The Kidney in Diabetes Understanding the Perspectives!

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Information about The Kidney in Diabetes Understanding the Perspectives!
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Published on July 14, 2016

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The Kidney in Diabetes: Understanding the Perspectives!: The Kidney in Diabetes: Understanding the Perspectives! Case of Ms. Diabetes: Case of Ms. Diabetes History 60 yrs. old married female K/c/o Type-2 diabetes mellitus since 7 years Diagnosed with non-proliferative retinopathy since 2 years K/c/o dyslipidemia since 5 years; well-controlled No h/o hypertension / smoke exposure / other relevant history Receiving metformin 1 g/d (500 mg BD) Case Discussion Case of Ms. Diabetes: Case of Ms. Diabetes On Examination BMI: 28 kg/1.73m 2 (Overweight) HbA1c: 8% (Uncontrolled) Renal function: Case Discussion Parameter Before 1 year Current Urine albumin (Dipstick) Negative Positive (microalbuminuria) Serum Creatinine (mg/ dL ) 0.69 0.72 eGFR (MDRD) (ml/min/1.73m 2 ) 92 88 What’s in a Name? Modern Understanding of DKD: What’s in a Name? Modern Understanding of DKD Diabetic Nephropathy Diabetic Kidney Disease (DKD) Diabetic Glomerulopathy Chronic Kidney Disease (CKD) in Diabetes PROTEINURIA Kidney Disease DUE TO DIABETES Kidney Disease DUE TO DIABETES / COMORBIDITIES HISTO-PATHOLOGY Findings Microalbuminuria in T2DM: 26.9%1 / 36.3%2 Do Visible Numbers Reflect Pathogenesis?: Microalbuminuria in T2DM: 26.9% 1 / 36.3% 2 Do Visible Numbers Reflect Pathogenesis? Nelson RG et al. N Engl J Med. 1996 Nov 28;335(22):1636-42. Diabetic Kidney Disease Deep Seated Pathogenesis…!!!: Diabetic Kidney Disease Deep Seated Pathogenesis…!!! Nelson RG et al. N Engl J Med. 1996 Nov 28;335(22):1636-42. Normal Glomerular Anatomy and Physiology: Normal Glomerular Anatomy and Physiology Keys Blood flow Filtrate flow Afferent Arteriole Vasoconstriction Decreases GFR Efferent Arteriole Vasoconstriction Increases GFR Auto-regulation of Blood Flow Modulation of Afferent / Efferent Arteriolar Tone : Auto-regulation of Blood Flow Modulation of Afferent / Efferent Arteriolar Tone RAAS, renin-angiotensin-aldosterone system; NO, nitric oxide Prostaglandins NO Adenosine RAAS Afferent Arteriole Efferent Arteriole Flow of filtrate Increased filtration Renal Auto-regulation Keeps Glomerular-pressure and Filtration-rate Stable: Renal A uto-regulation Keeps Glomerular-pressure and Filtration-rate Stable Stable GFR maintained by net 10 mmHg outward pressure Burke et al . Current Vascular Pharmacology 2014;12:845 Glomerular blood hydrostatic pressure (GBHP) = 55 mmHg Blood colloid osmotic pressure (BCOP) = 30 mmHg Net filtration pressure (NFP) = GBHP – BCOP – CHP = 55 – 15 – 30 = 10 mmHg Capsular hydrostatic pressure (CHP) = 15 mmHg Glomerular Hypertension Hydrostatic Stress → Glomerular Barotrauma: Glomerular Hypertension Hydrostatic Stress → Glomerular Barotrauma Burke et al . Current Vascular Pharmacology 2014;12:845 Glomerular blood hydrostatic pressure (GBHP) = 65 mmHg Blood colloid osmotic pressure (BCOP) = 30 mmHg Net filtration pressure (NFP) = GBHP – BCOP – CHP = 65 – 15 – 30 = 20 mmHg Capsular hydrostatic pressure (CHP) = 15 mmHg Doubling of Net Filtration Pressure Hyperfiltration Nephron Stress and Loss: 1. Brenner B et al . Kidney Int 1996;49:1774; 2. Kanzaki et al. Hypertension Res 2015;38:633 The single nephron hypothesis – Adaptive response due to loss in total amount of single nephrons Hyperfiltration Nephron Stress and Loss Glomerular hypertension in single nephrons, causes: Inflammation Fibrosis Sclerosis Hyperfiltration Nephron Stress and Loss: Eventually single nephrons are lost Remaining nephrons adapt, increasing filtration by glomerular hypertension Vicious cycle of progressive CKD 1. Brenner B et al . Kidney Int 1996;49:1774; 2. Kanzaki et al. Hypertension Res 2015;38:633 The single nephron hypothesis – Adaptive response due to loss in total amount of single nephrons Hyperfiltration Nephron Stress and Loss Brenner’s Concept of Hyperfiltration from 1996: Brenner’s Concept of H yperfiltration from 1996 Brenner et al . Kidney Int 1996;49:1774 Kidney Damage Fewer nephrons, reduced function Glomerular hypertension Remaining nephrons work harder Further glomerular damage Likelihood of DKD: Likelihood of DKD GFR (mL/min) Normo -albuminuria Micro-albuminuria Macro-albuminuria >60 At Risk (GFR <90) Possible DKD DKD 30-60 Unlikely DKD * Possible DKD DKD <30 Unlikely DKD * Unlikely DKD DKD KDOQI Guidelines. http://www2.kidney.org/professionals/kdoqi/guideline_diabetes/guide1.htm. Accessed 14 Jan, 2015. * Possible, but may need further investigations Who is At-risk of DKD?: Who is At-risk of DKD? KDOQI Guidelines. http://www2.kidney.org/professionals/kdoqi/guideline_diabetes/guide1.htm. Accessed 14 Jan, 2015. Diabetic Kidney Disease: Diabetic Kidney Disease Natural History of Diabetic Nephropathy Stage Feature GFR Albumin Chronology I Glomerular Hyperfiltration Hyper-filtration Maybe increased At diagnosis of diabetes II Silent Stage (Pathological damage) Normal <30 mg/day First 5 years III Incipient Stage (Microalbuminuria) GFR begins to decline 30 - 300 mg/day 5 - 15 years IV Overt Nephropathy (Macroalbuminuria) Rapid GFR decline >300 mg/day 15 - 25 years V Uremia and Renal failure End Stage Renal Disease Decreasing 25 - 30 years Case Discussion Adapted from: Batuman V . Diabetic Nephropathy. Medscape Drugs & Diseases. 2015 Jul. http:// emedicine.medscape.com/article/238946-overview . Accessed Dec 21, 2015. Diabetic Kidney Disease: Incipient stage of Diabetic Kidney Disease: GFR begins to decline (patient in CKD stage 2) Presence of microalbuminuria evident Management Considerations Diabetic Kidney Disease Case Discussion Adapted from: Batuman V . Diabetic Nephropathy. Medscape Drugs & Diseases. 2015 Jul. http:// emedicine.medscape.com/article/238946-overview . Accessed Dec 21, 2015. CKD in Type 2 Diabetes: Problem Statement for Asia Joint Asia Diabetes Evaluation (JADE) Registry: Adapted from: Luk AO et al. Diabet Med. 2015 Oct 29 . doi : 10.1111/dme.13014. CKD in Type 2 Diabetes: Problem Statement for Asia Joint Asia Diabetes Evaluation (JADE) Registry Case Discussion CKD in Type 2 Diabetes: Problem Statement for Asia Joint Asia Diabetes Evaluation (JADE) Registry: CKD in Type 2 Diabetes: Problem Statement for Asia Joint Asia Diabetes Evaluation (JADE) Registry 28, 110 Asian patients (including 3, 714 Indian patients) with Type 2 Diabetes, enrolled between Jul ‘07 - Dec ’12 Indian patients: Observations, as compared to the Patients from Other Asian Countries : Prevalence of ‘eGFR <60ml/min/1.73m 2 ’ was highest and ‘Albuminuria’ was second highest amongst Asians Lowest proportion of patients, who reached 3 metabolic targets ( HbA1c <7%, BP <130/80 mmHg, and LDL-C < 2.6mmol/L) Lowest proportion of patients who achieved HbA1c goal of <7 %, were from India and Vietnam Adapted from: Luk AO et al. Diabet Med. 2015 Oct 29 . doi : 10.1111/dme.13014. Case Discussion Kidney failure or Heart failure Vicious cycle: Cardiorenal connection: Haemodynamic control: Kidney failure or Heart failure Vicious cycle Bongartz L et al. Eur Heart J 2005;26:11 Nitric oxide/reactive oxygen species imbalance Sympathetic nervous system activation Renin angiotensin system activation Inflammation Kidney failure Heart failure Cardiovascular damage Multifactorial Intervention Strategy for DKD : Multifactorial Intervention Strategy for DKD ACE, angiotensin-converting-enzyme ; ARB , angiotensin receptor blocker; BP, blood pressure; HbA1c, glycated haemoglobin; LDL-C, low-density lipoprotein-cholesterol 1. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850; 2. NICE. Clinical guideline: Type 2 diabetes (CG87), May 2009 Glucose BP Lipids ACE/ ARB HbA1c target (adjustable) ~7% 1 Target of <130/80 mmHg if there is kidney, eye or cerebrovascular damage 2 Use ACE inhibitors or ARBs when albumin excretion ≥30 mg/g 1 Lipid-lowering recommended to reduce risk of atherosclerotic events; statins n ot recommended in patients on haemodialysis 1 Diabetic Nephropathy ‘Nip In The Bud’ Approach?: Diabetic Nephropathy ‘Nip In The Bud’ Approach? Hyperglycemia is a major determinant of progression of diabetic nephropathy 1 Glycemic control can reverse the lesions of diabetic kidney disease 1-3 Control glomerular hypertrophy and hyperfiltration Delay the development of microalbuminuria Stabilize or even reverse microalbuminuria Slow progression of renal injury even in overt nephropathy Case Discussion Batuman V. Diabetic Nephropathy. Medscape Drugs & Diseases. 2015 Jul. http://emedicine.medscape.com/article/238946-overview . Accessed Dec 21, 2015. Fioretto P et al . Diabetologia . 2008 Aug;51(8):1347-55. Fioretto P et al . Diabetes Res Clin Pract . 2014 Jun;104(3): 323-8 Considerations for DPP4-inhibitor Use in Diabetic Kidney Disease: Considerations for DPP4-inhibitor Use in Diabetic Kidney Disease Case Discussion DPP-4 inhibitors Evidence and Dose-adjustment in Renal Impairment (RI): DPP-4 inhibitors Evidence and Dose-adjustment in Renal Impairment (RI) Linagliptin Sitagliptin Saxagliptin Vildagliptin Teneligliptin Mild RI 5 mg OD 100 mg OD 5mg OD 50 mg BD 20 mg OD Moderate RI 50 mg OD 2.5 mg OD 50 mg OD Server RI/ ESRD 25 mg OD Clinical Concerns Efficacy established in all stages of RI including Hemodialysis Adjusting dose according to renal function is a clinical challenge No dose adjustment based on pharmacokinetic study. But no safety / efficacy studies across CKD stages. QT-interval prolongation and Liver enzyme elevations observed in patients with renal impairment 3 1)US Prescribing information of all gliptins except EU wherein EU PI was used as source., 2 ) Graefe Mody DOM 2011 (3) . Teneligliptin PMDA review 2012 Slide25: Medication Errors! Renally Excreted Drugs (sitagliptin / metformin) Dosed Inappropriately in Renal Insufficiency Juliana Meyers et al. Postgraduate Medicine, Vol 123, issue 2, 2011 Source: U.S. Database (2000 - 2009) 3,44,770 T2DM patients 1,21,395 Renal insufficiency patients 84.89 % 15.11 % 99.89 % 0.11 % Linagliptin with Insulin Patients with Type 2 Diabetes and Renal Impairment: Linagliptin with Insulin Patients with Type 2 Diabetes and Renal Impairment Patients with Mild Renal Impairment ( eGFR : 60 to <90 mL/min/1.73 m 2 ; CKD stage 2) Case Discussion Efficacy Profile Safety Profile Adverse Event Placebo Linagliptin Acute Renal Failure (%) 1.5 0.3 Hypo- glycemia (%) 37.5 34.9 Severe Hypo- glycemia (%) 1.4 2.1 Low frequency of new / worsening hypertension, despite 40 - 52% of patients in linagliptin groups also receiving ACE inhibitors Adapted from: McGill JB et al . Diab Vasc Dis Res. 2015 Jul;12(4):249-57. Slide27: Cardio-Renal Continuum Clinical Measures to Prevent, Regress, Retard CKD! Adapted García-Donaire JA et al . Int J Nephrol . 2011;2011:975782 . Adapted Dzau V et al . Am Heart J. 1991 Apr;121(4 Pt 1):1244-63. Slide28: “…linagliptin, which is primarily eliminated by the liver and requires no dose adjustment in CKD, appears to be an attractive agent for use in patients with DN. A meta-analysis of 13 randomised controlled trials involving over 5,500 patients demonstrated that use of linagliptin caused a 16% reduction in a composite renal end point consisting of micro- or macro-albuminuria, loss of eGFR >50 % from baseline, acute renal failure or death” Ward F et al. Clin Med ( Lond ). 2015 Dec;15(6):550-7. Linagliptin in Type 2 Diabetes Proof of Concept for Renal Outcomes: Linagliptin in Type 2 Diabetes Proof of Concept for Renal Outcomes Pooled analysis of individual patient-level data from 13 phase 2/3 randomized, double-blind, placebo-controlled trials of linagliptin 5,466 individuals with inadequately controlled type 2 diabetes 3,505 received linagliptin (5 mg/d); 1,961 received placebo Case Discussion 16% Reduction Cooper ME et al . Am J Kidney Dis. 2015 Sep;66(3):441-9. Slide30: Linagliptin in Type 2 Diabetes Proof of Concept for Renal Outcomes Case Discussion Adapted from: Cooper ME et al . Am J Kidney Dis. 2015 Sep;66(3):441-9. Slide31: Adapted from: Cooper ME et al . Am J Kidney Dis. 2015 Sep;66(3):441-9. Linagliptin in Type 2 Diabetes Proof of Concept for Renal Outcomes Case Discussion Slide32: Placebo Linagliptin Drug-related adverse events (% of patients) 13.4 12.9 Hypotensive episodes (% of patients) 0.4 0.3 ↑ Serum K + (% of patients) 1.2 0.8 Adapted from: Cooper ME et al . Am J Kidney Dis. 2015 Sep;66(3):441-9. Linagliptin in Type 2 Diabetes Safety Outcomes Case Discussion Safety and Tolerability Observations With / Without Renin-Angiotensin System (RAS) Inhibitors Nearly 45% of patients were receiving RAS-inhibitor at baseline Similar observations with linagliptin use, with / without RAS-inhibitor Proof of Principle of Linagliptin in Animal-Model of Type 2 Diabetes: Proof of Principle of Linagliptin in Animal-Model of Type 2 Diabetes Case Discussion DPP-4 Integrin β1 Endothelial-mesenchymal transition Renal fibrosis Linagliptin Adapted from: Zeisberg M et al . Kidney Int. 2015 Sep;88(3):429-31. Proof of Concept in Type 2 Diabetes with Renal Impairment: Linagliptin with Renin-Angiotensin-Aldosterone-System Inhibitor: Pooled analysis of 4 studies (24 weeks) Patients of Type 2 Diabetes with prevalent albuminuria (UACR 30 - 3000 mg/g), receiving stable doses of RAAS inhibitors N = 217 Linagliptin 5 mg/day (n = 162) Placebo (n = 55 ) Efficacy at Week 24: (% HbA1c ↓ ) - 0.61% (95% CI - 0.88 to -0.34 % ) Proof of Concept in Type 2 Diabetes with Renal Impairment: Linagliptin with Renin-Angiotensin-Aldosterone-System Inhibitor Case Discussion Adapted from: Groop PH et al. Diabetes Care. 2013 Nov;36(11):3460-8. Proof of Concept in Type 2 Diabetes with Renal Impairment: Linagliptin with Renin-Angiotensin-Aldosterone-System Inhibitor: Linagliptin Associated with Significant Reduction in Albuminuria, Over Stable RAS-inhibitor Therapy, Independent of Changes in Glycemia or Systolic BP Case Discussion Adapted from: Groop PH et al. Diabetes Care. 2013 Nov;36(11):3460-8. Proof of Concept in Type 2 Diabetes with Renal Impairment: Linagliptin with Renin-Angiotensin-Aldosterone-System Inhibitor Hypoglycemia in Diabetic Kidney Disease: A Common, Important Adverse Effect: Hypoglycemia in Diabetic Kidney Disease: A Common, Important Adverse Effect Causes of Hypoglycemia in Diabetic Kidney Disease Prolonged action of hypoglycemic agents (particularly sulfonylureas and insulin) Alcohol intake Chronic malnutrition Acute caloric deprivation Deficiency of gluconeogenic precursors Case Discussion Adapted from: Tuttle KR et al . Diabetes Care. 2014 Oct;37(10):2864-83. Linagliptin with Insulin: Lower Risk of Hypoglycemia Elderly Patients with Type 2 Diabetes: Elderly (≥70 years of age) patients; n = 247 Approximately 80% of patients had Renal Impairment (>50% of patients had Mild Renal Impairment) Baseline: HbA1c 8.2±0.8 %; Basal insulin dose 36±25 IU/day 55% Lower Hazard of Hypoglycaemia (confirmed) in Elderly Patients with Renal Impairment, Who Received Linagliptin with Basal Insulin Linagliptin with Insulin: Lower Risk of Hypoglycemia Elderly Patients with Type 2 Diabetes Case Discussion Inzucchi SE et al. Diabetes Obes Metab. 2015 Sep;17(9):868-77. Confirmed Hypoglycemia: Confirmed Hypoglycemia Linagliptin with Insulin: Lower Risk of Hypoglycemia Elderly Patients with Type 2 Diabetes Case Discussion Hazard Ratio Inzucchi SE et al. Diabetes Obes Metab. 2015 Sep;17(9):868-77. Slide39: Linagliptin with Insulin: Possible Mechanism for Lower Risk of Hypoglycemia Case Discussion Inzucchi SE et al. Diabetes Obes Metab. 2015 Sep;17(9):868-77. Back to the Case of Ms. Diabetes: Reinforce lifestyle management (dietary control; exercise) Add linagliptin 5 mg OD (either as free combination with metformin, or as fixed-drug combination) Manage to target HbA1c of <7% with frequent follow-up Consider appropriate management strategy with statin and ACE-inhibitor / ARB 1 Regularly monitor renal function for eGFR and albuminuria Back to the Case of Ms. Diabetes Case Discussion 1 . Adapted from: Molitch ME et al. Kidney Int. 2015 Jan;87(1):20-30. Thank you: Thank you

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