Diabetic Nephropathy Review

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JaFAR AL-SAID. M.B.ChB. MD. FASn. FACP.CHAIR OF Internal Medicine.Nephrology and internal medicine Consultant.Bahrain Specialist Hospital. Diabetic Nephropathy1Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

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Introduction.Epidemiology.Pathogenesis. Progression. Diagnosis. Management.Scheme4Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Historical Points18th Century Proteinuria was recognized in DM.

1930 Kimmelstiel and Wilson described the typical nodular glomerular lesion in Dm with Proteinuria.

1950 Kidney disease was recognized as DM complication.

Current Leading cause of ESRD in USA and western societies. BatumanVecihi, Khardori Romesh, et. Al. Diabetic Nephropathy: Background, Pathophysiology, Etiology Medscape. Updated: Jul 31, 20155Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

20-40% of DM patient will develop Nephropathy.

In the presence of Minimal Albuminuria > 300mg/dl It will develop in:

80% of DM I.

20-40% of DM II.

IntroductionSuma Dronavalli, Irena Duka, George L. Bakris. The Pathogenesis of Diabetic Nephropathy Posted: 08/01/2008; Nat Clin Pract Endocrinol Metab CME 2008. http://www.medscape.org/viewarticle/5771566Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Definition A syndrome characterized in diabetics by 2 of the following:

Persistent albuminuria > 300mg/day. On at least to occasions 3 -6m apart. Progressive decline in GFR.Elevated BP.

BatumanVecihi, Khardori Romesh, et. Al. Diabetic Nephropathy: Background, Pathophysiology, Etiology Medscape. Updated: Jul 31, 20157Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

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Distribution of NHANES participants with diabetes, self-reported cardiovascular disease, & single-sample markers of CKD, 2007-2012

Data Source: National Health and Nutrition Examination Survey (NHANES), 19881994, 1999-2004 & 20072012 participants aged 20 & older. Cardiovascular disease designation is based on self-report of any CVD. CKD is defined as eGFR 7%, self-reported, or currently taking glucose-lowering medications.

Hypertension defined as BP 130/80 for those with diabetes or CKD, otherwise BP 140/90, or taking medication for hypertension.10Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Distribution of markers of CKD in NHANES participants with diabetes, hypertension, self-reported cardiovascular disease, & obesity, 20072012National Health and Nutrition Examination Survey (NHANES), 20072012 participants aged 20 & older. Single-sample estimates of eGFR & ACR; eGFR calculated using the CKD-EPI equation.11Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Trends in annual number of ESRD incident cases (in thousands), by primary cause of ESRD, in the U.S. population, 1996-2013

ESRD Incidence by cause12Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

ESRD prevalence by cause

Trends in annual number of prevalent ESRD cases (in thousands), by primary cause of ESRD, in the U.S. population, 1996-201313Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Trends in adjusted* prevalence (per million) of ESRD,by primary cause of ESRD, in the U.S. population, 1996-2013

ESRD Prevalence per populationBy cause 14Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Progression

Hemodynamic changesThickening of GBM. Mesangial expiation.Glom. hypertrophy

Irreversible Scarring

Hypertension. Decreased eGFR.Proteinuria.15Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Microalbuminuria

Macroalbuminuria

?Steinke JM et al. (2005) The early natural history of nephropathy in type 1 diabetes: III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes54:2164-2171Progression16Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Albuminuria as continuum valueMicroalbuminuriaKDIGO Reference 2217Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Is a continuum.

Varies according to:Time.Physical Activity.Fever.Blood pressure.Labs variation. Dietary Prot. intake.

AlbuminuriaTuttle K, Bakris G. et. al. Diabetic Kidney Disease: A Report From an ADA Consensus Conference. Diabetes Care 2014;37:28642883 | DOI: 10.2337/dc14-12918Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Factors Contributing to development of Diabetic NephropathyNephropathyZiyadeh FN (2004) Mediators of diabetic renal disease: the case for TGF- as the major mediator. J Am Soc Nephrol 15 (Suppl 1): S55-S5719Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Hemodynamic PathwayProstanoid.NO2.VEGF.RAAS.Endothilin.TGF-B1.

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Hyperglycemia Injury

Mesangial Matrix expansion.Cell apoptosis.Increased Podocyte Permeability

VEGFTGFB1

Over expression GLUT 1,4Friedman EA (1999) Advanced glycation endproducts in diabetic nephropathy. Nephrol Dial Transplant 14 (Suppl 3): S1-S9.Porte D Jr and Schwartz (1996) MW Diabetes complications: why is glucose potentially toxic? Science 272: 699-700.Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820.21Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Glycosylation End Products

Glucose+Amino A.Proteins.

Advanced glycosylation end products

Microvascular ComplicationsMakita Z et al. (1991) Advanced glycosylation end products in patients with diabetic nephropathy.N Engl J Med 325: 836-842Singh AK et al. (1998) Effect of glycated proteins on the matrix of glomerular epithelial cells. J Am Soc Nephrol 9: 802-81022Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Protein Kinase COxidative stressDiacyglycerol

Hyperglycemia

ActivationPKC

TGF B1

Mesangial ExpansionGBM thickening

Yamagishi S et al. (2007) Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets 8: 952-95923Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

TGF-B1

Hyperglycemia

Increase expression of TGF-B1

Cellular Hypertrophy.Collagen Synthesis

Sharma K et al. (1999) Captopril-induced reduction of serum levels of transforming growth factor-1 correlates with long-term renoprotection in insulindependent diabetic patients. Am J Kidney Dis. 34:818-823Sharma K and Ziyadeh FN (1995) Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 44: 1139-114624Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Pathogenesis of Diabetic Nephropathy

BatumanVecihi, Khardori Romesh, et. Al. Diabetic Nephropathy: Background, Pathophysiology, Etiology Medscape. Updated: Jul 31, 2015Metabolic

Hemodynamic

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Diabetic Nephropathy is more common within first degree relatives.

Among Pima Indian developed Overt Proteinuria:14 % neither parents had Proteinuria. 23% one parent had proteinuria.46% both parents had proteinuria. Genetic susceptibilityTrevisan R and Viberti G (1995) Genetic factors in the development of diabetic nephropathy. J Lab Clin Med 126: 342-349.Pettitt DJ et al. (1990) Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 33: 438-443.26Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Susceptibility loci for Microvascular complication on Chromosomes: 3, 7, 9, 20.

Diabetic Nephropathy susceptible gene areas on chromosomes:7q21.310p15.314q23.118q22.3 Genetic susceptibilityImperatore G et al. (1998) Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47: 821-830.

Vardarli I et al. (2002) Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q223-23. Kidney Int 62: 2176-2183.

Iyengar SK et al. (2007) Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 56: 1577-158527Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

PathologyECM expansion.Mesangial expansion.Kimmelstiel-Wilson nodule.Arteriolar Hyalinosis.Glomerular sclerosis. Thickening of GBM.Thickening of TBM. 28Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Which one started first ??High CV risk patient29Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

CVD risk Assessment=Tonelli M, Muntner P, Lloyd A, et al.; Alberta Kidney Disease Network. Risk of coronary events in people with chronic kidney diseasecompared with those with diabetes: a population level cohort study. Lancet 2012;380:807814AtherosclerosisAMI.Cardiac fibrosis.Art. Calcification.30Jafar Al-Said. GCC Diabetes Conference Bahrain March 2016

Absence of retinopathy.Rapid decrease eGFR.Rapidly increasing Proteinuria.Refractory HTN.Active urinary sediments.> 30% reduction of GFR with RAAS. Clinical picture for other systemic disease. Increased possibility of causes other than DM leading to the kidney disease:National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendationsfor Diabetes and