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Section C

Pathophysiology of diabetic nephropathy & risk factors for the development of CKD. Section C. Objectives and background for this learning resource. Introduction:

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Section C

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  1. Pathophysiology of diabetic nephropathy & risk factors for the development of CKD Section C

  2. Objectives and background for this learning resource Introduction: This learning resource has been developed as part of a medical education initiative supported by Janssen. The content of this slide kit has been developed by an advisory board of renal physicians, GPs and specialist nurses. The panel of experts includes members of the British Renal Society Chronic Kidney Disease (CKD) Strategy Group. Bedrock Healthcare, a medical communications agency, has provided editorial support in developing the content; Janssen has reviewed the content for technical accuracy. Educational objectives: • To provide clear and applicable clinical guidance on chronic kidney disease (CKD) in people with type 2 diabetes to primary care healthcare professionals • To advise primary healthcare professionals on what people with type 2 diabetes need to know about their own condition with relation to CKD Usability objectives: • To provide essential, relevant and up to date information in concise presentations • To enable primary healthcare professionals to locate, select and use the content of the learning resource, as appropriate to their needs • To enable secondary care experts in CKD to refer their primary care colleagues to the resource

  3. Contents overview This learning resource comprises the following 10 sections (A-E):

  4. Contents overview (cont.) This learning resource comprises the following 10 sections (F-J):

  5. Section C – 3 key learning objectives • The kidneys play an essential role in glycaemic control • Diabetic kidney disease implies widespread vascular disease • The main drivers of diabetic complications are: • Hyperglycaemia • Hypertension • Obesity

  6. Functions of the kidney Excretion oftoxic substances Acid/basebalance Filtration andreabsorption Hormone production: • Calcitrol (healthy bones) • Renin (BP regulation) • Erythropoieitin(red blood cell production) ElectrolyteBalance Glucose reabsorptionand gluconeogenesis

  7. The kidneys’ contribution to glucose homeostasis • Kidneys contribute to glucose homeostasis in many ways including: producing, filtering, reabsorbing and excreting glucose • The kidneys produce approximately 20-25%1,2 of the total endogenousglucose production • In a healthy individual* virtually all of the filtered glucose is actively reabsorbed into the blood by the sodium glucose co-transporters 2 and 1 (SGLT2 and SGLT1); virtually none is excreted in the urine2,3 *Normal physiological blood glucose range <6.5mmol/L before meals and <7.8mmol/L after meals References: 1. Gerich JE. Physiology of glucose homeostasis. Diabetes ObesMetab. 2000;2:345-50. 2. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010 Feb;27(2):136-42. 3. Mitrakou A. Kidney: its impact on glucose homeostasis and hormonal regulation. Diabetes Res ClinPract. 2011 Aug;93 Suppl 1:S66-72

  8. The role of the kidney in glucose reabsorption • There are two main sodium-glucose cotransporters: SGLT2 and SGLT11 • SGLT2 is mainly found in the proximal tubules of the kidneys1 • SGLT2 is responsible for reabsorbing approximately 90%of the glucose reabsorbed bythe kidney2 • The remaining glucose is reabsorbed by SGLT1 furtheralong the proximal tubule1 • The reabsorbed glucose is then returned to the blood2 Adapted from Nair S, Wilding JP. J ClinEndocrinolMetab. 2010;95:34-42. Reference: 1. Nair S, Wilding JP. J ClinEndocrinolMetab. 2010;95:34-42. 2. DeFronzo RA, et al. Diabetes ObesMetab. 2012;14:5-14.

  9. The role of the kidney in glucose reabsorption A kidney in a patientwith type 2 diabetes • A normal kidney ~180L filtered per day by the kidney1 Average blood glucose of ~100mg/dL2 Average blood glucose of ~150mg/dL2 ~180g of glucose filtered per day2 ~250g of glucose filtered per day2 Increase in SGLT2 cotransporters2 No increase in SGLT2 cotransporters2 glucose reabsorption and elimination of glucose in the urine2 Hyperglycaemia References: 1. DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes ObesMetab. 2012 Jan;14(1):5-14. 2. Clifford J. Bailey. Medscape Education Diabetes & Endocrinology. The Role of the Kidney in Glucose Control.. CME Released: 02/26/2013 ; Valid for credit through 02/26/2014.

  10. The role of the kidney in gluconeogenesis • The kidney is involved in the production of glucose (gluconeogenesis)1,2 • 20-25% of total glucose release is attributed to gluconeogenesis in the kidney2,3 • The glucose-6-phosphatase enzyme is necessary for the release of glucose and is present in the following tissues2 • Liver • Cortex of the kidney • Intestinal epithelium References: 1.Gerich JE. Physiology of glucose homeostasis. Diabetes ObesMetab. 2000;2:345-50. 2 Andrianesis V and Doupis J. The Role of Kidney in Glucose Homeostasis - SGLT2 Inhibitors, a New Approach in Diabetes Treatment. Expert Rev ClinPharmacol. 2013;6(5):519-539. 3.Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010 Feb;27(2):136-42.

  11. The role of the kidney in insulin elimination • The kidney plays a central role in the metabolism of insulin1 • Increased insulin levels suppress gluconeogenesis in the kidney and enhance glucose reuptake by the kidney2 • Six to eight units of insulin are degraded by a healthy kidney each day1 • This is approximately 25% of the daily production of insulin by the pancreas References: 1. Palmer BF and Henrich WL Carbohydrate and insulin metabolism in chronic kidney disease.. Available at: http://www.uptodate.com/contents/carbohydrate-and-insulin-metabolism-in-chronic-kidney-disease. 2. Andrianesis V and Doupis J. The Role of Kidney in Glucose Homeostasis - SGLT2 Inhibitors, a New Approach in Diabetes Treatment. Expert Rev ClinPharmacol. 2013;6(5):519-539.

  12. Diabetic kidney disease implies widespread vascular disease • The epidemiology of albuminuria (abnormal levels of albumin in the urine) reveals a close association with vascular disease1 • Meta-analyses in general population and high risk cohorts demonstrated that albuminuria is associated with cardiovascular mortality independently of traditional cardiovascular risk factors2,3 • The presence of both generalised vascular dysfunction and albuminuria suggests a common cause of proteinuria4 Hazard ratios (HR) and 95% confidence intervals for cardiovascular mortality according to ACR2 0.5 4 2 1 HR for CVD mortality (ACR studies) 300 1000 30 2.5 5 10 ACR, mg/g Adapted from Matsushita K, van der Velde M, Astor BC, et al. Lancet 2010;375:2073–2081. Reference: 1. Satchell SC and Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51:714-725. 2. Matsushita K, van der Velde M, Astor BC, et al. Lancet 2010;375(9731):2073–20813. Gansevoort RT, Matsushita K, van der Velde M, et al. Kidney Int. 2011;80(1):93–104. 4. Deckert T, et al. Diabetologia. 1989;32(4):219-26.

  13. Pathways within diabetes that lead to the development of vascular disease Glomerular endothelial dysfunction (in particular, damage to the glycocalyx) is the likely step in initiating albuminuria1This diagram shows the relationship between hyperglycaemia, insulin resistance, endothelial dysfunction, macrovascular disease and albuminuria in diabetes.1,2 Type 1 diabetes Type 2 diabetes Insulin resistancesyndrome Glucose Effector pathways Notes on this diagram1: Proposed major pathways are represented by pink arrows. Pathways of less certain significance are represented by grey arrows. In type 2 diabetes, other pathways not directly involving endothelial dysfunction, are likely in the pathogenesis of macrovascular disease and may also contribute to albuminuria (broken arrows). Endothelial (includingglycocalyx) dysfunction Cardiovasculardisease albuminuria Reference: 1.Satchell SC and Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008;51:714-725. 2.Deckert T, et al. Diabetologia. 1989;32(4):219-26.

  14. Hyperglycaemia drives diabetic kidney disease • Activation of protein kinase C1 • Acceleration of the renin-angiotensin-aldosterone system (RAAS)1 • Non-enzymatic glycationthat generates advanced glycation end products1 • Circulating levels are raised in people with diabetes, particularly those with renal insufficiency, since they are normally excreted in the urine1 • Oxidative stress seems to be a theme common to all three pathways3 Three mechanisms have been postulated that explain how hyperglycaemia causes tissue damage in the kidney:1-3 Hyperglycaemia Protein kinase C andgrowth factors Advanced glycationend products (AGEs) Accelerationof RAAS Tubulointerstitialinjury Hypertension Overproduction of mesangial cell matrix Glomerulardamage Nephron loss Proteinuria Reference: 1.Cade WT. Diabetes-Related Microvascular and macrovascular diseases in the physical therapy setting. PhysTher. 2008;88(11):1322–1335. 2.Wolf G et al. (2005) From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54: 1626-1634. 3.Dronavalli S, Duka I and Bakris GL. Nat ClinPractEndocrinolMetab. 2008;4(8):444-52.

  15. Hypertension drives diabetic kidney disease • Uncontrolled hypertension is a risk factor for developing kidney disease and is associated with a more rapid progression of chronic kidney disease1 • Conversely, progressive kidney disease resulting in glomerulosclerosis can exacerbate hypertension. This is due to increased blood flow to the remaining functioning nephrons and increased systemic vascular resistance2 Glomerulosclerosis Decline in RENAL FUNCTION Reduction innumber of functioning glomeruli Intraglomerular hypertension Increased blood flow to remaining nephrons References: 1.Botdorf J, Chaudhary K, Whaley-Connell A. Hypertension in cardiovascular and kidney disease.Cardiorenal Med. 2011;1:183–192. 2.El-Atat FA, et al. The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease. J Am SocNephrol 2004;15: 2816–2827.

  16. Obesity drives diabetes and other complications • Pulmonary disease • Abnormal function1 • Obstructive sleep apnoea5 Stroke5 • Eye diseases • Age-related cataract2 • Glaucoma2 • Age-related maculopathy 2 • Diabetic retinopathy2 • Fatty liver disease3 • Steatosis3 • Steatohepatitis3 • Cirrhosis3 • Coronary heart disease5 • Diabetes5 • Dyslipidaemia5 • Hypertension5 Gall bladder disease4 Pancreatitis4 • Gynaecologicabnormalities1 • Infertility1 • Polycystic ovary syndrome2 • Cancer1 • Breast1 • Colon1 • Endometrial1 • Renal2 Osteoarthritis1 Skin conditions6 References: 1.National Center for Chronic Disease Prevention and Health Promotion. OBESITY Halting the epidemic by making health easier.2011. Available at: http://www.cdc.gov/chronicdisease/resources/publications/aag/pdf/2011/obesity_aag_web_508.pdf. Accessed 23/01/2015. 2.Cheung N and Wong TY. Obesity and Eye Diseases. SurvOphthalmol. 2007 ; 52(2): 180–195. 3. Ix JH and Sharma K. Mechanisms Linking Obesity, Chronic Kidney Disease,and Fatty Liver Disease: The Roles of Fetuin-A, Adiponectin, and AMPK. J Am SocNephrol 2010. 21:406 –412. 4.Torgerson JS et al.Gallstones, gallbladder disease, and pancreatitis: cross-sectional and 2-year data from the Swedish Obese Subjects (SOS) and SOS reference studies. Am J Gastroenterol. 2003;98:1032-41. 5.Malnick S.D.H. and Knobler H. The medical complications of obesity. Q J Med 2006;99:565-579. 6.Hidalgo GL. Dermatological complications of obesity. Am J Clin Dermatol. 2002;3(7):497-506.

  17. Obesity drives diabetic kidney disease Insulin resistance/diabetes/increased visceral adiposity Hypertension Obesity Glomerular hyper-filtrationand hyper-perfusion Glomerular hypertrophy Proteinuria Glomerulosclerosis/end stagekidney disease Altered adipokines Chronic kidney disease Reduced adiponectin Increased leptin Increased sympathetic nervous system Increased adipose renin-angiotensin-aldosterone system Increased visfatin and endothelial dysfunction Increased resistin Adapted from Garland JS. Elevated body mass index as a risk factor for chronic kidney disease: current perspectivesDiabetes Metab Syndr Obes. 2014;7:347-55.

  18. Section C – summary • The kidney has an important role in glycaemic control through: • Glucose reabsorption from filtrate • Gluconeogenesis • Elimination of insulin • Diabetic kidney disease implies widespread vascular disease • Endothelial dysfunction is part of the pathogenesis of vascular disease in type 2 diabetes • Hyperglycaemia leads to acceleration of the renin-angiotensin-aldosterone system, which leads to hypertension and glomerular damage • Diabetic kidney disease is driven by: • Hyperglycaemia • Hypertension • Obesity

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