of 15 – 25%75 – 85% in all diabetic nephropathy
Effect of Increased Glomerular Permeability to Proteins on Progressive Renal Injury.Remuzzi G, Bertani T. N Engl J Med 1998;339:1448-1456.Gilbert RE, Marsden PA. N Engl J Med 2008;358:1628-1630.
Pathological classification of DNClass Description Inclusion CriteriaIMild or nonspecific LM changes andEM-proven GBM thickeningBiopsy does not meet any of the criteria mentioned belowfor class II, III, or IVGBM > 395 nm in female and >430 nm in male individuals9 years of age and olderaIIaMild mesangial expansionBiopsy does not meet criteria for class III or IVMild mesangial expansion in >25% of the observedmesangiumIIbSevere mesangial expansionBiopsy does not meet criteria for class III or IVSevere mesangial expansion in >25% of the observedmesangiumIII Nodular sclerosis (Kimmelstiel–Wilson lesion)Biopsy does not meet criteria for class IVAt least one convincing Kimmelstiel–Wilson lesionIV Advanced diabeticglomerulosclerosisGlobal glomerular sclerosis in >50% of glomeruliLesions from classes I through III
Table 2. Recommendations for the ComprehensiveManagement of T2DM Patients with CKDFactor RecommendationsLifestyle factors Advice concerning smoking, diet, exercise, and alcohol intakeBlood glucose Treatment goal:HbA1c <7.0%Preprandial plasma glucose 90-130 mg/dlPostprandial plasma glucose <180 mg/dlBlood pressure Goal ≤130/80 mm HgUse maximal tolerated dose of ACE inhibitor or ARB beforeadding a second agentCholesterol Goal <4.0 mmol/L for total cholesterol and <2.0 mmol/L forLDL-CConsider use of a statin irrespective of baseline lipid values forthe secondary prevention of cardiovascular diseasePlatelets Consider use of low dose aspirin for the secondary preventionof cardiovascular diseaseMonitoring Annual monitoring of eGFR and ACR
Criteria for the Diagnosis of DiabetesA1C ≥6.5%ORFasting plasma glucose (FPG)≥126 mg/dL (7.0 mmol/L)Ono caloric intake for at least 8h2-h plasma glucose ≥200 mg/dL(11.1 mmol/L) during an OGTTORA random plasma glucose ≥200 mg/dL (11.1 mmol/L)ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.A1c Target :Intensive / conventionalOutcomeUKPDS10 yrs7% / 7.9% Significant reduction of microvascualrcomp. in intensive groupADVANCE5 yrs6.5% / 7.3% Reduction of macro and micro vascuarand meanly nephropathyACCORD <6% / 7- 7.9% Stopped because of increasedincidence of hypoglycemic evets
Prediabetes: IFG, IGT, Increased A1CCategories of increased risk for diabetes (prediabetes)*FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFGOR2-h plasma glucose in the 75-g OGTT140–199 mg/dL (7.8–11.0 mmol/L): IGTORA1C 5.7–6.4%*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater athigher ends of the range.ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.Category Spot collection (µg/mgcreatinine)Normal <30Microalbuminuria 30-299Macroalbuminuria (clinical) ≥300
Recommendations: Nephropathy• To reduce risk or slow the progression of nephropathy– Optimize glucose control (A)– Optimize blood pressure control (A)ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S34.• Assess urine albumin excretion annually– In type 1 diabetic patients with diabetes duration of ≥5 years– In all type 2 diabetic patients at diagnosis• Measure serum creatinine at least annually– In all adults with diabetes regardless of degree of urine albuminexcretion– Serum creatinine should be used to estimate GFR and stagelevel of chronic kidney disease, if present
The therapeutic strategies for DKD are limited due to severalfactors:– Lack of screening for DKD,– Lack of implementation of optimal standard therapy for DKD,– Current therapies primarily slow down, but do not halt theprogression of DKD.These therapies include:1. blood pressure, RAS blockers2. lipid, glycemic, and weight control;3. diet and lifestyle modifications;4. antiplatelet aggregation therapy;Statins have been shown to have1. multiple antioxidant properties and improve vascularremodeling (Briones et al., 2009).2. shown to reduce proteinuria (Nakamura et al., 2005)3. Shown to reduce the progression of DKD (Agarwal, 2007).
ACE inhibitors TrailHeart Outcome Prevention TrailCaptopril Prevention TrailFosinopril versus Amliodepine Cardiovascular Events TrailAppropriate BP Control Diabetes TrailUK prospective Diabetes StudyDiabetes Exposed to Telmisartan And EnalapriIL TrailBENEDICT TRAIL
ACE Inhibitors can prevent progression of renalfailure120160200240280320350400800 1 2 3 4 5 6YearsAnn Intern Med 118 577-581.1993J Am Soc Nephrol 2006PlaceboEnalapril 859095100105110800 1 2 3 4 5 6YearsPlaceboEnalaprilNormotensive Type 2 DiabeticsProteinuria(mg/day)% Initial GFRRisk reduction is 51%Reduce microalbuminuriaAll causes of mortality
Ruggenenti P et al. N Engl J Med 2004;351:1941-1951.ConclusionsIn subjects with type 2 DM and HTN but withnormoalbuminuria, the use of trandolapril plusverapamil and trandolapril alone decreasedthe incidence of microalbuminuria to a similarextent. The effect of verapamil alone wassimilar to that of placebo.
Olmesartan for the Delay or Prevention of Microalbuminuriain Type 2 Diabetes• 4447 patients to receive olmesartan 40 mg once daily or placebofor a median of 3.2 years.• BP <130/80 mm Hg.• The primary outcome was the time to the first• onset of microalbuminuria.• The times to the onset of renal and CV events were analyzed assecondary end points.Conclusion:• Olmesartan was associated with a delayed onset ofmicroalbuminuria, even though blood-pressure control• The higher rate of fatal cardiovascular events with olmesartanamong patients withpreexisting coronary heart disease is ofconcern.
Incidence of Progression to Diabetic Nephropathy during Treatment with 150 mgof Irbesartan Daily, 300 mg of Irbesartan Daily, or Placebo in HypertensivePatients with Type 2 Diabetes and Persistent Microalbuminuria.Parving H et al. N Engl J Med 2001;345:870-878.
Bardoxolyne methyl, has been shown to significantly improve the creatinine GFR andcystatin C GFR in patients with DKD after only 4 weeks(Schwartz, Denham, Hurwitz, Meyer, & Pergola, 2009).Recent landmark phase 2 trial of 227 adults with CKD and type 2 DM demonstratedthat bardoxolone methyl ( 75 mg is the optimal dose) improved GFR by at least8.2 +/-1.5 ml/min over placebo after 24 weeks of treatment and that this effectwas maintained after a year of therapy.(Pergola, et al., 2011).Bardoxolone methyl did not improve urinary albumin excretion.In 3 phase BEACON study in CKD 4 stage disappointing resultsPIRFENIDONE:Antifibrotic (reduction of: ECM deposition, fibrogenic growth factor, fibroblastproliferation)Anti-inflammatory (reducation of: inflam. Cytokinase and inflam.cell accumulationAntioxidant reduction of: markers of oxid. Stress, and its response.ParicalcitolRuboxistaurtinAllopurinol
Metformin in Patients with T2DM and CKD first-line treatment weight neutral, inexpensive, Low ris of hypoglycemia inhibits the generation of glucose in the liver. excreted unchanged by the kidney• The recommendation from NICE in England and Wales, and supportedby the ADA/EASD position paper, is that metformin can be used– down to an eGFR of 30 mL/min/1.73 m2,– the dose of metformin should be reduced when eGFR is less than 45mL/min/1.73 m2.– Kidney function should be checked regularly (every 6 months)– discontinued if eGFR falls below 30 mL/min/1.73 m2.– prescribed with caution in patients with an eGFR less than 45 mL/min/1.73m2, which is rapidly deteriorating.[22,24]– All patients should be warned that if they develop a condition that can lead todehydration.• Contradictory to guidance from NICE, the Study of Treatment andPrevalence of Renal Disease in UK Diabetes Mellitus
Keys of diabetic nephropathyGlomerulus:Increased intraglomerular hypertensionLoss of neg. charged glycosaminoglycans in GBMIncreased GBM pore sizePodocyte changes and damagesPathological abnormalities:Thickening of GBMAccumulation of mesangial matrixIncrease numbers of mesangial cellsTubular part:Thickening of TBMTubular atrophyInterstitial fibrosisArteriosclerosisHypoglycemia as glucose toxicity.Glycation and formation of advanced glycationproductsIncreased flux through the polyol andhexosamine pathwaysOxidative stressFibrotic changes seen in mesangium andinterstitium caused by• Transforming growth factor B-1• Connective tissue growth factorGlomerular hyperfiltration and hypertrophy dueto:• Growth fator• Insulin-like growth factor -1Vascular endothelial growth factor synthesisedby the podocyte maintains the fenestrae inglom. endothelial cells, its cause constrictionof the efferent glomerular arteriole,angiotensin II increases glomerular capillarypermeability to proteins stimulate mesangialcell proliferation and accumulation ofmesangial matrix
Anti-DM drugs in CKDBelieved to be safe GliplzideRepaglidineGlitazonesLinagliptinModifying dose InsulinDDP-4 ISitaVildaSaxaC/I metforminGlebincamideGlimepridenataglinide
Poor food intakeInsufficient exerciseUraemia –induced anorexiaInsulin metabolism disorderInsulin resistanceReduced insulin clearanceInadequate drug therapyFluctuation of blood glucose and monitoring of glycemiaRecommended diabetes targets :A1CThe Renal Association 2011 7.5%Joint British societies 2005 6.5%NICE 2011 6.5 – 7.5 % (individualize)
Indication of pancreas transplantationPancreas alone Pancreas after kidney Both K and P- Low C peptide- Rapid progressive diab.Complications- Low C peptide- successful KT- GFR > 40 ml/min/1.7 m2-Low C peptide- advance nephropahy- GFR < 20 ml/min/1.7 m2
Avoid too many pain medicationsDrink plenty of waterPrevention urinary tract infectionsCorrelated with Prevention Kidney Disease:Healthy body weightExercise (30 min/day: improve diabetic control,BP control, and heart function,body weight).9. Normal blood lipid levelsSlowing & preventing Kidney Disease
Criteria for Testing for Diabetes in AsymptomaticAdult Individuals (1)• Physical inactivity• First-degree relative with diabetes• Women who delivered a babyweighing >9 lb or were diagnosedwith GDM• Hypertension (≥140/90 mmHg or ontherapy for hypertension)• HDL cholesterol level<35 mg/dL (0.90 mmol/L) and/or atriglyceride level >250 mg/dL (2.82mmol/L)• Women with polycystic ovariansyndrome (PCOS)• A1C ≥5.7%, IGT, or IFG on previoustesting• Other clinical conditions associatedwith insulin resistance (e.g., severeobesity, acanthosis nigricans)• History of CVD*At-risk BMI may be lower in some ethnic groups.1. Testing should be considered in all adults who are overweight(BMI ≥25 kg/m2*) and who have one or more additional risk factors:ADA. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S14. Table 4.
Pathogenesis:Abnormalities of glomerular endothelial barrier:Stage of Increased filtrationReduction of renal tubular cell albumin degradationGlomerular hypertensionInflammationOxidative stressAll this cause albuminuria